Afstyla

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT

AFSTYLA 250 IU powder and solvent for solution for injection

AFSTYLA 500 IU powder and solvent for solution for injection

AFSTYLA 1000 IU powder and solvent for solution for injection

AFSTYLA 1500 IU powder and solvent for solution for injection

AFSTYLA 2000 IU powder and solvent for solution for injection

AFSTYLA 2500 IU powder and solvent for solution for injection

AFSTYLA 3000 IU powder and solvent for solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

AFSTYLA 250 IU powder and solvent for solution for injection
Each vial contains nominally 250 IU recombinant, single-chain coagulation factor VIII (rVIII-
SingleChain, INN = lonoctocog alfa). After reconstitution with 2.5 ml water for injections the 
solution contains 100 IU/ml of rVIII-SingleChain.

AFSTYLA 500 IU powder and solvent for solution for injection
Each vial contains nominally 500 IU recombinant, single-chain coagulation factor VIII (rVIII-
SingleChain, INN = lonoctocog alfa). After reconstitution with 2.5 ml water for injections the 
solution contains 200 IU/ml of rVIII-SingleChain.

AFSTYLA 1000 IU powder and solvent for solution for injection
Each vial contains nominally 1000 IU recombinant, single-chain coagulation factor VIII (rVIII-
SingleChain, INN = lonoctocog alfa). After reconstitution with 2.5 ml water for injections the 
solution contains 400 IU/ml of rVIII-SingleChain.

AFSTYLA 1500 IU powder and solvent for solution for injection
Each vial contains nominally 1500 IU recombinant, single-chain coagulation factor VIII (rVIII-
SingleChain, INN = lonoctocog alfa). When reconstituted with 5 ml water for injections the 
solution contains 300 IU/ml of rVIII-SingleChain.

AFSTYLA 2000 IU powder and solvent for solution for injection
Each vial contains nominally 2000 IU recombinant, single-chain coagulation factor VIII (rVIII-
SingleChain, INN = lonoctocog alfa). When reconstituted with 5 ml water for injections the 
solution contains 400 IU/ml of rVIII-SingleChain.

AFSTYLA 2500 IU powder and solvent for solution for injection
Each vial contains nominally 2500 IU recombinant, single-chain coagulation factor VIII (rVIII-
SingleChain, INN = lonoctocog alfa). When reconstituted with 5 ml water for injections the 
solution contains 500 IU/ml of rVIII-SingleChain.



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AFSTYLA 3000 IU powder and solvent for solution for injection
Each vial contains nominally 3000 IU recombinant, single-chain coagulation factor VIII (rVIII-
SingleChain, INN = lonoctocog alfa). When reconstituted with 5 ml water for injections the 
solution contains 600 IU/ml of rVIII-SingleChain.

The potency (IU) is determined using the European Pharmacopoeia chromogenic assay. The 
specific activity of AFSTYLA is 7400 - 16000 IU/mg protein.

AFSTYLA is a single-chain recombinant human factor VIII produced in Chinese hamster ovary 
(CHO) cells. It is a construct where most of the B-domain occurring in wild-type, full-length 
factor VIII and 4 amino acids of the adjacent acidic a3 domain were removed (amino acids 765 to 
1652 of full-length factor VIII).

The newly formed linkage of the heavy and light chain of factor VIII introduces a new N-
glycosylation site. As the furin cleavage site present in wild type factor VIII between the B-
domain and the a3 domain was removed, AFSTYLA is expressed as a single-chain factor VIII 
molecule.

Excipient with known effect:

AFSTYLA 250, 500 and 1000 IU (2.5 ml solvent)
Each vial contains 17.5 mg (0.76 mmol) of sodium.

AFSTYLA 1500, 2000, 2500 and 3000 IU (5 ml solvent)
Each vial contains 35 mg (1.52 mmol) of sodium.

For the full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM

Powder and solvent for solution for injection.
White or slightly yellow powder or friable mass and clear, colourless solvent for solution for 
injection.

pH: 6.6 - 7.3

Osmolality: 500 - 600 mOsm/kg

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII 
deficiency).

AFSTYLA 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 VIII levels is advised to guide 
the dose to be administered and the frequency of repeated injections. Individual patients may vary 
in their responses to factor VIII, demonstrating different half-lives and recoveries. Dose based on 



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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.

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 according to Ph. Eur. This is of importance 
particularly when changing the laboratory and/or reagents used in the assay.

Plasma factor VIII activity in patients receiving AFSTYLA using either the chromogenic assay or 
the one-stage clotting assay should be monitored to guide the dose administered and the frequency 
of repeat injections. The chromogenic assay result most accurately reflects the clinical hemostatic 
potential of AFSTYLA and is preferred. The one-stage clotting assay result underestimates the 
factor VIII activity level compared to the chromogenic assay result by approximately 45%. If the 
one-stage clotting assay is used, multiply the result by a conversion factor of 2 to determine the 
patient’s factor VIII activity level.

Posology
The dose and duration of the substitution therapy depend on the severity of the factor VIII 
deficiency, on the location and extent of the bleeding and on the patient's clinical condition. 

The number of units of factor VIII administered is expressed in International Units (IU), which 
are related to the current WHO concentrate standard for factor VIII products. Factor VIII activity 
in plasma is expressed either as a percentage (relative to normal human plasma) or preferably in 
International Units (relative to an International Standard for factor VIII in plasma).

One International Unit (IU) of factor VIII activity is equivalent to that quantity of factor VIII in 
one ml of normal human plasma.

Potency assignment is determined using a chromogenic substrate assay.
Plasma factor VIII levels can be monitored using either a chromogenic substrate assay or a one-
stage clotting assay.

On demand treatment
The calculation of the required dose of factor VIII is based on the empirical finding that 1 
International Unit (IU) 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:

Dose (IU) = body weight (kg) x Desired factor VIII rise (IU/dl or % of normal) x 0.5 (IU/kg per 
IU/dl)

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 VIII activity should not fall below the 
given plasma activity level (in % of normal or IU/dl) within 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 (%) (IU/dl)

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

Haemorrhage
Early haemarthrosis, 
muscle bleeding or oral 
bleeding

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



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achieved.
More extensive
haemarthrosis, muscle 
bleeding or haematoma

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

Life threatening 
haemorrhages

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

Surgery
Minor surgery including 
tooth extraction

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

Major surgery 80 - 100 
(pre- and
postoperative)

Repeat injection every 8 to 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 
The recommended starting regimen is 20 to 50 IU/kg of AFSTYLA administered 2 to 3 times 
weekly. The regimen may be adjusted based on patient response.

Paediatric population 
The recommended starting regimen in children (0 to <12 years of age) is 30 to 50 IU per kg of 
AFSTYLA administered 2 to 3 times weekly. More frequent or higher doses may be required in 
children <12 years of age to account for the higher clearance in this age group. 

For adolescents of 12 years of age and above, the dose recommendations are the same as for 
adults (please refer to section 5.2).

Elderly
Clinical studies of AFSTYLA did not include subjects over 65 years of age.

Method of administration
Intravenous use. 

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

The reconstituted preparation should be injected slowly at a rate comfortable for the patient at a 
maximum injection rate of 10 ml/min.

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

Traceability
In order to improve traceability of biological medicinal products, the name and the batch number 
of the administered product should be clearly recorded.

Hypersensitivity
Allergic type hypersensitivity reactions are possible with AFSTYLA. The 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. 



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For patients with previous hypersensitivity reactions appropriate pre-medication may be considered.

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 procoagulant activity, which are quantified in Bethesda Units (BU) per 
ml of plasma using the modified assay. The risk of developing inhibitors is correlated to the severity of 
the disease as well as the exposure to factor VIII, this risk being highest within the first 50 exposure 
days but continues throughout life although the risk is uncommon. 

The clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low titre 
posing less of a risk of insufficient clinical response than high titre inhibitors.

In general, all patients treated with coagulation factor VIII products should be carefully monitored 
for the development of inhibitors by appropriate clinical observations and laboratory tests. If the 
expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an 
appropriate dose, testing for factor VIII inhibitor presence should be performed. In patients with 
high levels of inhibitor, factor VIII therapy may not be effective and other therapeutic options 
should be considered. Management of such patients should be directed by physicians with 
experience in the care of haemophilia and factor VIII inhibitors.

Monitoring laboratory tests
If the one-stage clotting assay is used, multiply the result by a conversion factor of 2 to determine 
the patient’s factor VIII activity level (see section 4.2).

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. 

Sodium content
This medicine contains up to 7 mg (0.3 mmol) sodium per ml after reconstitution. To be taken
into consideration by patients on a controlled sodium diet.

Paediatric population
The listed warnings and precautions apply both to adults and children.

4.5 Interaction with other medicinal products and other forms of interaction

No interactions of human 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. Based on 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 lactation only if clearly indicated.

4.7 Effects on ability to drive and use machines



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AFSTYLA 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 
injection site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, 
restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed 
rarely with the use of factor VIII products and may in some cases progress to severe anaphylaxis 
(including shock).

Development of neutralizing antibodies (inhibitors) may occur in patients with haemophilia A treated 
with factor VIII, including with AFSTYLA. 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). The frequencies in the table below were observed in completed clinical 
studies in previously treated patients with severe haemophilia A.

Frequencies have been evaluated on a per patient basis according to the following convention: 
very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare 
(≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the 
available data). 

MedDRA 
System Organ Class

Adverse reaction Frequency

Blood and lymphatic 
system disorders

FVIII inhibition
uncommon (PTPs)*

very common 
(PUPs)*

Immune system disorders Hypersensitivity common
Nervous system disorders Dizziness common

Paraesthesia common
Skin and subcutaneous 
tissue disorders

Rash common
Erythema uncommon
Pruritus uncommon

General disorders and 
administration site 
conditions

Pyrexia common
Injection site pain uncommon
Chills uncommon
Feeling hot uncommon

*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 
No age-specific differences in adverse reactions were observed between paediatric and adult 
subjects. 

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization 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

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


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In a completed clinical trial a patient who received more than double the prescribed dose of 
AFSTYLA experienced dizziness, feeling hot, and itching not considered related to AFSTYLA 
but more plausibly attributed to co-administration of an analgesic.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antihemorrhagics: Blood coagulation factor VIII. 
ATC code: B02BD02

Mechanism of Action 

AFSTYLA (INN: lonoctocog alfa) is a recombinant human protein that replaces the missing 
coagulation factor VIII needed for effective hemostasis. AFSTYLA is a single polypeptide chain 
with a truncated B-domain that allows for a covalent bridge to link the factor VIII heavy and light 
chains. AFSTYLA has demonstrated a higher VWF affinity relative to full-length rFVIII. VWF 
stabilizes factor VIII and protects it from degradation. Activated AFSTYLA has an amino acid 
sequence identical to endogenous FVIIIa.

Pharmacodynamic effects
The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von 
Willebrand factor) with different physiological functions. When infused into a haemophiliac 
patient, factor VIII binds to von Willebrand factor 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 can be formed.
Haemophilia A is an x-linked hereditary disorder of blood coagulation due to decreased levels of 
factor VIII and results in profuse bleeding into joints, muscles or internal organs, either 
spontaneously or as 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.

Clinical efficacy and safety

Adult and adolescent population 12 - 65 years of age
Study 1001 determined the efficacy and safety in the prevention of bleeding events in prophylaxis, 
hemostatic efficacy in the control of bleeding events and during perioperative management. The study 
enrolled 175 previously treated patients (12 to 65 years of age) with severe haemophilia A (1 subject 
>60 years of age was enrolled) who accumulated a total of 14,306 EDs with rVIII-SingleChain. No 
patient developed an inhibitor or experienced an anaphylactic reaction. 

Prophylaxis: 146 subjects were assigned to a prophylaxis regimen (median ABR, 1.14 (interquartile 
range: 0.0, 4.2)), 79 (54%) were assigned a 3-times per week regimen and 47 (32%) a 2-times per 
week regimen. Patients on prophylaxis 2- and 3-times per week were assigned median doses of 35 and 
30 IU/kg per injection respectively with a median annual consumption across all prophylaxis regimens 
of 4,283 IU/kg year.

Treatment of bleeding: Of the 848 bleeding events observed during Study 1001, 93.5% were 
controlled with 2 or fewer injections. The median dose to treat a bleeding episode was 34.7 IU/kg.

Perioperative management (surgical prophylaxis): A total of 16 major surgical procedures were 
performed and assessed in 13 subjects in Study 1001. Hemostatic efficacy of rVIII-SingleChain in 
surgical prophylaxis was rated as excellent or good in all surgeries. No paediatric subjects <18 years 
of age were included in the surgery population.



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Paediatric population <12 years of age
Study 3002 enrolled a total of 84 previously treated patients <12 years of age (35 <6 years of age and 
49 6 to <12 years of age). The study participants accumulated a total of 5,239 EDs with rVIII-
SingleChain. No patient developed an inhibitor or experienced an anaphylactic reaction.

Individualised prophylaxis: Of the 81 patients on prophylaxis (median ABR 3.69 (interquartile range: 
0.00, 7.20)), 43 (53%) were assigned to a 2-times weekly regimen and 25 (31%) to a 3-times per week 
regimen. Patients on prophylaxis 2- and 3-times per week were assigned median doses of 35 and 32
IU/kg per injection respectively with a median annual consumption across all prophylaxis regimens of 
4,109 IU/kg year.

Treatment of bleeding: Of the 347 bleeding events observed during Study 3002, 95.7%were controlled 
with 2 or fewer injections. The median dose used to treat a bleeding event was 27.6 IU/kg 

Of note, annualized bleeding rate (ABR) is not comparable between different factor concentrates and 
between different clinical studies.

Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with 
AFSTYLA in the treatment of hereditary factor VIII deficiency in previously untreated paediatric 
patients (PUPs) (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Adult population 
The pharmacokinetics (PK) of AFSTYLA was evaluated in 81 previously treated adult subjects 
who had been diagnosed with severe haemophilia A with <1% factor VIII and with age from 18-
60 years old, following an intravenous injection of 50 IU/kg. 
The PK parameters were based on plasma factor VIII activity measured by the chromogenic 
substrate assay (for discrepancy in the factor VIII activity determined with one-stage clotting 
assay, please see section 4.2).The PK profile obtained 3 to 6 months after the initial PK 
assessment was comparable with the PK profile obtained after the first dose.

Pharmacokinetic Parameters following a Single Injection of 50 IU/kg of AFSTYLA -
Chromogenic Substrate Assay:

PK Parameters

rVIII-SingleChain
50 IU/kg
(N=81)

Mean (CV%)
Median (Min,Max)

IR (IU/dl)/(IU/kg)
2.00 (20.8)

1.99 (0.868, 2.90)

Cmax (IU/dl)
106 (18.1)

106 (62.4, 151)

AUC0-inf (IU*h/dl)
1960 (33.1)

1910 (932, 4090)

t1/2 (h)
14.2 (26.0)

13.7 (7.54, 23.9)

MRT (h)
20.4 (25.8)

20.2 (10.8, 35.1)

CL (ml/h/kg)
2.90 (34.4)

2.67 (1.26, 5.79)

Vss (ml/kg)
55.2 (20.8)

53.2 (32.4, 99.6)
IR = incremental recovery recorded at 30 minutes after injection; Cmax = maximum concentration, AUC0-inf = area under 
the factor VIII activity time curve extrapolated to infinity; t1/2 = half-life; MRT = mean residence time; CL = body 
weight adjusted clearance with N = 80; Vss = body weight adjusted volume of distribution at steady-state. IR and Cmax
were baseline corrected while the remaining parameters were not baseline corrected with N = 81.



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Paediatric population 
The pharmacokinetics (PK) of AFSTYLA were evaluated in 10 previously treated adolescents (12 
to <18 years of age) and 39 previously treated children (0 to <12 years of age) following an 
intravenous injection of a single dose of 50 IU/kg. All patients had been diagnosed with severe 
haemophilia A with <1% factor VIII.

The PK parameters were based on plasma factor VIII activity measured by the chromogenic 
substrate assay (for discrepancy in the factor VIII activity determined with one-stage clotting 
assay, please see Section 4.2).

Comparison of Pharmacokinetic Parameters by Age Category following a Single Injection of 50 
IU/kg of AFSTYLA - Chromogenic Assay:

PK Parameters

0 to <6 years
(N=20)

Mean (CV%)
Median (Min,Max)

6 to <12 years
(N=19)

Mean (CV%)
Median (Min,Max)

12 to <18 years
(N=10)

Mean (CV%)
Median (Min,Max)

IR (IU/dl)/(IU/kg)
1.60 (21.1)

1.55 (1.18, 2.76)
1.66 (19.7)

1.69 (0.92, 2.35)
1.69 (24.8)

1.76 (0.88, 2.44)

Cmax (IU/dl)
80.2 (20.6)

78.6 (59.3, 138)
83.5 (19.5)

84.5 (46.4, 117)
89.7 (24.8)

92.4 (45.5, 131)

AUC0-inf (IU*h/dl)
1080 (31.0)

985 (561, 2010)
1170 (26.3)

1120 (641, 1810)
1540 (36.5)

1520 (683, 2380)

t1/2 (h)
10.4 (28.7)

10.1 (5.19, 17.8)
10.2 (19.4)

10.0 (6.92, 14.8)
14.3 (33.3)

13.5 (6.32, 23.8)

MRT (h)
12.4 (25.0)

13.0 (6.05, 17.9)
12.3 (16.8)

12.8 (8.22, 16.0)
20.0 (32.2)

18.6 (9.17, 31.7)

CL (ml/h/kg)
5.07 (29.6)

5.08 (2.52, 8.92)
4.63 (29.5)

4.48 (2.79, 7.71)
3.80 (46.9)

3.31 (2.10, 7.32)

Vss (ml/kg)
71.0 (11.8)

70.7 (57.3, 88.3)
67.1 (22.3)

64.9 (44.3, 111)
68.5 (29.9)

62.0 (45.9, 121)
IR = incremental recovery recorded at 30 minutes after injection for subjects 12 to < 18 years and at 60 minutes after 
injection for subjects 1 to < 12 years; Cmax = maximum concentration, AUC = area under the factor VIII activity time 
curve extrapolated to infinity; t1/2 = half-life; MRT = mean residence time; CL = body weight adjusted clearance; Vss = 
body weight adjusted volume of distribution at steady-state. IR and Cmax were baseline corrected while the remaining 
parameters were not baseline corrected.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, single and repeated dose toxicity studies, local tolerability and thrombogenicity 
assessments.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder:
L-Histidine, Polysorbate 80, Calcium chloride dihydrate, Sodium chloride, Sucrose

Solvent:
Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other 
medicinal products or solvents except those mentioned in sections 2 and 6.5.



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6.3 Shelf life

3 years.

After reconstitution the chemical and physical in-use stability has been demonstrated for 48 hours 
at room temperature (below 25 °C). From a microbiological point of view, the product should be 
used immediately. If not used immediately, in-use storage times and conditions prior to use are in 
the responsibility of the user.

6.4 Special precautions for storage

Store in a refrigerator (2 °C to 8 °C).

Do not freeze. Keep vials in the outer carton in order to protect from light.

AFSTYLA may be stored at room temperature, not to exceed 25 °C, for a single period of up to 3 
months, within the expiration date printed on the carton and vial labels. Once the product has been 
taken out of the refrigerator, the product must not be returned to the refrigerator. Please record the 
beginning of storage at room temperature on the product carton.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

AFSTYLA 250 IU powder and solvent for solution for injection
Powder (250 IU) in a 6 ml vial (type I glass) with a stopper (rubber), an orange disc (plastic), and 
a green striped cap (aluminium).
2.5 ml of solvent in a vial (type I glass) with a stopper (rubber), a disc (plastic), and a cap 
(aluminium).

AFSTYLA 500 IU powder and solvent for solution for injection
Powder (500 IU) in a 6 ml vial (type I glass) with a stopper (rubber), a blue disc (plastic), and a 
green striped cap (aluminium).
2.5 ml of solvent in a vial (type I glass) with a stopper (rubber), a disc (plastic), and a cap 
(aluminium).

AFSTYLA 1000 IU powder and solvent for solution for injection
Powder (1000 IU) in a 6 ml vial (type I glass) with a stopper (rubber), a green disc (plastic), and a 
green striped cap (aluminium).
2.5 ml of solvent in a vial (type I glass) with a stopper (rubber), a disc (plastic), and a cap 
(aluminium).

AFSTYLA 1500 IU powder and solvent for solution for injection
Powder (1500 IU) in a 10 ml vial (type I glass) with a stopper (rubber), a turquoise disc (plastic),
and a green striped cap (aluminium).
5 ml of solvent in a vial (type I glass) with a stopper (rubber), a disc (plastic), and a cap 
(aluminium).

AFSTYLA 2000 IU powder and solvent for solution for injection
Powder (2000 IU) in a 10 ml vial (type I glass) with a stopper (rubber), a purple disc (plastic), and 
a green striped cap (aluminium).
5 ml of solvent in a vial (type I glass) with a stopper (rubber), a disc (plastic), and a cap 
(aluminium).

AFSTYLA 2500 IU powder and solvent for solution for injection



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Powder (2500 IU) in a 10 ml vial (type I glass) with a stopper (rubber), a light grey disc (plastic),
and a green striped cap (aluminium).
5 ml of solvent in a vial (type I glass) with a stopper (rubber), a disc (plastic), and a cap 
(aluminium).

AFSTYLA 3000 IU powder and solvent for solution for injection
Powder (3000 IU) in a 10 ml vial (type I glass) with a stopper (rubber), a yellow disc (plastic),
and a green striped cap (aluminium).
5 ml of solvent in a vial (type I glass) with a stopper (rubber), a disc (plastic), and a cap 
(aluminium).

Presentations
One pack with 250, 500 or 1000 IU containing:
1 vial with powder
1 vial with 2.5 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 5 ml syringe
1 venipuncture set 
2 alcohol swabs
1 non- sterile plaster

One pack with 1500, 2000, 2500 or 3000 IU containing:
1 vial with powder
1 vial with 5 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 10 ml syringe
1 venipuncture set 
2 alcohol swabs
1 non- sterile plaster

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

General instructions
- The solution should be almost colourless, clear or slightly opalescent. After 

filtering/withdrawal (see below) the reconstituted product should be inspected visually for 
particulate matter and discoloration prior to administration. 

- Do not use visibly cloudy solutions or solutions still containing flakes or particles. 
- Reconstitution and withdrawal must be carried out under aseptic conditions.

Reconstitution and administration
Bring the solvent to room temperature. Ensure powder and solvent vial flip caps are removed and 
the stoppers are treated with an antiseptic solution and allowed to dry prior to opening the 
Mix2Vial package.

1

1. Open the Mix2Vial by peeling off the lid. Do not remove 
the Mix2Vial from the blister package!



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2

2. Place the solvent vial on an even, clean surface and hold 
the vial tight. Take the Mix2Vial together with the blister 
package and push the spike of the blue adapter end 
straight down through the solvent vial stopper.

3

3. Carefully remove the blister package from the Mix2Vial 
set by holding at the rim, and pulling vertically upwards.
Make sure that you only pull away the blister package and 
not the Mix2Vial set.

4

4. Place the powder vial on an even and firm surface. Invert 
the solvent vial with the Mix2Vial set attached and push 
the spike of the transparent adapter end straight down
through the powder vial stopper. The solvent will 
automatically flow into the powder vial.

5

5. With one hand grasp the product-side of the Mix2Vial set 
and with the other hand grasp the solvent-side and 
unscrew the set carefully counterclockwise into two 
pieces.
Discard the solvent vial with the blue Mix2Vial adapter 
attached.

6

6. Gently swirl the product vial with the transparent adapter 
attached until the substance is fully dissolved. Do not 
shake.

7

7. Draw air into an empty, sterile syringe. While the product 
vial is upright, connect the syringe to the Mix2Vial's Luer 
Lock fitting by screwing clockwise. Inject air into the 
product vial.

Withdrawal and administration



14

8

8. While keeping the syringe plunger pressed, turn the 
system upside down and draw the solution into the syringe 
by pulling the plunger back slowly.

9

9. Now that the solution has been transferred into the 
syringe, firmly hold on to the barrel of the syringe 
(keeping the syringe plunger facing down) and disconnect 
the transparent Mix2Vial adapter from the syringe by 
unscrewing counterclockwise.

For injection of AFSTYLA the provided administration sets are recommended to be used because 
treatment failure can occur as a consequence of factor VIII adsorption to the internal surface of 
some injection equipment.

Care should be taken that no blood enters the syringe filled with product, as there is a risk that the 
blood could coagulate in the syringe and fibrin clots could therefore be administered to the 
patient. 

The AFSTYLA solution must not be diluted.

The reconstituted solution should be administered by a separate injection/infusion line by slow 
intravenous injection, at a rate comfortable to the patient, up to a maximum of 10 ml/min.

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 

7. MARKETING AUTHORISATION HOLDER

CSL Behring GmbH
Emil-von-Behring-Str. 76
35041 Marburg
Germany

8. MARKETING AUTHORIZATION NUMBER(S)

EU/1/16/1158/001
EU/1/16/1158/002
EU/1/16/1158/003
EU/1/16/1158/004
EU/1/16/1158/005
EU/1/16/1158/006
EU/1/16/1158/007

9. DATE OF FIRST AUTHORIZATION/RENEWAL OF THE AUTHORIZATION



15

Date of first authorisation: 04 January 2017

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/


16

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



17

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer of the biological active substance

CSL Behring GmbH
Emil-von-Behring Strasse 76
35041 Marburg
GERMANY

Name and address of the manufacturer responsible for batch release

CSL Behring GmbH
Emil-von-Behring Strasse 76
35041 Marburg
GERMANY

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.

The marketing authorisation holder shall submit the first periodic safety update report for this 

product within 6 months following authorisation.

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.



18

ANNEX III

LABELLING AND PACKAGE LEAFLET



19

A. LABELLING



20

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
Carton 250 IU

1. NAME OF THE MEDICINAL PRODUCT

AFSTYLA 250 IU
powder and solvent for solution for injection
Lonoctocog alfa (recombinant coagulation factor VIII)

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Lonoctocog alfa 250 IU

3. LIST OF EXCIPIENTS

Other ingredients: L-Histidine, Polysorbate 80, Calcium chloride dihydrate, Sodium chloride, 
Sucrose

4. PHARMACEUTICAL FORM AND CONTENTS

powder and solvent for solution for injection
1 vial with powder: 250 IU lonoctocog alfa (100 IU/ml after reconstitution)
1 vial with 2.5 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 5 ml syringe
1 venipuncture set
2 alcohol swabs
1 non-sterile plaster

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
For intravenous 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

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator (2 °C to 8 °C). Do not freeze.
May be stored at room temperature up to 25 °C for a single 3 months period.
Keep the vials in the outer carton in order to protect from light.



21

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

CSL Behring GmbH, 35041 Marburg, Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/16/1158/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

AFSTYLA 250 IU

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
Powder vial 250 IU

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

AFSTYLA 250 IU powder for solution for injection
Lonoctocog alfa
For intravenous use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER



23

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
Carton 500 IU

1. NAME OF THE MEDICINAL PRODUCT

AFSTYLA 500 IU
powder and solvent for solution for injection
Lonoctocog alfa (recombinant coagulation factor VIII)

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Lonoctocog alfa 500 IU

3. LIST OF EXCIPIENTS

Other ingredients: L-Histidine, Polysorbate 80, Calcium chloride dihydrate, Sodium chloride, 
Sucrose

4. PHARMACEUTICAL FORM AND CONTENTS

powder and solvent for solution for injection
1 vial with powder: 500 IU lonoctocog alfa (200 IU/ml after reconstitution)
1 vial with 2.5 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 5 ml syringe
1 venipuncture set
2 alcohol swabs
1 non-sterile plaster

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
For intravenous 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

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator (2 °C to 8 °C). Do not freeze.
May be stored at room temperature up to 25 °C for a single 3 months period.
Keep the vials in the outer carton in order to protect from light.



24

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

CSL Behring GmbH, 35041 Marburg, Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/16/1158/002

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

AFSTYLA 500 IU

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: 
SN: 
NN: 



25

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Powder vial 500 IU

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

AFSTYLA 500 IU powder for solution for injection
Lonoctocog alfa
For intravenous use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER



26

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
Carton 1000 IU

1. NAME OF THE MEDICINAL PRODUCT

AFSTYLA 1000 IU
powder and solvent for solution for injection
Lonoctocog alfa (recombinant coagulation factor VIII)

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Lonoctocog alfa 1000 IU

3. LIST OF EXCIPIENTS

Other ingredients: L-Histidine, Polysorbate 80, Calcium chloride dihydrate, Sodium chloride, 
Sucrose

4. PHARMACEUTICAL FORM AND CONTENTS

powder and solvent for solution for injection
1 vial with powder: 1000 IU lonoctocog alfa (400 IU/ml after reconstitution)
1 vial with 2.5 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 5 ml syringe
1 venipuncture set
2 alcohol swabs
1 non-sterile plaster

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
For intravenous 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

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator (2 °C to 8 °C). Do not freeze.
May be stored at room temperature up to 25 °C for a single 3 months period.
Keep the vials in the outer carton in order to protect from light.



27

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

CSL Behring GmbH, 35041 Marburg, Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/16/1158/003

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

AFSTYLA 1000 IU

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: 
SN: 
NN: 



28

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Powder vial 1000 IU

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

AFSTYLA 1000 IU powder for solution for injection
Lonoctocog alfa
For intravenous use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER



29

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
Carton 1500 IU

1. NAME OF THE MEDICINAL PRODUCT

AFSTYLA 1500 IU
powder and solvent for solution for injection
Lonoctocog alfa (recombinant coagulation factor VIII)

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Lonoctocog alfa 1500 IU

3. LIST OF EXCIPIENTS

Other ingredients: L-Histidine, Polysorbate 80, Calcium chloride dihydrate, Sodium chloride, 
Sucrose

4. PHARMACEUTICAL FORM AND CONTENTS

powder and solvent for solution for injection
1 vial with powder: 1500 IU lonoctocog alfa (300 IU/ml after reconstitution)
1 vial with 5 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 10 ml syringe
1 venipuncture set
2 alcohol swabs
1 non-sterile plaster

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
For intravenous 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

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator (2 °C to 8 °C). Do not freeze.
May be stored at room temperature up to 25 °C for a single 3 months period.
Keep the vials in the outer carton in order to protect from light.



30

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

CSL Behring GmbH, 35041 Marburg, Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/16/1158/004

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

AFSTYLA 1500 IU

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: 
SN: 
NN: 



31

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Powder vial 1500 IU

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

AFSTYLA 1500 IU powder for solution for injection
Lonoctocog alfa
For intravenous use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER



32

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
Carton 2000 IU

1. NAME OF THE MEDICINAL PRODUCT

AFSTYLA 2000 IU
powder and solvent for solution for injection
Lonoctocog alfa (recombinant coagulation factor VIII)

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Lonoctocog alfa 2000 IU

3. LIST OF EXCIPIENTS

Other ingredients: L-Histidine, Polysorbate 80, Calcium chloride dihydrate, Sodium chloride, 
Sucrose

4. PHARMACEUTICAL FORM AND CONTENTS

powder and solvent for solution for injection
1 vial with powder: 2000 IU lonoctocog alfa (400 IU/ml after reconstitution)
1 vial with 5 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 10 ml syringe
1 venipuncture set
2 alcohol swabs
1 non-sterile plaster

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
For intravenous 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

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator (2 °C to 8 °C). Do not freeze.
May be stored at room temperature up to 25 °C for a single 3 months period.
Keep the vials in the outer carton in order to protect from light.



33

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

CSL Behring GmbH, 35041 Marburg, Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/16/1158/005

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

AFSTYLA 2000 IU

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: 
SN: 
NN: 



34

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Powder vial 2000 IU

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

AFSTYLA 2000 IU powder for solution for injection
Lonoctocog alfa
For intravenous use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER



35

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
Carton 2500 IU

1. NAME OF THE MEDICINAL PRODUCT

AFSTYLA 2500 IU
powder and solvent for solution for injection
Lonoctocog alfa (recombinant coagulation factor VIII)

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Lonoctocog alfa 2500 IU

3. LIST OF EXCIPIENTS

Other ingredients: L-Histidine, Polysorbate 80, Calcium chloride dihydrate, Sodium chloride, 
Sucrose

4. PHARMACEUTICAL FORM AND CONTENTS

powder and solvent for solution for injection
1 vial with powder: 2500 IU lonoctocog alfa (500 IU/ml after reconstitution)
1 vial with 5 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 10 ml syringe
1 venipuncture set
2 alcohol swabs
1 non-sterile plaster

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
For intravenous 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

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator (2 °C to 8 °C). Do not freeze.
May be stored at room temperature up to 25 °C for a single 3 months period.
Keep the vials in the outer carton in order to protect from light.



36

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

CSL Behring GmbH, 35041 Marburg, Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/16/1158/006

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

AFSTYLA 2500 IU

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: 
SN: 
NN: 



37

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Powder vial 2500 IU

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

AFSTYLA 2500 IU powder for solution for injection
Lonoctocog alfa
For intravenous use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER



38

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
Carton 3000 IU

1. NAME OF THE MEDICINAL PRODUCT

AFSTYLA 3000 IU
powder and solvent for solution for injection
Lonoctocog alfa (recombinant coagulation factor VIII)

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Lonoctocog alfa 3000 IU

3. LIST OF EXCIPIENTS

Other ingredients: L-Histidine, Polysorbate 80, Calcium chloride dihydrate, Sodium chloride, 
Sucrose

4. PHARMACEUTICAL FORM AND CONTENTS

powder and solvent for solution for injection
1 vial with powder: 3000 IU lonoctocog alfa (600 IU/ml after reconstitution)
1 vial with 5 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 10 ml syringe
1 venipuncture set
2 alcohol swabs
1 non-sterile plaster

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
For intravenous 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

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator (2 °C to 8 °C). Do not freeze.
May be stored at room temperature up to 25 °C for a single 3 months period.
Keep the vials in the outer carton in order to protect from light.



39

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

CSL Behring GmbH, 35041 Marburg, Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/16/1158/007

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

AFSTYLA 3000 IU

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: 
SN: 
NN: 



40

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Powder vial 3000 IU

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

AFSTYLA 3000 IU powder for solution for injection
Lonoctocog alfa
For intravenous use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER



41

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Solvent vial label 2.5 ml and 5 ml

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Water for injections

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

2.5 ml [for reconstitution of strengths 250/500/1000 IU]
5 ml [for reconstitution of strengths 1500/2000/2500/3000 IU]

6. OTHER



42

PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton administration set (inner box)

1. NAME OF THE MEDICINAL PRODUCT

Administration set

2. STATEMENT OF ACTIVE SUBSTANCE(S)

-not applicable-

3. LIST OF EXCIPIENTS

-not applicable-

4. PHARMACEUTICAL FORM AND CONTENTS

-not applicable-

5. METHOD AND ROUTE(S) OF ADMINISTRATION

-not applicable-

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE REACH AND SIGHT OF CHILDREN

-not applicable-

7. OTHER SPECIAL WARNING(S), IF NECESSARY

-not applicable-

8. EXPIRY DATE

Exp. date

9. SPECIAL STORAGE CONDITIONS

-not applicable-

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

-not applicable-

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

CSL Behring

12. MARKETING AUTHORISATION NUMBER(S)

-not applicable-

13. BATCH NUMBER



43

Lot No.

14. GENERAL CLASSIFICATION FOR SUPPLY

-not applicable-

15. INSTRUCTIONS ON USE

-not applicable-

16. INFORMATION IN BRAILLE

-not applicable-



44

B. PACKAGE LEAFLET



45

Package Leaflet: Information for the user

AFSTYLA 250 IU powder and solvent for solution for injection
AFSTYLA 500 IU powder and solvent for solution for injection

AFSTYLA 1000 IU powder and solvent for solution for injection
AFSTYLA 1500 IU powder and solvent for solution for injection
AFSTYLA 2000 IU powder and solvent for solution for injection
AFSTYLA 2500 IU powder and solvent for solution for injection
AFSTYLA 3000 IU powder and solvent for solution for injection
Lonoctocog alfa (recombinant, single-chain coagulation factor VIII)

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4
for how to report side effects. 

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, 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 AFSTYLA is and what it is used for
2. What you need to know before you use AFSTYLA
3. How to use AFSTYLA
4. Possible side effects
5. How to store AFSTYLA
6. Contents of the pack and other information

1. What AFSTYLA is and what it is used for 

AFSTYLA is a human clotting (coagulation) factor VIII product that is produced by recombinant 
DNA technology. The active substance in AFSTYLA is lonoctocog alfa.

AFSTYLA is used to treat and prevent bleeding episodes in patients with haemophilia A (inborn factor 
VIII deficiency). Factor VIII is involved in blood clotting. Lack of this factor means that blood does 
not clot as quickly as it should so there is an increased tendency to bleed. AFSTYLA works by 
replacing the missing factor VIII in haemophilia A patients to enable their blood to clot normally.

AFSTYLA can be used for all age groups.

2. What you need to know before you use AFSTYLA

Do not use AFSTYLA
 if you have had an allergic reaction to AFSTYLA, or any of its ingredients (listed in section 6).
 if you are allergic to hamster proteins.

Warnings and precautions

Traceability



46

It is strongly recommended that every time AFSTYLA is given, you record the date of administration, 
the batch number and the injected volume in your treatment diary.

Talk to your doctor, pharmacist or nurse before using AFSTYLA.

 Allergic (hypersensitivity) reactions are possible. The product contain traces of hamster proteins 
(see also “Do not use AFSTYLA”). If symptoms of allergic reactions occur, stop using the 
medicine immediately and contact your doctor. Your doctor should inform you of the early 
signs of allergic reactions. These include hives, generalised skin rash, tightness of the chest, 
wheezing, fall in blood pressure and anaphylaxis (a serious allergic reaction that causes severe 
difficulty in breathing, and dizziness). 

 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 you or your child´s bleeding is not being controlled with 
AFSTYLA, tell your doctor immediately.

 If you have been told you have heart disease or are at risk for heart disease, tell your doctor or 
pharmacist.

 If you need a central venous access device (CVAD for injection of AFSTYLA), the risk of 
complications including local infections, bacteria in the blood (bacteremia) and the formation of 
a blood clot in the blood vessel (thrombosis) where the catheter is inserted should be considered 
by your doctor.

Other medicines and AFSTYLA
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, 

ask your doctor or pharmacist for advice before taking this medicine. 
 During pregnancy and breast-feeding, AFSTYLA should be given only if it is clearly needed.

Driving and using machines
AFSTYLA does not affect your ability to drive and use machines.

AFSTYLA contains sodium
AFSTYLA contains up to 7 mg (0.3 mmol) sodium per ml after reconstitution.
However depending on your body weight and your dose of AFSTYLA, you could receive more than 
one vial. This should be taken into consideration if you are on a controlled sodium diet.

3. How to use AFSTYLA

Your treatment should be monitored by a doctor who is experienced in the treatment of blood clotting
disorders.

Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure.

Dose
The amount of AFSTYLA you need to take and the duration of treatment depend on:
 the severity of your disease
 the site and intensity of the bleeding
 your clinical condition and response
 your body weight

Follow the directions given to you by your doctor.



47

Reconstitution and administration

General Instructions
 The powder must be mixed with the solvent (liquid) and withdrawn from the vial under aseptic 

conditions.
 AFSTYLA must not be mixed with other medicines or solvents except those mentioned in 

section 6.
 The solution should be clear or slightly opalescent, yellow to colourless, i.e., it might be 

sparkling when held up to the light but must not contain any obvious particles. After filtering or 
withdrawal (see below) the solution should be checked by eye, before it is used. Do not use the 
solution if it is visibly cloudy or if it contains flakes or particles.

 Any unused product or waste material should be disposed of in accordance with local 
requirements and as instructed by your doctor. 

Reconstitution and administration
Without opening the vials, warm the AFSTYLA powder and the liquid to room or body temperature. 
This can be done either by leaving the vials at room temperature for about an hour, or by holding them 
in your hands for a few minutes. 
Do not expose the vials to direct heat. The vials must not be heated above body temperature (37 °C).

Carefully remove the protective caps from the vials, and clean the exposed rubber stoppers with an 
alcohol swab. Allow the vials to dry before opening the Mix2Vial package (which contains the filter 
transfer device), then follow the instructions given below.

1

1. Open the Mix2Vial by peeling off the lid. Do not remove 
the Mix2Vial from the blister package!

2

2. Place the solvent vial on an even, clean surface and hold 
the vial tight. Take the Mix2Vial together with the blister 
package and push the spike of the blue adapter end 
straight down through the solvent vial stopper.

3

3. Carefully remove the blister package from the Mix2Vial 
set by holding at the rim, and pulling vertically upwards. 
Make sure that you only pull away the blister package and 
not the Mix2Vial set.

4

4. Place the powder vial on an even and firm surface. Invert 
the solvent vial with the Mix2Vial set attached and push 
the spike of the transparent adapter end straight down
through the powder vial stopper. The solvent will 
automatically flow into the powder vial.



48

5

5. With one hand grasp the product-side of the Mix2Vial set 
and with the other hand grasp the solvent-side and 
unscrew the set carefully counterclockwise into two 
pieces.
Discard the solvent vial with the blue Mix2Vial adapter 
attached.

6

6. Gently swirl the product vial with the transparent adapter 
attached until the substance is fully dissolved. Do not 
shake.

7

7. Draw air into an empty, sterile syringe. While the product 
vial is upright, connect the syringe to the Mix2Vial's Luer 
Lock fitting by screwing clockwise. Inject air into the 
product vial.

Withdrawal and administration

8

8. While keeping the syringe plunger pressed, turn the 
system upside down and draw the solution into the syringe 
by pulling the plunger back slowly.

9

9. Now that the solution has been transferred into the 
syringe, firmly hold on to the barrel of the syringe 
(keeping the syringe plunger facing down) and disconnect 
the transparent Mix2Vial adapter from the syringe by 
unscrewing counterclockwise.

Use the venipuncture kit supplied with the product, insert the needle into a vein. Let blood flow back 
to the end of the tube. Attach the syringe to the threaded, locking end of the venipuncture kit. Inject
the reconstituted solution slowly (as comfortable for you, up to a maximum of 10 ml/min) into 
the vein following the instructions given to you by your doctor. Take care not to get any blood in the 
syringe containing the product.

Check yourself for any side effects that might happen straight away. If you have any side effects that 
might be related to the administration of AFSTYLA, the injection should be stopped (see also section 
2).



49

Use in children and adolescents
AFSTYLA can be used in children and adolescents of all ages. In children below the age of 12 higher 
doses or more frequent injections may be needed. Children above 12 years of age can use the same 
dose as adults.

If you use more AFSTYLA than you should
If you have injected more AFSTYLA than you should, please inform your doctor.

If you forget to use AFSTYLA
Do not take a double dose to make up for a forgotten dose. Proceed with the next dose immediately 
and continue as advised by your doctor or pharmacist.

If you stop using AFSTYLA
If you stop using AFSTYLA you may no longer be protected against bleeding or a current bleed may 
not stop. Do not stop using AFSTYLA 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, AFSTYLA can cause side effects, although not everybody gets them.

Please stop using the medicine immediately and contact your doctor if:
 you notice symptoms of allergic reactions 

Allergic reactions may include the following symptoms: hives, generalised urticaria (itchy rash), 
tightness of the chest, difficulty in breathing, wheezing, low blood pressure, dizziness, and 
anaphylaxis. If this happens, you should stop using the medicine immediately and contact your
doctor.

 you notice that the medicine stops working properly (bleeding is not stopped)
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 you 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.

Common side effects (may affect up to 1 in 10 users)
 allergic reaction
 dizziness
 tingling or numbness (paraesthesia)
 rash
 fever

Uncommon side effects (may affect up to 1 in 100 users)
 itching
 redness of the skin
 pain at the injection site 
 chills
 feeling hot

Side effects in children and adolescents
No age-specific differences in adverse reactions were observed between children, adolescents and 
adult subjects.



50

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. 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 AFSTYLA

 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 label and carton.
 Store in a refrigerator (2 °C to 8 °C).
 Before the AFSTYLA powder is reconstituted it may be kept at room temperature (below 

25 °C) for a single period not exceeding 3 months, within the expiration date printed on the 
cartons and the vials. Please record the date from when you start to store AFSTYLA at room 
temperature on the product carton.

 Once the product has been taken out of the refrigerator, the product must not be returned to the 
refrigerator.

 Do not freeze.
 Keep the vial in the outer carton in order to protect from light.
 The reconstituted product should preferably be used immediately.
 If the reconstituted product is not administered immediately, storage times and conditions prior 

to use are in the responsibility of the user.

6. Contents of the pack and other information

What AFSTYLA contains

The active substance is:
250 IU per vial; after reconstitution with 2.5 ml of water for injections the solution contains 100 IU/ml 
of lonoctocog alfa.
500 IU per vial; after reconstitution with 2.5 ml of water for injections the solution contains 200 IU/ml 
of lonoctocog alfa.
1000 IU per vial; after reconstitution with 2.5 ml of water for injections the solution contains 
400 IU/ml of lonoctocog alfa.
1500 IU per vial; after reconstitution with 5 ml of water for injections the solution contains 300 IU/ml 
of lonoctocog alfa.
2000 IU per vial; after reconstitution with 5 ml of water for injections the solution contains 400 IU/ml 
of lonoctocog alfa.
2500 IU per vial; after reconstitution with 5 ml of water for injections the solution contains 500 IU/ml 
of lonoctocog alfa.
3000 IU per vial; after reconstitution with 5 ml of water for injections the solution contains 600 IU/ml 
of lonoctocog alfa.

The other ingredients are:
L-Histidine, polysorbate 80, calcium chloride dihydrate, sodium chloride (see last paragraph of 
section 2), sucrose.

Solvent: Water for injections.

What AFSTYLA looks like and contents of the pack

AFSTYLA is presented as white or slightly yellow powder or friable mass and clear, colourless 
solvent for solution for injection.

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


51

The reconstituted solution should be clear to slightly opalescent, yellow to colourless i.e., it might 
sparkle when held up to the light but must not contain any obvious particles. 

Presentations
One pack with 250, 500 or 1000 IU containing:
1 vial with powder
1 vial with 2.5 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 5 ml syringe
1 venipuncture set
2 alcohol swabs
1 non- sterile plaster

One pack with 1500, 2000, 2500 or 3000 IU containing:
1 vial with powder
1 vial with 5 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 10 ml syringe
1 venipuncture set
2 alcohol swabs
1 non- sterile plaster

Not all pack sizes may be marketed.

Immediate containers

250 IU Glass vial with a rubber stopper, an orange plastic disc, and a green striped aluminium cap
500 IU Glass vial with a rubber stopper, a blue plastic disc, and a green striped aluminium cap
1000 IU Glass vial with a rubber stopper, a green plastic disc, and a green striped aluminium cap
1500 IU Glass vial with a rubber stopper, a turquoise plastic disc, and a green striped aluminium cap
2000 IU Glass vial with a rubber stopper, a purple plastic disc, and a green striped aluminium cap
2500 IU Glass vial with a rubber stopper, a light grey plastic disc, and a green striped aluminium cap
3000 IU Glass vial with a rubber stopper, a yellow plastic disc, and a green striped aluminium cap

Marketing Authorization Holder and Manufacturer

CSL Behring GmbH
Emil-von-Behring-Straße 76
35041 Marburg
Germany

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

België/Belgique/Belgien
CSL Behring NV
Tél/Tel: +32 15 28 89 20

Lietuva
CSL Behring GmbH
Tel: +49 69 30584437

България
Ей енд Ди Фарма България ЕАД
Тел: +359 2 810 3949

Luxembourg/Luxemburg
CSL Behring NV
Tél/Tel: +32 15 28 89 20



52

Česká republika
CSL Behring s.r.o.
Tel: + 420 702 137 233

Magyarország
CSL Behring Kft.
Tel.: +36 1 213 4290

Danmark
CSL Behring AB
Tel: +46 8 544 966 70

Malta
AM Mangion Ltd.
Tel: +356 2397 6333

Deutschland
CSL Behring GmbH
Tel: +49 69 30584437

Nederland
CSL Behring BV
Tel: + 31 85 111 96 00

Eesti
CSL Behring GmbH
Tel: +49 69 30584437

Norge
CSL Behring AB
Tlf: +46 8 544 966 70

Ελλάδα
CSL Behring ΕΠΕ
Τηλ: +30 210 7255 660

Österreich
CSL Behring GmbH
Tel: +43 1 80101 2463

España
CSL Behring S.A.
Tel: +34 933 67 1870

Polska
CSL Behring Sp.z o.o.
Tel: +48 22 213 22 65

France
CSL Behring S.A.
Tél: + 33 –(0)-1 53 58 54 00

Portugal
CSL Behring Lda
Tel: +351 21 782 62 30

Hrvatska 
Marti Farm d.o.o.
Tel: +385 1 5588297

România
Prisum International Trading srl
Tel: +40 21 322 0171

Ireland
CSL Behring GmbH
Tel: +49 69 30517254

Slovenija
MediSanus d.o.o.
Tel: +386 1 25 71 496

Ísland
CSL Behring AB
Sími: +46 8 544 966 70

Slovenská republika
CSL Behring s.r.o.
Tel: +421 911 653 862

Italia
CSL Behring S.p.A.
Tel: +39 02 34964 200

Suomi/Finland
CSL Behring AB
Puh/Tel: +46 8 544 966 70

Κύπρος
CSL Behring ΕΠΕ
Τηλ: +30 210 7255 660

Sverige
CSL Behring AB
Tel: +46 8 544 966 70

Latvija
CSL Behring GmbH
Tel: +49 69 30584437

United Kingdom
CSL Behring UK Ltd.
Tel: +44 1444 447405

This leaflet was last revised in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

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


53

----------------------------------------------------------------------------------------------------------

The following information is intended for healthcare professionals only:

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 injections. Individual patients may vary 
in their responses 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.

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 according to Ph. Eur. This is of importance 
particularly when changing the laboratory and/or reagents used in the assay.

Plasma factor VIII activity in patients receiving AFSTYLA using either the chromogenic assay or 
the one-stage clotting assay should be monitored to guide the dose administered and the frequency 
of repeat injections. The chromogenic assay result most accurately reflects the clinical hemostatic 
potential of AFSTYLA and is preferred. The one-stage clotting assay result underestimates the 
factor VIII activity level compared to the chromogenic assay result by approximately 45%. If the 
one-stage clotting assay is used, multiply the result by a conversion factor of 2 to determine the 
patient’s factor VIII activity level. 

Posology
The dose and duration of the substitution therapy depend on the severity of the factor VIII 
deficiency, on the location and extent of the bleeding and on the patient's clinical condition. 

The number of units of factor VIII administered is expressed in International Units (IU), which 
are related to the current WHO concentrate standard for factor VIII products. Factor VIII activity 
in plasma is expressed either as a percentage (relative to normal human plasma) or in preferably 
International Units (relative to an International Standard for factor VIII in plasma).

One International Unit (IU) of factor VIII activity is equivalent to that quantity of factor VIII in 
one ml of normal human plasma.

Potency assignment is determined using a chromogenic substrate assay.
Plasma factor VIII levels can be monitored using either a chromogenic substrate assay or a one-stage 
clotting assay.

On demand treatment
The calculation of the required dose of factor VIII is based on the empirical finding that 1 
International Unit (IU) 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:

Dose (IU) = body weight (kg) x Desired factor VIII rise (IU/dl or % of normal) x 0.5 (IU/kg per 
IU/dl)

The amount to be administered and the frequency of administration should always be oriented to 
the clinical effectiveness in the individual case.



54

In the case of the following haemorrhagic events, the factor VIII activity should not fall below the 
given plasma activity level (in % of normal or IU/dl) within 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 (%) (IU/dl)

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

Haemorrhage
Early haemarthrosis, 
muscle bleeding or oral 
bleeding

20 - 40 Repeat injection every 12 to 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 injection every 12 to 24 
hours for 3-4 days or more until 
pain and acute disability are 
resolved.

Life threatening 
haemorrhages

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

Surgery
Minor surgery including 
tooth extraction

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

Major surgery 80 - 100 
(pre- and
postoperative)

Repeat injection every 8 to 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
The recommended starting regimen is 20 to 50 IU/kg of AFSTYLA administered 2 to 3 times 
weekly. The regimen may be adjusted based on patient response.

Paediatric population
The recommended starting regimen in children (0 to <12 years of age) is 30 to 50 IU per kg of 
AFSTYLA administered 2 to 3 times weekly. More frequent or higher doses may be required in 
children <12 years of age to account for the higher clearance in this age group. 
For adolescents of 12 years of age and above, the dose recommendations are the same as for 
adults.

Elderly
Clinical studies of AFSTYLA did not include subjects over 65 years of age.


	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