ADYNOVATE, Antihemophilic Factor (Recombinant), PEGylated, is a human antihemophilic factor
indicated in children and adults with hemophilia A (congenital factor VIII deficiency) for:
- On-demand treatment and control of bleeding episodes
- Perioperative management
- Routine prophylaxis to reduce the frequency of bleeding episodes
Limitation of Use
ADYNOVATE is not indicated for the treatment of von Willebrand disease.

For intravenous use after reconstitution only.
• Each vial label of ADYNOVATE states the actual factor VIII potency in international units. This may be
more or less than the nominal vial potency/content. One international unit corresponds to the activity of factor
VIII contained in one milliliter of normal human plasma.
• Dosage and duration of treatment depend on the severity of factor VIII deficiency, the location and extent of
the bleeding, and the patient’s clinical condition. Careful monitoring of replacement therapy is necessary in
cases of serious or life-threatening bleeding episodes.
• Potency assignment is determined using a one-stage clotting assay. Plasma factor VIII levels can be
monitored clinically using a one-stage clotting assay.
• Calculate the dose of ADYNOVATE based on the empirical finding that one international unit of
ADYNOVATE per kg body weight increases the plasma factor VIII level by 2 IU per dL of plasma. Use the
following formula to estimate the expected in vivo peak increase in factor VIII level expressed as IU per dL
(or % of normal) and the dose to achieve a desired in vivo peak increase in factor VIII level:
Estimated Increment of factor VIII (IU/dL or % of normal) = [Total Dose (IU)/body weight (kg)] x 2 (IU/dL
per IU/kg)
Dose (IU) = Body Weight (kg) x Desired factor VIII Rise (IU/dL or % of Normal) x 0.5 (IU/kg per IU/dL)
• Patients vary in their pharmacokinetic (e.g., clearance, half-life, in vivo recovery) and clinical response.
Base the dose and frequency of ADYNOVATE on the individual clinical response.
On-demand Treatment and Control of Bleeding Episodes
A guide for dosing of ADYNOVATE for the on-demand treatment and control of bleeding episodes is
provided in Table 1. Maintain plasma factor VIII activity level at or above the described plasma levels (in IU
per dL or % of normal).
Perioperative Management
A guide for dosing ADYNOVATE during surgery (perioperative management) is provided in Table 2.
Consideration should be given to maintain a factor VIII activity at or above the target range.
Type of bleeding Target Factor
VIII level
( % of normal
or IU/dL)
Dose*
(IU/kg)
Frequency of dosing
(hours)
Duration of
therapy
Minor
Including tooth extraction
60-100
30-50
Within one hour
before surgery.
Repeat after 24 hours
if necessary
Single dose or
repeat as needed
until bleeding is
resolved
Major
Intracranial, intra-abdominal, 80-120 40-60 Within one hour Until adequate
or intrathoracic surgery, joint (pre- and before the operation wound healing
replacement surgery postoperative) to achieve 100%
activity.
Repeat every 8 to 24
hours (6 to 24
hours for patients
<12 years of age)
to maintain FVIII
activity within the
target range
Type of bleeding Target Factor VIII
level
(IU/dl or % of normal)
Dose*
(IU/kg
)
Frequency of
dosing (hours)
Duration of
therapy
Minor
Early hemarthrosis, mild muscle
bleeding, or mild oral bleeding
episode.
20-40
10-20
12-24
Until bleeding is
resolved
Moderate
Muscle bleeding, moderate bleeding
into the oral cavity, definite
hemarthroses, and known trauma.
30-60
15-30
12-24
Until bleeding is
resolved
Major
Significant gastrointestinal bleeding,
intracranial, intra-abdominal or
intrathoracic bleeding, central nervous
system bleeding, bleeding in the
retropharyngeal or retroperitoneal
spaces or iliopsoas sheath, fractures,
head trauma.
60-100
30-50
8-24
Until bleeding is
resolved
Routine Prophylaxis
Administer 40-50 IU per kg body weight 2 times per week in children and adults (12 years and older).
Administer 55 IU per kg body weight 2 times per week in children (<12 years) with a maximum of 70 IU per
kg. Adjust the dose based on the patient’s clinical response.
Method of Administration
ADYNOVATE is for intravenous use.
ADYNOVATE should be administered at room temperature not more than 3 hours after reconstitution.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Hypersensitivity:
Hypersensitivity reactions are possible with ADYNOVATE. Allergic-type hypersensitivity reactions,
including anaphylaxis, have been reported with other recombinant antihemophilic factor VIII
products, including the parent molecule, ADVATE. Early signs of hypersensitivity reactions that can
progress to anaphylaxis may include angioedema, chest tightness, dyspnea, wheezing, urticaria, and
pruritus. Immediately discontinue administration and initiate appropriate treatment if hypersensitivity
reactions occur.
• Neutralizing Antibodies:
Formation of neutralizing antibodies (inhibitors) to factor VIII can occur following administration of
ADYNOVATE. Monitor patients regularly for the development of factor VIII inhibitors by
appropriate clinical observations and laboratory tests. Perform an assay that measures factor VIII
inhibitor concentration if the plasma factor VIII level fails to increase as expected, or if bleeding is
not controlled with expected dose
• Monitoring Laboratory Tests:
• Monitor plasma factor VIII activity by performing a validated one-stage clotting assay to confirm
the adequate factor VIII levels have been achieved and maintained.
• Monitor for the development of factor VIII inhibitors. Perform the Bethesda inhibitor assay to
determine if factor VIII inhibitor is present. If expected factor VIII activity plasma levels are not
attained, or if bleeding is not controlled with the expected dose of ADYNOVATE, use Bethesda
Units (BU) to determine inhibitor levels.

No interaction studies have been performed with ADYNOVATE.

Pregnancy
There are no data with ADYNOVATE use in pregnant women to inform a drug-associated risk.
Animal reproduction studies have not been conducted with ADYNOVATE. It is unknown whether
ADYNOVATE can cause fetal harm when administered to a pregnant woman or can affect reproduction
capacity. ADYNOVATE should be given to a pregnant woman only if clearly needed. In the U.S. general
population, the estimated background risk of major birth defect and miscarriage in clinically recognized
pregnancies is 2-4% and 15-20%, respectively.
Lactation
There is no information regarding the presence of ADYNOVATE in human milk, the effect on the breastfed
infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be
considered along with the mother’s clinical need for ADYNOVATE and any potential adverse effects on the
breastfed infant from ADYNOVATE or from the underlying maternal condition.

ADYNOVI has no influence on the ability to drive and use machines.

The most common adverse reactions (≥1% of subjects) reported in the clinical studies were headache and
nausea.
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not
reflect the rates observed in practice.
The safety of ADYNOVATE was evaluated in 237 previously treated patients (PTPs) and 6 previously
untreated patients (PUPs) with severe hemophilia A (factor VIII less than 1% of normal), who received at
least one dose of ADYNOVATE in 3 completed multi-center, prospective, open label clinical studies and 4
ongoing clinical studies. The median duration of participation per subject was 401 (min-max: 3-1034) days
and the median number of exposure days to ADYNOVATE per subject was 111 (min-max: 1-322). Table 3
lists the adverse reactions reported during clinical studies.
Immunogenicity
The risk of the development of factor VIII inhibitors with the use of ADYNOVATE was evaluated in 3
completed and 4 ongoing clinical trials. Subjects consisted of adolescent and adult (n=148 with ≥150 prior
EDs) and pediatric PTPs [(<6 years of age with ≥50 prior EDs (n=32), ≥6 years of age with ≥150 prior EDs
(n=57)], and pediatric PUPs (n=6). In 191 adult and pediatric PTPs who were treated for at least 50 exposure
days with ADYNOVATE, the factor VIII inhibitor frequency was 0 (95% CI of 0 to 0.019). One PUP subject
from an ongoing study, who received at least one infusion of ADYNOVATE, developed neutralizing
antibodies to factor VIII. Immunogenicity also was evaluated by measuring the development of binding IgG
and IgM antibodies against factor VIII, PEGylated (PEG)-factor VIII, PEG and Chinese hamster ovary
(CHO) protein using validated ELISA assays. The majority of subjects (238/243) with at least one infusion of
ADYNOVATE did not develop a persistent binding antibody response to any of these antigens. Twenty-eight
subjects in total showed pre-existing antibodies to factor VIII (n=3), PEG-factor VIII (n=25) and/or PEG
(n=3) prior to the first exposure to ADYNOVATE.
Thirteen subjects who tested negative at screening developed transient antibodies against factor VIII (n=6),
PEG-FVIII (n=8) at one or two consecutive study visits. Antibodies were transient and not detectable at
subsequent visits. Five subjects showed positive results for binding antibodies at study completion or at the
time of data cutoff. Binding antibodies that were detected prior to exposure to ADYNOVATE, that transiently
developed during the trial or were still detectable at study completion or data cutoff could not be correlated to
any impaired treatment efficacy or altered PK parameters. There was no causal relationship between observed
adverse events and binding antibodies except in one subject where a causal relationship cannot be ruled out
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based on available data. No subject had pre-existing or treatment-emergent antibodies to CHO protein. The
detection of antibodies that are reactive to factor VIII is highly dependent on many factors, including: the
sensitivity and specificity of the assay, sample handling, timing of sample collection, concomitant
medications and underlying disease. For these reasons, comparison of the incidence of antibodies to
ADYNOVATE with the incidence of antibodies to other products may be misleading.

No symptoms of overdose with recombinant coagulation factor VIII have been reported.

Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor VIII, ATC code: B02BD02.
Hemophilia A is a disorder characterized by a deficiency of functional coagulation factor VIII, resulting in a
prolonged, patient plasma clotting time as measured by the activated partial thromboplastin time (aPTT).
Treatment with ADYNOVATE normalizes the aPTT over the effective dosing period. The administration of
ADYNOVATE increases plasma levels of factor VIII and can temporarily correct the coagulation defect in
hemophilia A patients.
Original Safety and Efficacy Clinical Trial
The safety, efficacy, and PK of ADYNOVATE were evaluated in a multicenter, open-label, prospective, nonrandomized,
two-arm clinical trial that compared the efficacy of a twice weekly prophylactic treatment
regimen to on-demand treatment and determined hemostatic efficacy in the treatment of bleeding episodes. A
total of 137 male PTPs (12 to 65 years of age) with severe hemophilia A received at least one infusion with
ADYNOVATE. Twenty-five of the 137 subjects were adolescents (12 to less than 18 years of age).
Subjects received either prophylactic treatment (n = 120) with ADYNOVATE at a dose of 40-50 IU per kg
twice weekly or on-demand treatment (n = 17) with ADYNOVATE at a dose of 10-60 IU per kg for a 6-
month period. The mean (SD) dose per prophylaxis infusion was 44.4 (3.9) IU per kg with a median dosing
interval of 3.6 days. There were 91 out of 98 (93%) subjects previously treated prophylactically prior to
enrollment, who experienced a reduction in dosing frequency during routine prophylaxis in the trial, with a
median reduction of 33.7% (approximately one more day between doses). One hundred eighteen of 120
(98%) prophylaxis subjects remained on the starting recommended regimen without dose adjustment, and 2
subjects increased their dose to 60 IU/kg during prophylaxis due to bleeding in target joints.
On-demand Treatment and Control of Bleeding Episodes
A total of 518 bleeding episodes were treated with ADYNOVATE in the per-protocol population, i.e. dosed
according to the protocol specific dosing requirements. Of these, 361 bleeding episodes (n=17 subjects)
occurred in the on-demand arm and 157 (n=61 subjects) occurred in the prophylaxis arm. The median dose
per infusion to treat all bleeding episodes in the per-protocol population was 29 (Q1: 20.0; Q3: 39.2) IU per
kg. The median dose per infusion to treat a minor, moderate, or severe/major bleeding episode in the perprotocol
population was 25.5 (Q1: 16.9; Q3: 37.6) IU/kg, 30.9 (Q1: 23.0; Q3: 43.1) IU/kg, or 36.4 (Q1: 29.0;
Q3: 44.5)IU/kg, respectively.
Routine Prophylaxis
A total of 120 subjects (treated population) received a twice a week regimen in the prophylaxis arm, and an
additional 17 subjects were treated episodically in the on-demand arm. In the treated population, the median
[mean] annualized bleed rate (ABR) in the on-demand treatment arm was 41.5 [40.8] compared to 1.9 [4.7]
while on a twice a week prophylaxis regimen (Table 6). In the per-protocol population, the median [mean]
annualized bleed rate (ABR) in the on-demand treatment arm was 41.5 [40.8] compared to 1.9 [3.7] while on
a twice a week prophylaxis regimen. Using a negative binomial model to estimate the ABR, there was a
significant reduction in the ABR (p <0.0001) for subjects in the prophylaxis arm compared to the on-demand
arm.
In the treated population, the median [mean] ABR for the 23 adolescent subjects age 12 to <18 years of age
on routine prophylaxis was 2.1 [5.2] compared to a median [mean] ABR of 1.9 [4.6] for the 97 subjects 18
years and older. Reduction in ABR between the treatment arms was observed regardless of baseline
subgroups examined, including age, presence or absence of target joints, and pre-trial treatment regimen. The
majority of the bleeding episodes during prophylaxis (95%) were of minor/moderate severity. Forty-five out
of 120 subjects (38%) experienced no bleeding episodes and 68 out of 120 subjects (57%) experienced no
joint bleeding episodes in the prophylaxis arm. Of those subjects who were compliant to regimen (perprotocol
population), 40 out of 101 subjects (40%) experienced no bleeding episodes. All subjects in the ondemand
arm experienced a bleeding episode, including a joint bleeding episode.
Routine Prophylaxis Clinical Trial in Pediatric Subjects (<12 years of age)
The safety and efficacy of ADYNOVATE was evaluated in a total of 73 pediatric PTPs with severe
hemophilia A, of which 66 subjects were dosed (32 subjects aged <6 years and 34 subjects aged 6 to <12
years) in a separate pediatric clinical trial. The prophylactic regimen was 40 to 60 IU/kg of ADYNOVATE
twice a week, with a mean (SD) dose of 51.1 IU/kg. The median [mean] overall ABR was 2.0 [3.61] for the
66 subjects in the treated population and the median [mean] ABRs for spontaneous and joint bleeding
episodes were both 0. Of the 66 subjects treated prophylactically, 25 (38%) experienced no bleeding episodes,
44 (67%) experienced no spontaneous bleeding episodes, and 48 (73%) experienced no joint bleeding
episodes.
Of the 70 bleeding episodes observed during the pediatric trial, 82.9% were controlled with 1 infusion and
91.4% were controlled with 1 or 2 infusions. Control of bleeding was rated excellent or good in 63 out of 70
(90%) bleeding episodes. The definitions of excellent or good in the pediatric clinical trial were unchanged as
compared to the previously conducted prophylaxis clinical trial in adolescent and adult subjects.
Perioperative Management Clinical Trial
Eleven major surgical procedures (3 knee replacements, 2 arthroscopic synovectomies, 1 cyst extirpation, 1
port placement, 1 gastric band placement, and 3 multiple tooth extractions including 1 radicular cyst removal)
and 4 additional minor surgeries (1 synoviorthesis, 1 radiosynovectomy, 1 tooth extraction, 1 dermatological
surgery) were performed in 15 subjects. The preoperative loading dose ranged from 36 IU/kg to 99 IU/kg
(median: 65 IU/kg) and the total postoperative dose ranged from 177 IU/kg to 769 IU/kg (median: 305
IU/kg). The median total dose for major surgeries was 362 IU/kg (range: 237-863 IU/kg) and the median total
dose for minor surgeries was 97 IU/kg (range: 73-119 IU/kg).
Perioperative hemostatic efficacy was rated as excellent (blood loss less than or equal to that expected for the
same type of procedure performed in a non-hemophilic patient, and required blood components for
transfusions less than or similar to that expected in non-hemophilic population) for all 15 (11 major, 4 minor)
procedures. The median (QR) observed intraoperative blood loss (n=10) was 10.0 (Q1: 5.0, Q3: 50.0) mL
compared to the predicted average blood loss (n=11) of 50.0 (Q1: 6.0, Q3: 150.0) mL for major surgeries

The pharmacokinetics (PK) of ADYNOVATE were evaluated in a multi-center, prospective, open label
clinical trial and compared with ADVATE in 26 subjects prior to initiation of prophylactic treatment with
ADYNOVATE and in 22 subjects after 6 months of treatment with ADYNOVATE. A single dose of 45
IU/kg was utilized for both products. The PK parameters, as shown in Table 4, were based on plasma
coagulation factor VIII activity measured by the one-stage clotting assay and are presented by age groups.
Incremental recovery was comparable between both products. The PK parameters determined after 6 months
of prophylactic treatment with ADYNOVATE were consistent with
the initial parameter estimates.
Pediatric Pharmacokinetics
Pharmacokinetic parameters calculated from 39 subjects <18 years of age (intent-to-treat analysis) are
available for 14 children (2 to <6 years), 17 older children (6 to <12 years) and 8 adolescent subjects (12 to
<18 years of age), as shown in Table 4. The mean clearance (based on body weight) of ADYNOVATE was
higher and the mean half-life was lower in children <12 years of age than adults. A dose adjustment may be
required in children <12 years of age.

Long-term studies in animals to evaluate the carcinogenic potential of ADYNOVATE or studies to determine
the effects of ADYNOVATE on genotoxicity or fertility have not been performed.

Stabilizer and Excipient 5ml
Reconstitution
Target (per ml)
Tris(hydroxymethyl)aminomethane 1.22 mg
Calcium chloride 0.24mg
Mannitol 32 mg
Sodium chloride 5.26 mg
Trehalose dihydrate 8 mg
Glutathione 0.08 mg
Histidine 1.56 mg
Polysorbate 80 0.10 mg
Solvent:
Sterilized water for injection 5 ml

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.

Store ADYNOVATE in powder form refrigerated (2°C to 8 °C). Do not freeze.
ADYNOVATE with BAXJECT II Hi-Flow device: Keep the vial in the outer carton in order to protect from
light.
For storage conditions after reconstitution of the medicinal product, see section 6.3.

Type I glass vial, closed with a chlorobutyl rubber stopper, containing 250 IU, 500 IU or 1000 IU of powder.
Type I glass vial, closed with a chlorobutyl rubber stopper, containing 5 ml of sterilized water for injections.
The medicinal product is provided the following configuration:
- ADYNOVATE with BAXJECT II Hi-Flow device: Each pack contains a powder vial, a solvent vial and a
device for reconstitution (BAXJECT II Hi-Flow).

Preparation
• Do not remove ADYNOVATE or diluent vials from the external housing.
• Examine the packaging containing ADYNOVATE to ensure no damage or peeling of the lid is evident. Do
not use if the lid is not completely sealed on the blister.
• Use aseptic technique (clean and germ free) and a flat work surface during the reconstitution procedure.
Reconstitution
1. Allow the vials of ADYNOVATE and diluent to reach room temperature before use.
2. Remove plastic caps from the ADYNOVATE and diluent vials.
3. Cleanse rubber stoppers with a sterile alcohol prep pad and allow to dry prior to use.
4. Open the BAXJECT II Hi-Flow device package by peeling away the lid, without touching the inside
(Figure A). Do not remove the device from the package.
Figure A
5. Turn the package over. Press straight down to fully insert the clear plastic spike through the diluent vial
stopper (Figure B).
Figure B
6. Grip the BAXJECT II Hi-Flow package at its edge and pull the package off the device (Figure C). Do not
remove the blue cap from the BAXJECT II Hi-Flow device. Do not touch the exposed purple plastic spike.
Figure C
7. Turn the system over so that the diluent vial is on top. Quickly insert the purple plastic spike fully into the
ADYNOVATE vial stopper by pushing straight down (Figure D). The vacuum will draw the diluent into the
ADYNOVATE vial.
Figure D
8. Swirl gently until ADYNOVATE is completely dissolved. Do not refrigerate after reconstitution.
9. If the dose requires more than one vial of ADYNOVATE, reconstitute each vial using the above steps. Use
a different BAXJECT II Hi-Flow device to reconstitute each vial of ADYNOVATE and diluent.
Administration
• Visually inspect the reconstituted ADYNOVATE solution for particulate matter and discoloration prior to
administration, whenever solution and container permit. The final ADYNOVATE solution should be clear
and colorless. Do not use if particulate matter or discoloration is observed.
• Administer ADYNOVATE as soon as possible, but no later than 3 hours after reconstitution.
Administration Steps:
1. Remove the blue cap from the BAXJECT II Hi-Flow device. Connect the syringe to the BAXJECT II Hi-
Flow device (Figure E). Use of a Luer-lock syringe is recommended. Do not inject air.
Figure E
2. Turn the system upside down (ADYNOVATE vial now on top). Draw the factor concentrate into the
syringe by pulling the plunger back slowly
(Figure F).
Figure F
3. If a patient is to receive more than one vial of ADYNOVATE, the contents of multiple vials may be drawn
into the same syringe.
4. Disconnect the syringe; attach a suitable needle.
5. Inject ADYNOVATE intravenously over a period of less than or equal to 5 minutes (maximum infusion
rate 10 mL per min).