Adynovate Kit
FDA Label NDC 0944-4628

ADYNOVATE^® is indicated in adult and pediatric patients 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.

Limitations 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)] × 2 (IU/dL per IU/kg)

Dose (IU) = Body Weight (kg) × Desired factor VIII Rise (IU/dL or % of Normal) × 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.

Routine Prophylaxis

• Administer 40-50 IU/kg body weight twice weekly in adults and adolescents (12 years and older).
• Administer 55 IU per kg body weight two times per week in children (<12 years) with a maximum of 70 IU/kg.
• Adjust the dose and dosing intervals based on the patient’s clinical response.

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

• Allow the ADYNOVATE package to reach room temperature before use.
• Open the package by peeling away the lid. Remove ADYNOVATE from the package and verify that the expiration date on the label has not passed and the potency unit number is same as expected. Inspect parenteral drug products for discoloration and particulate matter. The ADYNOVATE powder should be white to off-white in color and the diluent free from foreign particles. Do not use if the criteria are not met.
• Place the ADYNOVATE on a flat surface with the diluent vial on top (Figure A). The diluent vial has a blue stripe. Do not remove the blue cap until instructed in a later step.

  Figure A

  Figure A (Adynovate 01)

• With one hand holding the ADYNOVATE housing, press down firmly on the diluent vial with the other hand until the system is fully collapsed and the diluent flows down into the ADYNOVATE vial (Figure B). Do not tilt the system until the transfer is complete.

  Figure B

  Figure B (Adynovate 02)

• Verify that diluent transfer is complete. Swirl gently until the powder is completely dissolved (Figure C). Do not shake. Do not refrigerate after reconstitution.

  Figure C

  Figure C (Adynovate 03)

Administration Steps:

• Remove the blue cap from the housing. Connect the syringe to the system (Figure D). Do not inject air into the ADYNOVATE.

  Figure D

  Figure D (Adynovate 04)

• Turn the system upside down (ADYNOVATE vial now on top). Draw the ADYNOVATE solution into the syringe by pulling the plunger back slowly (Figure E).

  Figure E

  Figure E (Adynovate 05)

• Disconnect the syringe, attach a suitable needle, and inject intravenously as instructed. If a patient is to receive more than one ADYNOVATE -BAXJECT^® III system or a combination of an ADYNOVATE -BAXJECT II and an ADYNOVATE -BAXJECT III system, the contents may be drawn into the same syringe.
• Administer ADYNOVATE intravenously over a period of less than or equal to 5 minutes (maximum infusion rate 10 mL per min).

Risk Summary

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.

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.

Risk Summary

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.

Pediatric Pharmacokinetics

Pharmacokinetic parameters calculated from 39 patients <18 years of age (intent-to-treat analysis) are available for 14 children (2 to <6 years), 17 older children (6 to <12 years) from Study 2 [see Clinical Studies (14)] and 8 adolescent patients (12 to <18 years of age) from Study 1 [see Clinical Studies (14)], 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.

Table 4: Pharmacokinetic Parameters (Arithmetic Mean ± SD)

PK Parameters	Pediatric Population PK with Sparse Sampling Population PK model with 3 post-infusion samples based on randomized drawing schedule.		Adult and Adolescent Individual PK with Full Sampling Individual PK with 12 post-infusion samples.
	<6 years N=14	6 to <12 years N=17	12 to <18 years N = 8	≥18 years N = 18
Abbreviations: MRT: mean residence time; CL: clearance; CI: confidence interval; AUC: area under the curve; Vss: body weight adjusted volume of distribution at steady-state; Cmax: maximum observed activity; Tmax: time to reach the maximum concentration.
Terminal half-life [h]	11.8 ± 2.43	12.4 ± 1.67	13.43 ± 4.05	14.69 ± 3.79
MRT [h]	17.0 ± 3.50	17.8 ± 2.42	17.96 ± 5.49	20.27 ± 5.23
CL [mL/(kg∙h)]	3.53 ± 1.29	3.11 ± 0.76	3.87 ± 3.31 (2.73 ± 0.93) Estimated mean and SD calculated not including one patient whose clearance estimate was 11.8 mL/(kg.h). Median including all patients is 2.78 mL/(kg.h).	2.27 ± 0.84
Incremental Recovery [(IU/dL)/(IU/kg)]	1.89 ± 0.49	1.95 ± 0.47	2.12 ± 0.60	2.66 ± 0.68
AUC0-Inf [IU∙h/dL]	1947 ± 757	2012 ± 495	1642 ± 752	2264 ± 729
Vss [dL/kg]	0.56 ± 0.12	0.54 ± 0.09	0.56 ± 0.18	0.43 ± 0.11
Cmax [IU/dL]	115 ± 30	115 ± 33	95 ± 25	122 ± 29
Tmax [h]	- Tmax could not be calculated for patients in the pediatric study as only one sample was drawn (15-30 minutes post-infusion) within the first 3 hours of the infusion.	-	0.26 ± 0.10	0.46 ± 0.29

Incremental recovery was further evaluated in 99 patients (PUP) <6 years of age in a prospective, uncontrolled, open-label, multicenter trial. Incremental recovery remained relatively stable over time of treatment with mean (SD) incremental recovery values (1‑stage clotting method) of 1.670 (0.594) (IU/dL)/(IU/kg) (n=99), 1.617 (0.640) (IU/dL)/(IU/kg) (n=47), 1.805 (0.593) (IU/dL)/(IU/kg) (n=87), and 1.873 (0.440) (IU/dL)/(IU/kg) (n=89), at baseline, visit 3 (ED 15 ± 1), visit 6 (ED 40 ± 3), and trial completion/termination (ED 100 to 110), respectively.

The efficacy of ADYNOVATE was evaluated in 4 clinical studies, as described below.

Study 1

The safety, efficacy, and PK of ADYNOVATE were evaluated in a multicenter, open-label, prospective, non-randomized, two-arm clinical trial (Study 261201, NCT01736475) 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 patients were adolescents (12 to less than 18 years of age).

Patients 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%) patients 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 patients remained on the starting recommended regimen without dose adjustment, and 2 patients 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 patients) occurred in the on-demand arm and 157 (n=61 patients) 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 per-protocol 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.

A total of 591 bleeding episodes were treated with ADYNOVATE in the treated population, which was identical to the safety analysis set of patients assigned to routine prophylaxis or on-demand treatment with ADYNOVATE and who received at least one dose of the product. Of these, 361 bleeding episodes (n=17 patients) occurred in the on-demand arm and 230 bleeding episodes (n=75 patients) occurred in the routine prophylaxis arm. Efficacy in control of bleeding episodes is summarized in Table 5.

Table 5: Summary of Efficacy in Control of Bleeding (Treated Population)

Bleeding Episode Etiology		All	Joint	Non-joint
Number of bleeds treated		591	455	136
Number of infusions to treat bleeding episodes	1 infusions:	85.4%	85.9%	83.8%
	2 infusions:	10.8%	10.8%	11.0%
	Total (1 or 2 infusions):	96.2%	96.7%	94.8%
Rate of success to treat bleeding episodes Excellent defined as full relief of pain and objective signs of bleeding cessation; Good defined as definite pain relief and/or improvement in signs of bleeding; Fair defined as probable and/or slight relief of pain and slight improvement in signs of bleeding after a single infusion. Required more than 1 infusion for complete resolution; None defined as no improvement or condition worsened.	Excellent or good	95.3%	95.8%	93.4%

Routine Prophylaxis

A total of 120 patients (treated population) received a twice a week regimen in the prophylaxis arm, and an additional 17 patients 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 patients in the prophylaxis arm compared to the on-demand arm.

Table 6: Annualized Bleed Rate by Treatment for ≥ 12 Years of Age (Treated Population)

Bleeding Episode Etiology	On-Demand Treatment		Routine Prophylaxis Treatment
	Median	Mean (SD)	Median	Mean (SD)
Overall	41.5	40.8 (16.3)	1.9	4.7 (8.6)
Joint	38.1	34.7 (15.1)	0.0	2.9 (8.0)
Non-Joint	3.7	6.1 (6.7)	0.0	1.8 (3.0)
Spontaneous	21.6	26.0 (19.6)	0.0	2.9 (7.1)
Traumatic	9.3	14.9 (15.3)	0.0	1.8 (3.1)

In the treated population, the median [mean] ABR for the 23 adolescent patients 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 patients 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 patients (38%) experienced no bleeding episodes and 68 out of 120 patients (57%) experienced no joint bleeding episodes in the prophylaxis arm. Of those patients who were compliant to regimen (per-protocol population), 40 out of 101 patients (40%) experienced no bleeding episodes. All patients in the on-demand arm experienced a bleeding episode, including a joint bleeding episode.

Study 2

Routine Prophylaxis Clinical Trial in Pediatric Patients (<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 patients were dosed (32 patients aged <6 years and 34 patients aged 6 to <12 years) in a separate pediatric clinical trial (Study 261202, NCT02210091). The prophylactic regimen was 40 to 60 IU/kg of ADYNOVATE twice a week, with a mean (SD) dose of 51.1 IU/kg (5.5). The median [mean] overall ABR was 2.0 [3.61] for the 66 patients in the treated population and the median [mean] ABRs for spontaneous and joint bleeding episodes were both 0 [1.18 and 1.12, respectively]. Of the 66 patients 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 patients.

Study 3

An extension study (Study 261302, NCT01945593) in adult and pediatric patients evaluated the safety and efficacy of prophylactic treatment regimen in 216 previously treated patients with severe hemophilia A. Majority had completed the adult and adolescent study or the pediatric study. Similar efficacy was noted in this extension study.

Study 4

Perioperative Management Clinical Trial

The safety and efficacy of ADYNOVATE in PTPs (aged 12 to 65 years) with severe hemophilia A, who were undergoing elective surgical or other invasive procedures, was evaluated in a multicenter, open-label clinical trial (Study 261204, NCT01913405). In this clinical trial 21 major surgical procedures comprising of 14 orthopedic, and 7 non-orthopedic procedures, and 5 additional minor surgeries were performed in 21 patients. The preoperative loading dose ranged from 36 IU/kg to 99 IU/kg (median: 60 IU/kg) and the total post-operative dose ranged from 23 IU/kg to 769 IU/kg (median: 183 IU/kg). The median total dose (including all administrations from pre-surgical PK and loading doses to post-hospital follow up) was 629 IU/kg (range: 464 – 1,457 IU/kg) for major orthopedic surgeries, 489 IU/kg (range: 296 – 738 IU/kg) for major non-orthopedic surgeries.

Overall 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, for all 24 (21 major, 3 minor) procedures with available assessments.

How Supplied

ADYNOVATE in a BAXJECT III system is packaged with 2 mL or 5 mL of Sterile Water for Injection, one Terumo Microbore Infusion set (2 mL only), one full prescribing physician insert and one patient insert. Components not made with natural rubber latex.

ADYNOVATE is available in single-dose vials that contain the following nominal product strengths:

Nominal Strength	Potency Color Code	Carton NDC (Includes 2 mL sWFI Diluent)	Carton NDC (Includes 5 mL sWFI Diluent)
250 IU	Light Blue	0944-4622-01
500 IU	Pink	0944-4623-01
750 IU	Red	0944-4626-01
1000 IU	Light Green	0944-4624-01
1500 IU	Purple	0944-4627-01
2000 IU	Orange		0944-4625-01
3000 IU	Silver		0944-4628-01

Actual factor VIII activity in IU is stated on the label of each ADYNOVATE carton and housing.

Takeda Pharmaceuticals U.S.A., Inc.
Cambridge, MA 02142
U.S. License No. 1898

ADYNOVATE, ADVATE and BAXJECT are registered trademarks of Baxalta Incorporated.

Takeda and are registered trademarks of Takeda Pharmaceutical Company Limited.

©2025 Takeda Pharmaceutical Company Limited. All rights reserved.

Patented: see www.takeda.com/en-us/patents

• 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.

ADYNOVATE is available as a white to off-white lyophilized powder in single-dose vials containing nominally (approximately) 250, 500, 750, 1000, 1500, 2000, and 3000 International Units (IU, units). The 250-1500 IU strengths come with 2 mL Sterile Water for Injection (sWFI); the 2000 and 3000 IU strengths come with 5 mL of sWFI. The actual factor VIII potency/content is labeled on each ADYNOVATE vial.

The potency assignment employs a factor VIII concentrate standard that is referenced to a WHO (World Health Organization) international standard for factor VIII concentrates and is evaluated by appropriate methodology to ensure accuracy of the results.

ADYNOVATE is contraindicated in patients who have had prior anaphylactic reaction to ADYNOVATE, to the parent molecule (ADVATE^®), mouse or hamster protein, or excipients of ADYNOVATE (e.g. Tris, mannitol, trehalose, glutathione, and/or polysorbate 80).

Hypersensitivity reactions including anaphylaxis, have been reported with ADYNOVATE. Hypersensitivity reactions that can progress to anaphylaxis may include angioedema, chest tightness, dyspnea, wheezing, urticaria, pruritus, and nausea and vomiting. Immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur.

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.

• 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 [see Dosage and Administration (2)].
• 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.

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 pooled safety database described in this section reflects exposure of ADYNOVATE in 478 previously treated patients (PTPs) and previously untreated patients (PUPs) with severe hemophilia A (factor VIII less than 1% of normal), who received at least one dose of ADYNOVATE in 7 clinical studies [see Immunogenicity (12.6) and Clinical Studies (14)]. The total number of infusions within the safety database is 92173. Table 3 lists the adverse reactions reported during clinical studies.

The most common adverse reactions (≥1% of patients) were cough, headache, diarrhea, vomiting, rash, nausea, urticaria, and dizziness.

Two cases of acute pancreatitis, with no precipitating cause identified in one case, were reported in adults during an extension study of the clinical trial which evaluated 216 patients. Administration of ADYNOVATE continued and both cases resolved.

Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.

Immune System Disorders: Anaphylactic Reaction

The safety and efficacy of ADYNOVATE have been established in pediatric patients. The use of ADYNOVATE for routine prophylaxis, on-demand treatment of bleeding episodes, or perioperative management was supported by five clinical studies which included 115 previously treated pediatric patients 1 to 16 years of age (78 patients <12 years of age). The safety and efficacy of ADYNOVATE in routine prophylaxis and the treatment of bleeding episodes were comparable between pediatric patients and adults. [see Adverse Reactions (6), Clinical Pharmacology (12), and Clinical Studies (14)]

Pharmacokinetic studies in children (<12 years) have demonstrated higher clearance, a shorter half-life and lower incremental recovery of factor VIII compared to adults. Because clearance (based on per kg body weight) has been demonstrated to be higher in children (<12 years), dose adjustment or more frequent dosing based on per kg body weight may be needed in this population. [see Clinical Pharmacology (12.3)]

Clinical studies of ADYNOVATE did not include patients aged 65 years and over.

ADYNOVATE, Antihemophilic Factor (Recombinant), PEGylated, is formulated as a sterile, non-pyrogenic, white to off-white lyophilized powder for reconstitution for intravenous injection. The product is supplied in single-dose vials containing nominal (approximate) potencies of 250, 500, 750, 1000, 1500, 2000, or 3000 international units (IU). Each vial of ADYNOVATE is labeled with the actual factor VIII activity in IU determined using one-stage clotting assay, using a reference material calibrated against a World Health Organization (WHO) International Standard for factor VIII concentrates. One IU, as defined by the WHO standard for blood coagulation factor VIII, human, is approximately equal to the level of factor VIII activity found in 1 mL of fresh pooled human plasma.

When reconstituted with 2 mL or 5 mL sterile water for injection, the final solution contains the following excipients and stabilizers in targeted amounts per mL of reconstituted product:

ADYNOVATE contains no preservative. The specific activity of ADYNOVATE is 2700-8000 IU/mg protein.

ADYNOVATE is a recombinant full-length human coagulation factor VIII (2,332 amino acids with a molecular weight (MW) of 280 kDa) covalently conjugated with one or more molecules of polyethylene glycol (MW 20 kDa) [see Clinical Pharmacology (12.1)]. The therapeutic activity of ADYNOVATE is derived from its parent drug substance, ADVATE [Antihemophilic Factor (Recombinant)], which is produced by recombinant DNA technology from the CHO cell line. ADVATE is purified from the culture medium using a series of chromatography columns. The purification process includes an immunoaffinity chromatography step in which a monoclonal antibody directed against factor VIII is employed to selectively isolate the factor VIII from the medium. The production process includes a dedicated, viral inactivation solvent-detergent treatment step. The ADVATE molecule is then covalently conjugated with the polyethylene glycol, which mainly targets lysine residues.

The cell culture, pegylation, purification process and formulation used in the manufacture of ADYNOVATE do not use additives of human or animal origins.

ADYNOVATE, a PEGylated form of recombinant antihemophilic factor (ADVATE), [see Description (11)], temporarily replaces the missing coagulation factor VIII needed for effective hemostasis in congenital hemophilia A patients. ADYNOVATE exhibits an extended terminal half-life through pegylation of the parent molecule, ADVATE, which reduces binding to the physiological factor VIII clearance receptor (LRP1).

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.

The pharmacokinetics (PK) of ADYNOVATE were evaluated in a multicenter, prospective, open-label clinical trial (Study 1) [see Clinical Studies (14)] and compared with ADVATE in 26 patients prior to initiation of prophylactic treatment with ADYNOVATE and in 22 patients 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.

The observed incidence of anti-drug antibodies (FVIII, PEG FVIII, PEG, CHO) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies to ADYNOVATE in the studies described below with the incidence of anti-drug antibodies in studies with other products.

Immunogenicity was evaluated during 7 clinical trials with ADYNOVATE in 365 previously treated patients and 120 previously untreated patients with severe hemophilia A.

Previously Treated Patients

In 6 clinical studies with previously treated patients, immunogenicity was evaluated by monitoring neutralizing (inhibitory) antibodies to FVIII and 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.

Two previously treated patients developed a transient low titer FVIII inhibitor at 0.6 BU/mL with ADYNOVATE, only one of which was confirmed with repeat testing. Both of these patients continued treatment without change in the dose of ADYNOVATE.

Out of 365 patients, thirty-six patients showed pre-existing antibodies to factor VIII (n=5), PEG-factor VIII (n=31) and/or PEG (n=6) prior to the first exposure to ADYNOVATE. Twenty-four patients who tested negative at screening developed transient antibodies against factor VIII (n=10), PEG-FVIII (n=16) and/or PEG (n=3) at one or two consecutive study visits. 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 pharmacokinetic parameters. There was no causal relationship between observed adverse events and binding antibodies except in one patient where a causal relationship cannot be ruled out based on available data. No patient had pre-existing or treatment-emergent antibodies to CHO protein.

Previously Untreated Patients

In the clinical study with previously untreated patients, immunogenicity was evaluated by monitoring neutralizing (inhibitory) antibodies to FVIII and by measuring the development of binding IgG and IgM antibodies against factor VIII, PEGylated (PEG)-factor VIII, and PEG using validated ELISA assays.

Of the 120 dosed patients, 100 patients were evaluable for inhibitor development. Of these, 11 (11%) patients developed confirmed FVIII inhibitors after mean (SD) exposure days of 7.6 (4) to ADYNOVATE.

Of the 11 patients who developed inhibitors, 6 (55%) developed high titer inhibitors (>5 BU/mL) and 5 (45%) developed low titer inhibitors (≤5 BU/mL).

Of the 120 patients, 4 patients (3%) had preexisting IgG binding antibodies to FVIII, 13 patients (11%) had preexisting IgM binding antibodies to PEG, 11 patients (9%) had preexisting IgG binding antibodies to PEG FVIII, and 7 patients (6%) had preexisting IgM binding antibodies to PEGFVIII. Of the 120 patients, 59 patients developed transient binding non-neutralizing antibodies to FVIII, PEG FVIII, and PEG after exposure to ADYNOVATE. There was no identified clinically significant effect of anti-drug antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness of ADYVONATE over the treatment duration.

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.

Storage and Handling

• Store ADYNOVATE in powder form at 2°C to 8°C (36°F to 46°F).
• Do not freeze.
• ADYNOVATE may be stored at room temperature not to exceed 30°C (86°F) for a period of up to 3 months not to exceed the expiration date. If stored at room temperature, write the date on the carton when ADYNOVATE is removed from refrigeration.
• After storage at room temperature, do not return the product to the refrigerator.
• Do not use beyond expiration date printed on the carton or housing.
• Store ADYNOVATE in the original box and protect from extreme exposure to light.

Advise the patients to:

• Read the FDA-approved patient labeling (Patient Information and Instructions for Use).
• Call their healthcare provider or go to the emergency department right away if a hypersensitivity reaction occurs. Early signs of hypersensitivity reactions may include rash, hives, itching, facial swelling, tightness of the chest, and wheezing. Advise patients to discontinue use of the product if these symptoms occur and seek immediate emergency treatment.
• Contact their healthcare provider or treatment facility for further treatment and/or assessment if they experience a lack of a clinical response to factor VIII therapy because this may be a sign of inhibitor development.
• Consult with their physicians or healthcare provider prior to travel. While traveling, advise patients to bring an adequate supply of ADYNOVATE based on their current regimen of treatment.

To enroll in the confidential, industry-wide Patient Notification System, call 1-888-873-2838.

ADYNOVATE^®
[Antihemophilic Factor
(Recombinant), PEGylated]

NDC 0944-4622-01

Single-dose only

For Intravenous Administration After Reconstitution Only

Lyophilized powder for reconstitution

ADYNOVATE and diluent preassembled in BAXJECT III system

Rx Only

Actual potency

Takeda

Principal Display Panel (Kit Carton)

ADYNOVATE^®
[Antihemophilic Factor
(Recombinant), PEGylated]

For Intravenous Administration Only

ADYNOVATE and diluent preassembled
in BAXJECT^® III system

Directions for use: see package insert

Rx Only

IU:

LOT:

EXP:

Takeda

6521221

Principal Display Panel (Barrel Label)

ADYNOVATE^®
[Antihemophilic Factor
(Recombinant), PEGylated]

NDC 0944-4622-02

Single-dose only

6521479

For Intravenous Administration Only

ADYNOVATE and diluent preassembled in BAXJECT^® III system

Do not open until time of use

Do not use if packaging is opened or damaged

Discard unused portion.

Rx Only

Takeda

Principal Display Panel (Blister Label)

ADYNOVATE^®
[Antihemophilic Factor
(Recombinant), PEGylated]

NDC 0944-4623-01

Single-dose only

For Intravenous Administration After Reconstitution Only

Lyophilized powder for reconstitution

ADYNOVATE and diluent preassembled in BAXJECT III system

Rx Only

Actual potency

Takeda

Principal Display Panel (Kit Carton)

ADYNOVATE^®
[Antihemophilic Factor
(Recombinant), PEGylated]

For Intravenous Administration Only

ADYNOVATE and diluent preassembled
in BAXJECT^® III system

Directions for use: see package insert

Rx Only

IU:

LOT:

EXP:

Takeda

6521223

Principal Display Panel (Barrel Label)

ADYNOVATE^®
[Antihemophilic Factor
(Recombinant), PEGylated]

NDC 0944-4623-02

Single-dose only

6521484

For Intravenous Administration Only

ADYNOVATE and diluent preassembled in BAXJECT^® III system

Do not open until time of use

Do not use if packaging is opened or damaged

Discard unused portion.

Rx Only

Takeda

Principal Display Panel (Blister Label)

ADYNOVATE^®
[Antihemophilic Factor
(Recombinant), PEGylated]

NDC 0944-4626-01

Single-dose only

For Intravenous Administration After Reconstitution Only

Lyophilized powder for reconstitution

ADYNOVATE and diluent preassembled in BAXJECT III system

Rx Only

Actual potency

Takeda

Principal Display Panel (Kit Carton)

ADYNOVATE^®
[Antihemophilic Factor
(Recombinant), PEGylated]

For Intravenous Administration Only

ADYNOVATE and diluent preassembled
in BAXJECT^® III system

Directions for use: see package insert

Rx Only

IU:

LOT:

EXP:

Takeda

6521228

Principal Display Panel (Barrel Label)

ADYNOVATE^®
[Antihemophilic Factor
(Recombinant), PEGylated]

NDC 0944-4626-02

Single-dose only

6521490

For Intravenous Administration Only

ADYNOVATE and diluent preassembled in BAXJECT^® III system

Do not open until time of use

Do not use if packaging is opened or damaged

Discard unused portion.

Rx Only

Takeda

Principal Display Panel (Blister Label)

ADYNOVATE^®
[Antihemophilic Factor
(Recombinant), PEGylated]

NDC 0944-4624-01

Single-dose only

For Intravenous Administration After Reconstitution Only

Lyophilized powder for reconstitution

ADYNOVATE and diluent preassembled in BAXJECT III system

Rx Only

Actual potency

Takeda

Principal Display Panel (Kit Carton)

ADYNOVATE^®
[Antihemophilic Factor
(Recombinant), PEGylated]

For Intravenous Administration Only

ADYNOVATE and diluent preassembled
in BAXJECT^® III system

Directions for use: see package insert

Rx Only

IU:

LOT:

EXP:

Takeda

6521224

Principal Display Panel (Barrel Label)

ADYNOVATE^®
[Antihemophilic Factor
(Recombinant), PEGylated]

NDC 0944-4624-02

Single-dose only

6521493

For Intravenous Administration Only

ADYNOVATE and diluent preassembled in BAXJECT^® III system

Do not open until time of use

Do not use if packaging is opened or damaged

Discard unused portion.

Rx Only

Takeda

Principal Display Panel (Blister Label)

ADYNOVATE^®
[Antihemophilic Factor
(Recombinant), PEGylated]

NDC 0944-4627-01

Single-dose only

For Intravenous Administration After Reconstitution Only

Lyophilized powder for reconstitution

ADYNOVATE and diluent preassembled in BAXJECT III system

Rx Only

Actual potency

Takeda

Principal Display Panel (Kit Carton)

ADYNOVATE^®
[Antihemophilic Factor
(Recombinant), PEGylated]

For Intravenous Administration Only

ADYNOVATE and diluent preassembled
in BAXJECT^® III system

Directions for use: see package insert

Rx Only

IU:

LOT:

EXP:

Takeda

6521225

Principal Display Panel (Barrel Label)

ADYNOVATE^®
[Antihemophilic Factor
(Recombinant), PEGylated]

NDC 0944-4627-02

Single-dose only

6521495

For Intravenous Administration Only

ADYNOVATE and diluent preassembled in BAXJECT^® III system

Do not open until time of use

Do not use if packaging is opened or damaged

Discard unused portion.

Rx Only

Takeda

Principal Display Panel (Blister Label)

ADYNOVATE^®
[Antihemophilic Factor
(Recombinant), PEGylated]

NDC 0944-4625-01

Single-dose only

For Intravenous Administration After Reconstitution Only
Lyophilized powder for reconstitution
ADYNOVATE and diluent
preassembled in
BAXJECT III system
Rx Only

Actual potency

Takeda

Principal Display Panel (Kit Carton)

ADYNOVATE^®
[Antihemophilic Factor
(Recombinant), PEGylated]

For Intravenous Administration Only

ADYNOVATE and diluent preassembled
in BAXJECT^® III system

Directions for use: see package insert

Rx Only

IU:

LOT:

EXP:

Takeda

6521226

Principal Display Panel (Barrel Label)

ADYNOVATE^®
[Antihemophilic Factor
(Recombinant), PEGylated]

NDC 0944-4625-02

Single-dose only

6521498

For Intravenous Administration Only

ADYNOVATE and diluent preassembled in BAXJECT^® III system

Do not open until time of use

Do not use if packaging is opened or damaged

Discard unused portion.

Rx Only

Takeda

Principal Display Panel (Blister Label)

ADYNOVATE^®
[Antihemophilic Factor
(Recombinant), PEGylated]

NDC 0944-4628-01

Single-dose only

For Intravenous Administration After Reconstitution Only
Lyophilized powder for reconstitution
ADYNOVATE and diluent
preassembled in
BAXJECT III system
Rx Only

Actual potency

Takeda

Principal Display Panel (Kit Carton)

ADYNOVATE^®
[Antihemophilic Factor
(Recombinant), PEGylated]

For Intravenous Administration Only

ADYNOVATE and diluent preassembled
in BAXJECT^® III system

Directions for use: see package insert

Rx Only

IU:

LOT:

EXP:

Takeda

6521227

Principal Display Panel (Barrel Label)

ADYNOVATE^®
[Antihemophilic Factor
(Recombinant), PEGylated]

NDC 0944-4628-02

Single-dose only

6521500

For Intravenous Administration Only

ADYNOVATE and diluent preassembled in BAXJECT^® III system

Do not open until time of use

Do not use if packaging is opened or damaged

Discard unused portion.

Rx Only

Takeda

Principal Display Panel (Blister Label)

Antihemophilic Factor (Recombinant), PEGylated

6521222

Takeda

Lot No.:

Principal Display Panel (Antihemophilic Factor Vial Label)

Sterile Water for Injection

Lot No.:

Siegfried Hameln GmbH

0742211

Principal Display Panel (Sterile Water for Injection Vial Label)