Adynovate

Adynovate information, interactions and side effects, 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-use vials containing nominal (approximate) potencies of 250, 500, 1000, or 2000 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 5 mL sterile water for injection, the final solution contains the following excipients and stabilizer in targeted amounts per vial:

 

Stabilizer and Excipient 5 mL Reconstitution Target
Tris (hydroxymethyl) aminomethane 6.1 mg
Calcium Chloride 1.2 mg
Mannitol 160 mg
Sodium Chloride 26.3 mg
Trehalose Dihydrate 40 mg
Glutathione .04 mg
Histidine 7.8 mg
Polysorbate 80 0.5 mg

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). 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.

INDICATIONS

ADYNOVATE, Antihemophilic Factor (Recombinant), PEGylated, is a human antihemophilic factor indicated in adolescent and adult patients (12 years and older) with hemophilia A (congenital factor VIII deficiency) for:

  • On-demand treatment and control of bleeding episodes
  • Routine prophylaxis to reduce the frequency of bleeding episodes

ADYNOVATE is not indicated for the treatment of von Willebrand disease.

DOSAGE AND ADMINISTRATION

For intravenous use after reconstitution only.

Dose

  • 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.
  • Initiate treatment under the supervision of a physician experienced in the treatment of hemophilia A.
  • 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).

Table 1: Dosing for On-demand Treatment and Control of Bleeding Episodes

 

Type of Bleeding Target Factor VIII Level (IU/dL or % of normal) Dosea (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 the bleeding is resolved.
Moderate
Muscle bleeding, moderate bleeding into the oral cavity, definite hemarthroses, and known trauma.
30-60 15-30 12-24 Until the 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.
aDose (IU/kg) = Desired factor VIII rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL)

 

Routine Prophylaxis

Administer 40-50 IU per kg body weight 2 times per week. Adjust the dose based on the patient’s clinical response.

Preparation And Reconstitution

Preparation

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.

Figure A

adynovate1

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.

5. Turn the package over. Press straight down to fully insert the clear plastic spike through the diluent vial stopper (Figure B).

Figure B

adynovate2

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

adynovate3

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

adynovate4

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

adynovate5

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

adynovate6

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).

HOW SUPPLIED

Dosage Forms And Strengths

ADYNOVATE is a lyophilized powder in single-use vials containing nominally (approximately) 250, 500, 1000, and 2000 International Units (IU, units). 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 supplied in packages comprised of a single-use vial containing nominally (approximately) 250, 500, 1000, or 2000 international units (IU) of factor VIII potency, a diluents vial containing 5 mL of sterile Water for Injection (sWFI), and a BAXJECT II Hi-Flow Needleless Transfer Device. Components not made with natural rubber latex.

 

Nominal Strength Actual Factor VIII Potency Range Carton NDC (Includes 5 mL sWFI Diluent)
250 IU 200-400 IU per vial 0944-4252-02
500 IU 401-800 IU per vial 0944-4254-02
1000 IU 801-1250 IU per vial 0944-4256-02
2000 IU 1251-2500 IU per vial 0944-4258-02

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

Storage And Handling

  • Store ADYNOVATE in powder form at 2°to 8°C (36°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 1 month 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 vial.
  • Store vials in their original box and protect them from extreme exposure to light.
  • After reconstitution, do not refrigerate the solution. Use the reconstituted solution immediately or within 3 hours after reconstitution. Discard any remaining solution.

SIDE EFFECTS

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 refl ect the rates observed in practice.

The safety of ADYNOVATE was evaluated in 169 previously treated patients (PTPs) with severe hemophilia A (factor VIII less than 1% of normal), who received at least one dose of ADYNOVATE in 2 multi-center, prospective, open label clinical studies and 3 ongoing clinical studies. The median duration of participation per subject was 333 (min-max: 1-593) days and the median number of exposure days to ADYNOVATE per subject was 96 (min-max: 1-170). Table 2 lists the adverse reactions reported during clinical studies.

Table 2: Adverse Reactions Reported for ADYNOVATE

 

MedDRA System Organ Class MedDRA Preferred Term Number of Subjects n (%)
(N=169)
Percent of Infusion
(N=13579)
Gastrointestinal Disorders Diarrhea 1 (0.6%) 0.01%
Nausea 2 (1.2%) 0.01%
Nervous System Disorders Headache 5 (3.0%) 0.06%
Vascular Disorders Flushing 1 (0.6%) 0.01%

No events of hypersensitivity were reported.

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 137 subjects. Administration of ADYNOVATE continued and both cases resolved.

Immunogenicity

The risk of the development of factor VIII inhibitors with the use of ADYNOVATE was evaluated in 2 completed and 3 ongoing clinical trials. Study subjects consisted of adult (n= 143 with ≥ prior 150 EDs) and pediatric PTPs [( < 6 years of age with ≥ 50 prior EDs (n= 3), ≥ 6 years of age with ≥ 150 prior EDs (n= 23)]. In 120 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 0.03). None of the 169 individual subjects 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. None of the 169 treated subjects with at least one infusion of ADYNOVATE developed a persistent binding antibody response to any of these antigens. Thirteen subjects in total showed pre-existing antibodies to factor VIII (n=1), PEG-factor VIII (n=12) and/or PEG (n=3) prior to the first exposure to ADYNOVATE. Eight subjects who tested negative at screening developed transient IgG antibodies against factor VIII (n= 5), or PEG-FVIII (n= 3) at one or two consecutive study visits. Binding antibodies that were detected prior to exposure to ADYNOVATE or that transiently developed during the study could not be correlated to any impaired treatment efficacy, altered PK parameters, or adverse reactions. 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.

PRECAUTIONS

Hypersensitivity Reactions

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.

Patient Counseling Information

Advise patients to:

  • Read the FDA-approved patient labeling.
  • 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.
  • Advise patients to 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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.

Use In Specific Populations

Pregnancy

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. 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

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 Use

The safety, efficacy, or pharmacokinetic profiles of ADYNOVATE have not been established in pediatric patients less than 12 years old.

In the clinical trial, 25 adolescents aged 12 to less than 18 were included in the analysis. The safety, efficacy, and PK profile were comparable between adolescents and adults.

Geriatric Use

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

575 read