BeneFIX

1 

 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 

 
SUMMARY OF PRODUCT CHARACTERISTICS 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



 

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1. NAME OF THE MEDICINAL PRODUCT 

 
BeneFIX 250 IU powder and solvent for solution for injection 
BeneFIX 500 IU powder and solvent for solution for injection 
BeneFIX 1000 IU powder and solvent for solution for injection 
BeneFIX 1500 IU powder and solvent for solution for injection 
BeneFIX 2000 IU powder and solvent for solution for injection 
BeneFIX 3000 IU powder and solvent for solution for injection 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 
BeneFIX 250 IU powder and solvent for solution for injection 
Each vial contains nominally 250 IU nonacog alfa (recombinant coagulation factor IX). After 
reconstitution with the accompanying 5 mL (0.234%) sodium chloride solution for injection, each mL 
of the solution contains approximately 50 IU nonacog alfa. 
 
BeneFIX 500 IU powder and solvent for solution for injection 
Each vial contains nominally 500 IU nonacog alfa (recombinant coagulation factor IX). After 
reconstitution with the accompanying 5 mL (0.234%) sodium chloride solution for injection, each mL 
of the solution contains approximately 100 IU nonacog alfa. 
 
BeneFIX 1000 IU powder and solvent for solution for injection 
Each vial contains nominally 1000 IU nonacog alfa (recombinant coagulation factor IX). After 
reconstitution with the accompanying 5 mL (0.234%) sodium chloride solution for injection, each mL 
of the solution contains approximately 200 IU nonacog alfa. 
 
BeneFIX 1500 IU powder and solvent for solution for injection 
Each vial contains nominally 1500 IU nonacog alfa (recombinant coagulation factor IX). After 
reconstitution with the accompanying 5 mL (0.234%) sodium chloride solution for injection, each mL 
of the solution contains approximately 300 IU nonacog alfa. 
 
BeneFIX 2000 IU powder and solvent for solution for injection 
Each vial contains nominally 2000 IU nonacog alfa (recombinant coagulation factor IX). After 
reconstitution with the accompanying 5 mL (0.234%) sodium chloride solution for injection, each mL 
of the solution contains approximately 400 IU nonacog alfa. 
 
BeneFIX 3000 IU powder and solvent for solution for injection 
Each vial contains nominally 3000 IU nonacog alfa (recombinant coagulation factor IX). After 
reconstitution with the accompanying 5 mL (0.234%) sodium chloride solution for injection, each mL 
of the solution contains approximately 600 IU nonacog alfa. 
 
The potency (IU) is determined using the European Pharmacopoeia one-stage clotting assay. The 
specific activity of BeneFIX is not less than 200 IU/mg protein. 
 
BeneFIX contains recombinant coagulation factor IX, (INN = nonacog alfa). Nonacog alfa is a 
purified protein that has 415 amino acids in a single chain. It has a primary amino acid sequence that is 
comparable to the Ala148 allelic form of plasma-derived factor IX, and some post-translational 
modifications of the recombinant molecule are different from those of the plasma-derived molecule. 
Recombinant coagulation factor IX is a glycoprotein that is secreted by genetically engineered 
mammalian cells derived from a Chinese hamster ovary (CHO) cell line.  
 
For the full list of excipients, see section 6.1. 
 
 



 

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3. PHARMACEUTICAL FORM 

 
BeneFIX 250 IU, 500 IU, 1000 IU, 1500 IU, 2000 IU, 3000 IU powder and solvent for solution for 
injection 
Powder and solvent for solution for injection 
White/almost white powder and clear and colourless solvent. 
 
 
4. CLINICAL PARTICULARS 

 
4.1 Therapeutic indications 

 
Treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IX 
deficiency). 
 
BeneFIX can be used for all age groups. 
 
4.2 Posology and method of administration 

 
Treatment should be under the supervision of a physician experienced in the treatment of haemophilia. 
 
Treatment monitoring 
During the course of treatment, appropriate determination of factor IX 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 IX, 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 IX activity) is indispensable. 
 
When using an in vitro thromboplastin time (aPTT)-based one stage clotting assay for determining 
factor IX activity in patients’ blood samples, plasma factor IX activity results can be significantly 
affected by both the type of aPTT reagent and the reference standard used in the assay. This is of 
importance particularly when changing the laboratory and/or reagents used in the assay. 
 
Posology 
Dose and duration of the substitution therapy depend on the severity of the factor IX deficiency, on the 
location and extent of bleeding, and on the patient's clinical condition. 
 
The number of units of factor IX administered is expressed in International Units (IU), which is related 
to the current WHO standard for factor IX products. Factor IX activity in plasma is expressed either as 
a percentage (relative to normal human plasma) or in International Units (relative to an international 
standard for factor IX in plasma). 
 
One International Unit (IU) of factor IX activity is equivalent to that quantity of factor IX in one mL 
of normal human plasma. 
 
On demand treatment 

The calculation of the required dose of BeneFIX can be based on the finding that one unit of factor IX 
activity per kg body weight is expected to increase the circulating level of factor IX, an average of 
0.8 IU/dL (range from 0.4 to 1.4 IU/dL) in patients  12 years (further information in section 5.2). 
 
The required dose is determined using the following formula: 
 
Number of 
factor IX IU 
required 

= body weight (in kg) X desired factor IX 
increase (%) or (IU/dL) 

X reciprocal of 
observed recovery 

 



 

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Example: For a recovery of 0.8 IU/dL, the formula reads: 
 
Number of 
factor IX IU 
required 

= body weight (in kg) X desired factor IX 
increase (%) or (IU/dL) 

X 1.3 IU/kg 

 
The amount to be administered and the frequency of administration should always be oriented to the 
clinical effectiveness in the individual case. 
 
In the case of the following haemorrhagic events, the factor IX activity should not fall below the given 
plasma activity 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 IX 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 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 24 hours for 3-4 days or 
more until pain and acute disability are 
resolved. 
 

Life-threatening 
haemorrhages 

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

Surgery 
 
Minor: 
Including tooth extraction 
 
Major 

 
 

30-60 
 
 

80-100 
(pre- and 

postoperative) 

 
 
Every 24 hours, at least  
1 day, until healing is achieved. 
 
Repeat infusion every 8-24 hours until 
adequate wound healing, then therapy for at 
least another 7 days to maintain a factor IX 
activity of 30% to 60% (IU/dL) 
 

 
Prophylaxis 

BeneFIX may be administered for long term prophylaxis against bleeding in patients with severe 
haemophilia B. In a clinical study for routine secondary prophylaxis the average dose for previously 
treated patients (PTP) was 40 IU/kg (range 13 to 78 IU/kg) at intervals of 3 to 4 days. 
 
In some cases, especially in younger patients, shorter dosage intervals or higher doses may be 
necessary. 
 
Paediatric population 
There is limited documentation of on-demand treatment and surgery in paediatric patients less than 
6 years of age treated with BeneFIX. 
 
Mean dosage ( standard deviation) for prophylaxis was 63.7 ( 19.1) IU/kg at intervals of 3 to 
7 days. In younger patients, shorter dosage intervals or higher doses may be necessary. FIX 
consumption for routine prophylaxis in 22 evaluable patients was 4607 ( 1849) IU/kg per year and 
378 ( 152) IU/kg per month. 



 

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Close monitoring of factor IX plasma activity should be performed as clinically indicated, as well as 
calculation of pharmacokinetic parameters such as recovery and half-life, in order to adjust doses as 
appropriate. 
 
Elderly population 
Clinical studies of BeneFIX did not include sufficient numbers of subjects aged 65 and over to 
determine whether they respond differently from younger subjects. As with any patient receiving 
BeneFIX, dose selection for an elderly patient should be individualised. 
 
Method of administration 
BeneFIX is administered by intravenous infusion after reconstitution of the lyophilised powder for 
solution for injection with sterile 0.234% sodium chloride solution (see section 6.6). 
 
BeneFIX should be administered at a slow infusion rate. In most of the cases, an infusion rate of up to 
4 mL per minute has been used. The rate of administration should be determined by the patient’s 
comfort level. 
 
If any suspected hypersensitivity reaction takes place that is thought to be related to the administration 
of BeneFIX, the rate of infusion should be decreased or the infusion stopped (see sections 4.4 and 4.8). 
 
Agglutination of red blood cells in the tube/syringe 
There have been reports of agglutination of red blood cells in the tube/syringe with the administration 
of BeneFIX. No adverse events have been reported in association with this observation. To minimize 
the possibility of agglutination, it is important to limit the amount of blood entering the tubing. Blood 
should not enter the syringe. If agglutination of red blood cells in the tubing/syringe is observed, 
discard all this material (tubing, syringe and BeneFIX solution) and resume administration with a new 
package. 
 
Continuous infusion 
Administration by continuous infusion has not been approved and is not recommended (see also 
sections 4.4 and 6.6). 
 
For instructions on reconstitution of the medicinal product before 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 proteins. 
 
4.4 Special warnings and precautions for use 

 
Hypersensitivity 
Allergic-type hypersensitivity reactions are possible with BeneFIX. The product contains traces of 
hamster proteins. Potentially life-threatening anaphylactic/anaphylactoid reactions have occurred with 
factor IX products, including BeneFIX. 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 early signs of hypersensitivity reactions including difficult breathing, shortness 
of breath, swelling, hives, generalised urticaria, itching, tightness of the chest, bronchospasm, 
laryngospasm, wheezing, hypotension, blurred vision, and anaphylaxis. 
 
In some cases, these reactions have progressed to severe anaphylaxis. In the case of shock, the current 
medical standards for treatment of shock should be observed. In case of severe allergic reactions, 
alternative haemostatic measures should be considered. 
 



 

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Inhibitors 
Inhibitors are an uncommon event in previously treated patients (PTPs) receiving factor IX-containing 
products. As one PTP treated with BeneFIX developed a clinically relevant low responding inhibitor 
during clinical studies and experience on antigenicity with recombinant factor IX is still limited, 
patients treated with BeneFIX should be carefully monitored for the development of factor IX 
inhibitors that should be titrated in Bethesda Units using appropriate biological testing. 
 
There have been reports in the literature showing a correlation between the occurrence of a factor IX 
inhibitor and allergic reactions. Therefore, patients experiencing allergic reactions should be evaluated 
for the presence of an inhibitor. It should be noted that patients with factor IX inhibitors may be at an 
increased risk of anaphylaxis with subsequent challenge with factor IX. Preliminary information 
suggests a relationship may exist between the presence of major deletion mutations in a patient's factor 
IX gene and an increased risk of inhibitor formation and of acute hypersensitivity reactions. Patients 
known to have major deletion mutations of the factor IX gene should be observed closely for signs and 
symptoms of acute hypersensitivity reactions, particularly during the early phases of initial exposure 
to product. 
 
Because of the risk of allergic reactions with factor IX concentrates, the initial administrations of 
factor IX should, according to the treating physician’s judgement, be performed under medical 
observation where proper medical care for allergic reactions could be provided. 
 
Thrombosis 
Although BeneFIX contains only factor IX, the risk of thrombosis and disseminated intravascular 
coagulation (DIC) should be recognised. Since the use of factor IX complex concentrates has 
historically been associated with the development of thromboembolic complications, the use of factor 
IX-containing products may be potentially hazardous in patients with signs of fibrinolysis and in 
patients with disseminated intravascular coagulation (DIC). Because of the potential risk of 
thrombotic complications, clinical surveillance for early signs of thrombotic and consumptive 
coagulopathy should be initiated with appropriate biological testing when administering this product 
to patients with liver disease, to patients post-operatively, to new-born infants, or to patients at risk of 
thrombotic phenomena or DIC. In each of these situations, the benefit of treatment with BeneFIX 
should be weighed against the risk of these complications. 
 
The safety and efficacy of BeneFIX administration by continuous infusion have not been established 
(see also sections 4.2 and 4.8). There have been post-marketing reports of thrombotic events, including 
life-threatening superior vena cava (SVC) syndrome in critically ill neonates, while receiving 
continuous-infusion BeneFIX through a central venous catheter (see also section 4.8). 
 
Cardiovascular events 
In patients with existing cardiovascular risk factors, substitution therapy with FIX may increase the 
cardiovascular risk. 
 
Nephrotic syndrome 
Nephrotic syndrome has been reported following attempted immune tolerance induction in 
haemophilia B patients with factor IX inhibitors and a history of allergic reaction. The safety and 
efficacy of using BeneFIX for immune tolerance induction has not been established. 
 
Special populations 
Sufficient data have not been obtained from clinical studies on the treatment of previously untreated 
patients (PUPs) with BeneFIX. 
 
Record of use 
It is strongly recommended that every time BeneFIX is administered to a patient, the name and batch 
number of the product are recorded in order to maintain a link between the patient and the batch of the 
medicinal product. Patients can affix one of the peel-off labels found on the vial to document the batch 
number in their diary or for reporting any side effects. 
 



 

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4.5 Interaction with other medicinal products and other forms of interaction 

 
No interactions of human coagulation factor IX (rDNA) products with other medicinal products have 
been reported. 
 
4.6 Fertility, pregnancy and lactation 

 
Animal reproduction studies have not been conducted with factor IX. Based on the rare occurrence of 
haemophilia B in women, experience regarding the use of factor IX during pregnancy and 
breastfeeding is not available. Therefore, factor IX should be used during pregnancy and 
breast-feeding only if clearly indicated. 
 
The effect of BeneFIX on fertility has not been established. 
 
4.7 Effects on ability to drive and use machines 

 
BeneFIX has no influence on the ability to drive or 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 and 
may in some cases progress to severe anaphylaxis (including shock). In some cases, these reactions 
have progressed to severe anaphylaxis, and they have occurred in close temporal association with 
development of factor IX inhibitors (see also section 4.4). Nephrotic syndrome has been reported 
following attempted immune tolerance induction in haemophilia B patients with factor IX inhibitors 
and a history of allergic reaction. 
 
Very rarely development of antibodies to hamster protein with related hypersensitivity reactions has 
been observed. 
 
Patients with haemophilia B may develop neutralising antibodies (inhibitors) to factor IX. If such 
inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it 
is recommended that a specialised haemophilia centre be contacted. 
 
There is a potential risk of thromboembolic episodes following the administration of factor IX 
products, see section 4.4. 
 
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); uncommon (≥ 1/1,000 to < 1/100), not known (cannot 
be estimated from the available data). The table lists adverse reactions reported in the clinical trials of 
previously treated patients and identified in postmarketing use. The frequencies are based on all 
causality treatment emergent adverse events in pooled clinical trials with 224 subjects. 
 
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 
 



 

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System organ class Very 
common 

≥ 1/10 
 

Common 
≥ 1/100 

to < 1/10 
 

Uncommon 
≥ 1/1,000 to 

 < 1/100 
 

Frequency 
not known 
(cannot be 

estimated from  
the available data) 

Infections and 
infestations 

  Infusion-site 
cellulitisa 

 

Blood and lymphatic 
system disorders 

  Factor IX 
inhibitionb 

 

Immune system 
disorders 

 Hypersensitivityc  Anaphylactic 
reaction* 

Nervous system 
disorders  

Headached Dizziness;  
Dysgeusia 

Somnolence; 
tremor 

 

Eye disorders    Visual 
impairmente 

 

Cardiac disorders    Tachycardiaf  
Vascular disorders   Phlebitis; 

flushingg 
Hypotensionh Superior vena cava 

syndromei,* ;  
deep vein 
thrombosis*;  
thrombosis*; 
thrombophlebitis* 

Respiratory, thoracic 
and mediastinal 
disorders  

Coughj    

Gastrointestinal 
disorders  

 Vomiting; nausea 
 

  

Skin and subcutaneous 
tissue disorders  

 Rashk; urticaria   

Renal and urinary 
disorders  

  Renal infarctl  

General disorders and 
administration site 
conditions  

Pyrexia Chest discomforto; 
infusion-site 
reactionn; 
infusion-site painm 

 Inadequate therapeutic 
response* 

Investigations    Inadequate factor IX 
recovery p, * 

* ADR identified post-marketing 
a including cellulitis 
b low-titer transient inhibitor formation 
c including drug hypersensitivity, angioedema, bronchospasm, wheezing, dyspnoea, and laryngospasm 
d including migraine, sinus headache 
e including scintillating scotoma and blurred vision 
f including heart rate increased, sinus tachycardia 
g including hot flush, feeling hot, skin warm 
h including blood pressure decreased 
i superior vena cava (SVC) syndrome in critically ill neonates, while receiving continuous-infusion of BeneFIX 

through a central venous catheter  
j including productive cough 
k including rash macular, rash papular, rash maculopapular  
l developed in a hepatitis C antibody-positive patient 12 days after a dose of BeneFIX for a bleeding episode. 
m including injection site pain, infusion-site discomfort 
n including infusion-site pruritus, infusion-site erythema 
o including chest pain and chest tightness 
p This is a verbatim term. No MedDRA 17.1 PT was retrieved. 

 



 

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Description of selected adverse reactions 
 
Hypersensitivity/allergic reactions 

If any suspected hypersensitivity reaction takes place that is thought to be related to the administration 
of BeneFIX see sections 4.2 and 4.4. 
 
Inhibitor development 

A clinically relevant, low responding inhibitor was detected in 1 out of 65 BeneFIX patients 
(including 9 patients participating only in the surgery study) who had previously received plasma-
derived products. This patient was able to continue treatment with BeneFIX with no anamnestic rise in 
inhibitor or anaphylaxis (see section 4.4). 
 
Paediatric population 
Allergic reactions might be experienced more frequently in children than in adults. 
 
There are insufficient data to provide information on inhibitor incidence in PUPs (see also 
section 5.1). 
 
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 IX products. 
 
 
5. PHARMACOLOGICAL PROPERTIES 

 
5.1  Pharmacodynamic properties 

 
Pharmacotherapeutic group: Antihaemorrhagics, blood coagulation factor IX; ATC code: B02BD04 
 
Mechanism of action 
BeneFIX contains recombinant coagulation factor IX, (nonacog alfa). Recombinant coagulation 
factor IX is a single chain glycoprotein with an approximate molecular mass of 55,000 Daltons that is 
a member of the serine protease family of vitamin K-dependent coagulation factors. Recombinant 
coagulation factor IX is a recombinant DNA-based protein therapeutic which has structural and 
functional characteristics comparable to endogenous factor IX. Factor IX is activated by 
factor VII/tissue factor complex in the extrinsic pathway as well as factor XIa in the intrinsic 
coagulation pathway. Activated factor IX, in combination with activated factor VIII, activates 
factor X. This results ultimately in the conversion of prothrombin to thrombin. Thrombin then 
converts fibrinogen into fibrin and a clot can be formed. Factor IX activity is absent or greatly reduced 
in patients with haemophilia B and substitution therapy may be required. 
 
Pharmacodynamic effects 
Haemophilia B is a sex-linked hereditary disorder of blood coagulation due to decreased levels of 
factor IX 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 IX is 
increased, thereby enabling a temporary correction of the factor deficiency and correction of the 
bleeding tendencies. 
 
Paediatric population 
Efficacy analysis in study 3090A1-301-WW was based on 22 evaluable paediatric subjects on 
prophylaxis regimen including 4 on-demand patients who shortly changed to prophylaxis. Two 



 

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patients underwent surgical procedures (circumcision and port-a-catheter insertion). Safety analysis of 
25 evaluable patients reflected a safety profile as expected. The only documented serious adverse 
event related with BeneFIX was reported from the only included PUP, who experienced 
hypersensitivity and inhibitor development. 
 
In two open-label studies BeneFIX was found to be safely administered at 100 IU/kg once-weekly. 
However, the half-life of the product (see section 5.2) and the limited pharmacokinetic study data for 
the once-weekly regimen do not allow recommending this regimen in general for long-term 
prophylaxis in severe haemophilia B patients. 
 
5.2 Pharmacokinetic properties 

 
In a randomized, cross-over pharmacokinetic study, BeneFIX reconstituted in 0.234% sodium chloride 
diluent was shown to be pharmacokinetically equivalent to the previously marketed BeneFIX 
(reconstituted with sterile water) in 24 previously treated patients (≥12 years) at a dose of 75 IU/kg. In 
addition, pharmacokinetic parameters were followed up in 23 of the same patients after repeated 
administration of BeneFIX for six months and found to be unchanged compared with those obtained at 
the initial evaluation. A summary of pharmacokinetic data is presented in Table 1. 
 
Table 1. Pharmacokinetic Parameter Estimates for BeneFIX (75 IU/kg) at Baseline and Month 6 

in Previously Treated Patients with Haemophilia B 

Parameter Baseline n = 24 Mean ± SD 
Month 6 n = 23 

Mean ± SD 
Cmax (IU/dL)  54.5 ± 15.0  57.3 ± 13.2  
AUC∞ (IU∙hr/dL)  940 ± 237  923 ± 205  
t1/2 (hr)  22.4 ± 5.3  23.8 ± 6.5  
CL (mL/hr/kg)  8.47 ± 2.12  8.54 ± 2.04  
Recovery 
(IU/dL per IU/kg)  0.73 ± 0.20  0.76 ± 0.18  

Abbreviations: AUC∞ = area under the plasma concentration-time curve from time zero to infinity; Cmax = peak 
concentration; t1/2 = plasma elimination half-life; CL = clearance; SD = standard deviation. 
 
A population pharmacokinetic model was developed using data collected in 73 patients aged 7 months 
to 60 years. The parameters estimated using the final 2-compartment model are shown in Table 2. 
Infants and children had higher clearance, larger volume of distribution, shorter half-life and lower 
recovery than adolescents and adults. The terminal phase has not been covered unambiguously due to 
lack of data beyond 24 hours in paediatric subjects < 6 years of age. 
 

Table 2. Mean  SD Pharmacokinetic Parameters Based on Individual Bayes Estimates from 
Population Pharmacokinetic Analysis 

Age Group 
(years) 

Infants 
<2 

Children 
2 to < 6  

Children 
6 to < 12  

Adolescents 
12 to < 18  

Adults 
18 to 60  

Number of 
subjects 7 16 1 19 30 

Clearance 
(mL/h/kg) 13.1  2.1 13.1 ± 2.9 15.5 9.2 ± 2.3 8.0 ± 0.6 

Vss (mL/kg) 252  35 257 ± 25 303 234 ± 49 225 ± 59 
Elimination 
half-life (h) 15.6  1.2 16.7 ± 1.9 16.3 21.5 ± 5.0 23.9 ± 4.5 

Recovery 
(IU/dL per 

IU/kg) 
0.61  0.10 0.60 ± 0.08 0.47 0.69 ± 0.16 0.74 ± 0.20 

 



 

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5.3 Preclinical safety data 

 
Non-clinical data reveal no special hazard for humans based on conventional studies of genotoxicity. 
 
No investigations on carcinogenicity, fertility impairment and foetal development have been 
conducted. 
 
 
6. PHARMACEUTICAL PARTICULARS 

 
6.1 List of excipients 

 
Powder 
Sucrose 
Glycine 
L-Histidine  
Polysorbate 80 
 
Solvent 
Sodium chloride solution 
 
6.2 Incompatibilities 

 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products. Only the provided infusion set should be used. Treatment failure can occur as a consequence 
of human coagulation factor IX adsorption to the internal surfaces of some infusion equipment. 
 
6.3 Shelf life 

 
2 years 
 
The reconstituted product does not contain a preservative and should be used immediately, but no 
longer than 3 hours after reconstitution. Chemical and physical in-use stability has been demonstrated 
for 3 hours at temperatures up to 25C. 
 
6.4 Special precautions for storage 

 
Store below 30C. Do not freeze. 
 
6.5 Nature and contents of container 

 
BeneFIX 250 IU, 500 IU, 1000 IU, 1500 IU, 2000 IU, 3000 IU powder and solvent for solution for 
injection 
BeneFIX 250 IU, 500 IU, 1000 IU, 1500 IU, 2000 IU, 3000 IU of powder in a 10 mL vial (type 1 
glass) with a stopper (chlorobutyl) and a flip-off seal (aluminium) and 5 mL of clear, colourless 
solvent in a prefilled syringe (type 1 glass) with a plunger stopper (bromobutyl), a tip-cap 
(bromobutyl) and a sterile vial adapter reconstitution device, a sterile infusion set, two alcohol swabs, 
a plaster, and a gauze pad. 
 
6.6 Special precautions for disposal and other handling 

 
BeneFIX is administered by intravenous infusion after reconstitution of the lyophilised powder for 
injection with the supplied solvent (0.234% w/v sodium chloride solution) in the pre-filled syringe 
(see also section 3 of the package leaflet for reconstitution instructions). 
 



 

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BeneFIX, when reconstituted, contains polysorbate-80, which is known to increase the rate of 
di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC). This should be 
considered during the preparation and administration of BeneFIX. It is important that the 
recommendations in section 4.2 be followed closely. 
 
Any unused product or waste material should be disposed of in accordance with local requirements.  
 
Because the use of BeneFIX by continuous infusion has not been evaluated, BeneFIX should not be 
mixed with infusion solutions or be given in a drip. 
 
 
7. MARKETING AUTHORISATION HOLDER 

 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  

 
EU/1/97/047/004 
EU/1/97/047/005 
EU/1/97/047/006 
EU/1/97/047/009 
EU/1/97/047/007 
EU/1/97/047/008 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 
Date of first authorisation: 27 August 1997 
Date of latest renewal: 20 July 2012 
 
 
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 



 

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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 

 
 
 



 

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A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 

MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer of the biological active substance 
 
Wyeth BioPharma 
Division of Wyeth Pharmaceuticals LLC 
One Burtt Road 
Andover MA 01810 
USA 
 
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. 

 



 

15 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 

 
LABELLING AND PACKAGE LEAFLET 



 

16 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



 

17 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
OUTER CARTON 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
BeneFIX 250 IU powder and solvent for solution for injection 
 
BeneFIX 500 IU powder and solvent for solution for injection 
 
BeneFIX 1000 IU powder and solvent for solution for injection 
 
BeneFIX 1500 IU powder and solvent for solution for injection 
 
BeneFIX 2000 IU powder and solvent for solution for injection 
 
BeneFIX 3000 IU powder and solvent for solution for injection 
 
Nonacog alfa (recombinant coagulation factor IX) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial: 250 IU nonacog alfa (approx. 50 IU/ml after reconstitution). 
 
1 vial: 500 IU nonacog alfa (approx. 100 IU/ml after reconstitution). 
 
1 vial: 1000 IU nonacog alfa (approx. 200 IU/ml after reconstitution). 
 
1 vial: 1500 IU nonacog alfa (approx. 300 IU/ml after reconstitution). 
 
1 vial: 2000 IU nonacog alfa (approx. 400 IU/ml after reconstitution). 
 
1 vial: 3000 IU nonacog alfa (approx. 600 IU/ml after reconstitution). 
 
 
3. LIST OF EXCIPIENTS 
 
Sucrose, glycine, L-histidine, sodium chloride, polysorbate 80. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection  
 
1 vial with 250 IU nonacog alfa 
1 vial with 500 IU nonacog alfa 
1 vial with 1000 IU nonacog alfa 
1 vial with 1500 IU nonacog alfa 
1 vial with 2000 IU nonacog alfa 
1 vial with 3000 IU nonacog alfa 
 
1 pre-filled syringe with 5 ml solvent 
1 sterile vial adapter reconstitution device 
1 sterile infusion set 



 

18 

2 alcohol swabs 
1 plaster 
1 gauze pad 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use, single use administration only. 
Read the package leaflet before use. 
 
 
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 
 
Use only the pre-filled syringe of solvent provided in the box for reconstitution. 
 
 
8. EXPIRY DATE 
 
EXP  
Use immediately or within 3 hours of reconstitution. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C. Do not freeze. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
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/1/97/047/004 
EU/1/97/047/005 
EU/1/97/047/006 
EU/1/97/047/009 
EU/1/97/047/007 
EU/1/97/047/008 
 
 



 

19 

13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
BeneFIX 250 
BeneFIX 500 
BeneFIX 1000 
BeneFIX 1500 
BeneFIX 2000 
BeneFIX 3000 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC:  
SN: 
NN: 



 

20 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
BeneFIX 250 IU powder for solution for injection 
 
BeneFIX 500 IU powder for solution for injection 
 
BeneFIX 1000 IU powder for solution for injection 
 
BeneFIX 1500 IU powder for solution for injection 
 
BeneFIX 2000 IU powder for solution for injection 
 
BeneFIX 3000 IU powder for solution for injection 
 
Nonacog alfa (recombinant coagulation factor IX) 
Intravenous use 
 
 
2. METHOD OF ADMINISTRATION 
 
Single use injection. 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot 
 
See front label (Lot, Exp.) 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
250 IU 
 
500 IU 
 
1000 IU 
 
1500 IU 
 
2000 IU 
 
3000 IU 
 
 



 

21 

 
6. OTHER 
 
Store below 30 ºC. Do not freeze.  
 
Use only the pre-filled syringe provided in the box for reconstitution. 
 
 



 

22 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SOLVENT SYRINGE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Solvent for BeneFIX 
 
For intravenous use. 
 
 
2. METHOD OF ADMINISTRATION 
 
Use the entire contents. 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot 
 
Pfizer Europe MA EEIG 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
Contains 5 ml of 0.234% sodium chloride solution for injection 
 
 
6. OTHER 
 
 



 

23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 

 



 

24 

  

Package leaflet: Information for the user 

 
BeneFIX 250 IU powder and solvent for solution for injection 

BeneFIX 500 IU powder and solvent for solution for injection 

BeneFIX 1000 IU powder and solvent for solution for injection 

BeneFIX 1500 IU powder and solvent for solution for injection 

BeneFIX 2000 IU powder and solvent for solution for injection 

BeneFIX 3000 IU powder and solvent for solution for injection 

Nonacog alfa (recombinant coagulation factor IX) 
 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 

- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- 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, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 

1. What BeneFIX is and what it is used for 
2. What you need to know before you take BeneFIX 
3. How to take BeneFIX 
4. Possible side effects 
5. How to store BeneFIX 
6. Contents of the pack and other information 
 
 
1. What BeneFIX is and what it is used for 
 
BeneFIX is an injectable clotting (coagulation) factor IX product that is produced by recombinant 
DNA technology. The active ingredient in BeneFIX is nonacog alfa. People who are born with 
haemophilia B (Christmas disease) lack sufficient factor IX to control bleeding. BeneFIX works by 
replacing factor IX in haemophilia B patients to enable their blood to clot. 
 
BeneFIX is used for the treatment and prevention of bleeding in patients with haemophilia B 
(congenital factor IX deficiency) in all age groups. 
 
 
2. What you need to know before you take BeneFIX 
 
Do not take BeneFIX: 
 
- If you are allergic to nonacog alfa or any of the other ingredients of this medicine (listed in 

section 6). 
-  If you are allergic to hamster proteins. 
 
Warnings and precautions 
 
- See your doctor immediately if your bleeding does not stop as expected. 
 
- Allergic reactions are possible. The product may contain traces of hamster proteins (see Do not 

take BeneFIX). Potentially life-threatening anaphylactic reactions (severe allergic reactions) 
have occurred with factor IX products, including BeneFIX. Early signs of allergic reactions 
include difficulty breathing, shortness of breath, swelling, hives, itching, generalised urticaria, 
tightness of the chest, wheezing, low blood pressure, blurred vision and anaphylaxis (severe 



 

25 

allergic reaction that can cause difficulty in swallowing and/or breathing, red or swollen face 
and/or hands).  

 
- If allergic or anaphylactic-type reactions occur, stop the infusion immediately and contact a 

doctor or seek emergency medical care immediately. In case of severe allergic reactions, 
alternative therapy should be considered.  

 
- Activity-neutralizing antibodies (inhibitors) are an uncommon event in patients who have 

received previous treatment with factor IX-containing products. However, as with all factor IX 
products you should be carefully monitored for the development of factor IX inhibitors while 
being treated with BeneFIX.  

 
- Research has shown a link between the occurrence of a factor IX inhibitor and allergic 

reactions. Therefore, if you experience allergic reactions such as those described above, you 
should be tested for the presence of an inhibitor. It should be noted that patients with a factor IX 
inhibitor may be at an increased risk of anaphylaxis during future treatment with BeneFIX. 
 

- The production of factor IX in the body is controlled by the factor IX gene. Patients who have 
specific mutations of their factor IX gene such as major deletion may be more likely to develop 
an inhibitor to factor IX and/or experience allergic reactions. Therefore if you are known to 
have such a mutation your doctor may monitor you more closely for signs of an allergic 
reaction particularly when you first start to take BeneFIX. 

 
- Because of the risk of allergic reactions with factor IX, your initial administrations of BeneFIX 

should be performed under medical observation where proper medical care for allergic reactions 
can be provided. 

 
- Even in the absence of factor IX inhibitor, higher doses of BeneFIX may be needed than 

required for other plasma-derived factor IX products that you may have taken previously. 
Therefore, close monitoring of factor IX plasma activity (which measures the ability of your 
blood to form clots) has to be performed to adjust doses as appropriate. If bleeding is not 
controlled with the recommended dose, contact your doctor. 

 
- If you suffer from liver or heart disease or if you have recently had surgery, there is an 

increased risk for blood clotting (coagulation) complications. 
 
- A kidney disorder (nephrotic syndrome) has been reported following high doses of 

plasma-derived factor IX in haemophilia B patients with factor IX inhibitors and a history of 
allergic reactions. 

 
- Sufficient data have not been obtained from clinical studies on the treatment of previously 

untreated patients (patients who have never received a previous infusion of factor IX), with 
BeneFIX. 
 

- It is recommended that evey time you use BeneFIX, you record the name 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. 

 
Other medicines and BeneFIX 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Pregnancy and breast-feeding 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, you 
should only take BeneFIX upon specific instructions from your doctor. It is not known whether 



 

26 

BeneFIX can cause harm to an unborn baby when given to pregnant women. Your doctor may advise 
you to stop treatment with BeneFIX if you are breast-feeding or become pregnant. 
 
Ask your doctor or pharmacist for advice before taking this medicine. 
 
Driving and using machines 
 
BeneFIX has no influence on the ability to drive or use machines. 
 
 
3. How to take BeneFIX 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
Your doctor will decide the dose of BeneFIX you will receive. This dose and duration will depend 
upon your individual needs for replacement factor IX therapy and how quickly your body uses up 
factor IX, which will be checked regularly. You may notice a difference in the dose you receive if you 
are changing from a plasma-derived factor IX product to BeneFIX. 
 
Your doctor may decide to change the dose of BeneFIX you receive during your treatment. 
 
Reconstitution and administration  
 
The procedures below are provided as guidelines for the reconstitution and administration of 
BeneFIX. Patients should follow the specific venipuncture procedures provided by their doctor. 
 
BeneFIX is administered by intravenous (IV) infusion after reconstitution of the powder for injection 
with the supplied solvent (a sodium chloride (salt) solution) in the pre-filled syringe. 
 
Always wash your hands prior to performing the following procedures. Aseptic technique (meaning 
clean and germ free) should be used during the reconstitution procedure. 
 
Reconstitution: 
 
BeneFIX will be administered by intravenous infusion (IV) after reconstitution with sterile solvent for 
injection. 
 
1. Allow the vial of lyophilised (freeze-dried) BeneFIX and the pre-filled syringe to reach room 

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

rubber stopper. 

 
 
3. Wipe the top of the vial with an 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. 
 



 

27 

5. Place the vial on a flat surface. While holding the adapter in the 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 pushing and turning firmly. 
 
 
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 BeneFIX 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 BeneFIX vial 

 



 

28 

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

 

 

12. The final solution should be inspected visually for fine particles before administration. The 
solution should appear clear and colourless. 

 
 Note: If you use more than one vial of BeneFIX 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 separate large luer lock (a device that connects the syringe to the vial) syringe 
may be used to draw back the reconstituted contents of each individual vial. 

 
13. Ensuring that the syringe plunger rod is still fully depressed, invert the vial. Slowly draw back 

all the solution 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 should be carefully replaced. 

Do not touch the syringe tip or the inside of the cap. 
 
BeneFIX should be administered immediately or within 3 hours after reconstitution. The reconstituted 
solution may be stored at room temperature prior to administration. 
 
Administration (Intravenous Injection): 
 
BeneFIX should be administered using the pre-filled solvent syringe provided or a single sterile 
disposable plastic luer lock syringe. In addition, the solution should be withdrawn from the vial using 
the vial adapter. 
 
BeneFIX should be injected intravenously over several minutes. Your doctor may change your 
recommended infusion rate to make the infusion more comfortable. 
 
There have been reports of clumping (agglutination) of red blood cells in the tube/syringe with the 
administration of BeneFIX. No side effects have been reported in association with this observation. To 
minimize the possibility of agglutination, it is important to limit the amount of blood entering the 
tubing. Blood should not enter the syringe. If clumping of red blood cells in the tubing/syringe is 
observed, discard all this material (tubing, syringe and BeneFIX solution) and resume administration 
with a new package. 
 
Because the use of BeneFIX by continuous infusion (drip) has not been evaluated, BeneFIX should 
not be mixed with infusion solutions or be given in a drip. 



 

29 

 
Please dispose of all unused solution, empty vials and used needles and syringes in an appropriate 
container for throwing away waste as it may hurt others if not handled properly. 
 
If you take more BeneFIX than you should 
 
Please contact your doctor immediately if you inject more BeneFIX than your doctor recommends. 
 
If you stop taking BeneFIX 
 
Do not stop taking BeneFIX without consulting your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Hypersensitivity/allergic reactions  
 
Allergic-type hypersensitivity reactions are possible with BeneFIX. Such reactions may include 
swelling of the face or throat, burning and stinging at the infusion site, chills, flushing, itching, 
headache, hives, low blood pressure, lethargy, nausea, restlessness, fast heart rate, tightness of the 
chest, tingling, vomiting, wheezing). In some cases, these reactions have progressed to severe 
anaphylaxis. Allergic reactions may occur together with the development of factor IX inhibitor (see 
also “Warnings and precautions”). 
 
These reactions are potentially life-threatening. If allergic/anaphylactic reactions occur, stop the 
infusion immediately and contact your doctor or seek emergency medical care immediately. The 
treatment required depends on the nature and severity of side-effects (see also “Warnings and 
precautions”).  
 
Inhibitor development 
 
Patients with haemophilia B may develop neutralising antibodies (inhibitors) to factor IX. If such 
inhibitors occur, a sign may be an increase in the amount of BeneFIX typically required to treat a 
bleed and or continued bleeding after treatment. In such cases, it is recommended that a specialised 
haemophilia centre be contacted. Your doctor may want to monitor you for inhibitor development (see 
“Warnings and precautions”). 
 
A kidney disorder has been reported following high doses of plasma-derived factor IX to induce 
immune tolerance in haemophilia B patients with factor IX inhibitors and a history of allergic 
reactions (see also “Warnings and precautions”). 
 
Thrombotic events 
 
BeneFIX may increase the risk of thrombosis (abnormal blood clots) in your body if you have risk 
factors for developing blood clots, including an indwelling venous catheter. There have been reports 
of severe blood clotting events, including life-threatening blood clots in critically ill babies, while 
receiving continuous-infusion BeneFIX through a central venous catheter. Cases of peripheral 
thrombophlebitis (pain and redness of the veins) and deep venous thrombosis (blood clots in the 
extremities) have also been reported; in most of these cases, BeneFIX was administered via continuous 
infusion, which is not an approved method of administration.  
 
Very common side effects (may affect more than 1 in 10 people) 



 

30 

 Headache 
 Cough 
 Fever 

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

 Hypersensitivity/allergic reactions 
 Dizziness, altered taste 
 Phlebitis (pain and redness of veins), flushing 
 Vomiting, nausea 
 Rash, hives 
 Chest discomfort (including chest pain) 
 Infusion-site reaction (including itching and redness at the infusion site), infusion-site pain 

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

 Development of neutralising antibodies (inhibitors) 
 Infusion site cellulitis (pain and redness of the skin) 
 Sleepiness, shaking 
 Vision impairment (including blurred vision, appearance of spots/lights) 
 Fast heart rate, low blood pressure 
 Renal infarct (interruption to the blood supply to the kidney) 

 
Side effects with unknown frequency (frequency cannot be estimated from the available data) 

 Anaphylactic reaction 
 Thrombotic events (abnormal blood clots) 
 Lack of response to treatment (failure to stop or prevent bleeding episodes) 

 
Reporting of side effects 
 
If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible side 
effect 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 BeneFIX 
 
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 box and vial label. The 
expiry date refers to the last day of that month. 
 
BeneFIX must be stored below 30°C and must be used by the expiry date on the label.  
 
Do not freeze in order to prevent damage to the pre-filled syringe. 
 
Use the reconstituted solution immediately or within 3 hours. 
 
Do not use this medicine if you notice the solution is not clear or colourless. 
 
Use only the pre-filled syringe provided in the box for reconstitution. Other sterile disposable syringes 
may be used for administration. 
 
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.  



 

31 

 
 
6. Contents of the pack and other information 
 
What BeneFIX contains 
 
- The active substance is nonacog alfa (recombinant coagulation factor IX). Each vial of BeneFIX 

contains nominally 250, 500, 1000, 1500, 2000 or 3000 IU of nonacog alfa. 
- The other ingredients are sucrose, glycine, L-histidine, polysorbate 80. A solvent (0.234% 

sodium chloride solution) is also supplied for reconstitution. 
- After reconstitution with the supplied solvent (0.234% sodium chloride solution), each vial 

contains 50, 100, 200, 300, 400 or 600 IU/ml (see Table 1). 
 
   Table 1. Strength of BeneFIX per ml prepared solution 
 

Amount of BeneFIX per Vial  Amount of BeneFIX per 1 ml 
of prepared solution for 

injection 
 

250 IU 50 IU 
500 IU 100 IU 

1000 IU 200 IU 
1500 IU 300 IU 
2000 IU 400 IU 
3000 IU 600 IU 

 
What BeneFIX looks like and contents of the pack 
 
BeneFIX is provided as a powder for injection in a glass vial and a solvent provided in pre-filled 
syringe.  
 
The contents of the pack are: 
 
 one vial of BeneFIX 250, 500, 1000, 1500, 2000 or 3000 IU powder 
 one pre-filled syringe of solvent, 5 ml sterile 0.234% sodium chloride 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 
 



 

32 

Manufacturer 
 
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 medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België /Belgique / Belgien Lietuva 
Pfizer S.A./N.V.  Pfizer Luxembourg SARL filialas Lietuvoje 
Tél/Tel: +32 (0)2 554 62 11 Tel. +3705 2514000 
  
България  Luxembourg/Luxemburg 
Пфайзер Люксембург САРЛ, Клон 
България  

Pfizer S.A. 

Тел.: +359 2 970 4333 Tél/Tel: +32 (0)2 554 62 11 
  
Česká Republika Magyarország 
Pfizer PFE, spol. s r.o. Pfizer Kft. 
Tel: +420 283 004 111 Tel.: + 36 1 488 37 00 
  
Danmark Malta 
Pfizer ApS Vivian Corporation Ltd. 
Tlf: +45 44 20 11 00 Tel: +35621 344610 
  
Deutschland Nederland 
Pfizer Pharma GmbH Pfizer bv 
Tel: +49 (0)30 550055 51000 Tel: +31 (0)10 406 43 01 
  
Eesti Norge 
Pfizer Luxembourg SARL Eesti filiaal Pfizer Norge AS 
Tel: +372 666 7500 Tlf: +47 67 52 61 00 
  
Ελλάδα Österreich 
PFIZER ΕΛΛΑΣ Α.Ε. Pfizer Corporation Austria Ges.m.b.H. 
Τηλ:   +30 210 67 85 800 Tel: +43 (0)1 521 15-0 
  
España Polska 
Pfizer S.L. Pfizer Polska Sp. z o.o., 
Tel: +34 91 490 99 00 Tel.: +48 22 335 61 00 
  
France Portugal 
Pfizer  Pfizer Biofarmacêutica, Sociedade Unipessoal Lda 
Tél: +33 (0)1 58 07 34 40 Tel: +351 21 423 5500 
  
Hrvatska  România 
Pfizer Croatia d.o.o. Pfizer România S.R.L. 
Tel: + 385 1 3908 777 Tel: +40 21 207 28 00 
  



 

33 

Ireland Slovenija 
Pfizer Healthcare Ireland Pfizer Luxembourg SARL 

Pfizer, podružnica za svetovanje s področja 
farmacevtske dejavnosti, Ljubljana  

Tel: 1800 633 363 (toll free) Tel: + 386 (0) 1 52 11 400 
+44 (0)1304 616161  
  
Ísland Slovenská republika 
Icepharma hf. Pfizer Luxembourg SARL, organizačná zložka  
Sími: + 354 540 8000 Tel: +421-2-3355 5500 
  
Italia Suomi/Finland 
Pfizer S.r.l. Pfizer Oy 
Tel: +39 06 33 18 21 Puh/Tel: +358 (0)9 43 00 40 
  
Κύπρος Sverige  
PFIZER ΕΛΛΑΣ Α.Ε. (CYPRUS 
BRANCH) 

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

Τηλ: +357 22 817690  
  

Latvija United Kingdom 
Pfizer Luxembourg SARL filiāle Latvijā Pfizer Limited 
Tel: +371 670 35 775 Tel: +44 (0)1304 616161 
  

 
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 
 


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