Drug Detail:Advate (Antihemophilic factor (recombinant) [ ant-ee-hee-moe-fil-ik-fak-tor ])
Drug Class: Miscellaneous coagulation modifiers
Highlights of Prescribing Information
ADVATE [antihemophilic factor (recombinant)] lyophilized powder for
reconstitution, for intravenous injection
Initial U.S. Approval: 2003
Indications and Usage for Advate
ADVATE is a recombinant antihemophilic factor indicated for use in children and adults with hemophilia A for:
- Control and prevention of bleeding episodes.
- Perioperative management.
- Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.
ADVATE is not indicated for the treatment of von Willebrand disease. (1)
Advate Dosage and Administration
For intravenous injection after reconstitution only. (2)
Each vial of ADVATE contains the labeled amount of recombinant factor VIII in International Units (IU). (2.1)
Control and Prevention of Bleeding Episodes and Perioperative Management (2.1)
- Dose (IU) = body weight (kg) × desired factor VIII rise (IU/dL or % of normal) × 0.5 (IU/kg per IU/dL).
- Determine treatment frequency based on type of bleeding episode.
Routine Prophylaxis (2.1)
- 20 to 40 IU per kg every other day (3 to 4 times weekly).
- Alternatively, use every third day dosing regimen targeted to maintain FVIII trough levels ≥1%.
Dosage Forms and Strengths
ADVATE is available as a lyophilized powder in single-use vials containing nominally 250, 500, 1000, 1500, 2000, 3000 or 4000 IU. (3)
Contraindications
Do not use in patients who have life-threatening hypersensitivity reactions, including anaphylaxis, to mouse or hamster protein or other constituents of the product (mannitol, trehalose, sodium chloride, histidine, Tris, calcium chloride, polysorbate 80, and/or glutathione). (4)
Warnings and Precautions
- Hypersensitivity reactions, including anaphylaxis, may occur. Patients may develop hypersensitivity to mouse or hamster protein, which is present in trace amounts in the product. Should symptoms occur, discontinue treatment with ADVATE and administer appropriate treatment. (5.1)
- Development of activity-neutralizing antibodies may occur. If expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an appropriate dose, perform an assay that measures factor VIII inhibitor concentration. (5.2, 5.3)
Adverse Reactions/Side Effects
- Serious adverse drug reactions reported are hypersensitivity and factor VIII inhibitors. (6.1)
- The most common adverse drug reactions observed in greater than 5% of patients are pyrexia, headache, cough, nasopharyngitis, arthralgia, vomiting, upper respiratory tract infection, limb injury, nasal congestion, and diarrhea. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals U.S.A., Inc. at 1-877-TAKEDA-7 (1-877-825-3327) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Use In Specific Populations
Pediatric Use: Clearance (based on per kg body weight) is higher in the pediatric population. Dose adjustment may be needed. (8.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 3/2023
Full Prescribing Information
1. Indications and Usage for Advate
ADVATE [Antihemophilic Factor (Recombinant)] is a recombinant antihemophilic factor indicated for use in children and adults with hemophilia A (congenital factor VIII deficiency) for:
- Control and prevention of bleeding episodes.
- Perioperative management.
- Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.
ADVATE is not indicated for the treatment of von Willebrand disease.
2. Advate Dosage and Administration
For intravenous injection after reconstitution only.
2.1 Dose
- 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 control of replacement therapy is especially important in cases of major surgery or life-threatening bleeding episodes.
- Each vial of ADVATE has the recombinant factor VIII potency in International Units (IU) stated on the label. The expected in vivo peak increase in factor VIII level expressed as IU/dL of plasma or percent of normal can be estimated using the following formulas:
IU/dL (or % of normal) = [total dose (IU)/body weight (kg)] × 2 [IU/dL]/[IU/kg]
OR
Required dose (International Units) = body weight (kg) × desired factor VIII rise (IU/dL or % of normal) × 0.5 (IU/kg per IU/dL)
Examples (assuming patient's baseline factor VIII level is <1% of normal):
- A dose of 1750 IU ADVATE administered to a 70 kg patient should be expected to result in a peak postinfusion factor VIII increase of: 1750 IU × {[2 IU/dL]/[IU/kg]}/[70 kg] = 50 IU/dL (50% of normal).
- A peak level of 70% is required in a 40 kg child. In this situation, the appropriate dose would be 40 kg × 70 IU/dL/{[2 IU/dL]/[IU/kg]} = 1400 IU.
- Base the dose and frequency on the individual clinical response. Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses to ADVATE. Although the dose can be estimated by the calculations above, whenever possible, perform appropriate laboratory tests including serial factor VIII activity assays [see Warnings and Precautions (5.3), Clinical Pharmacology (12.3)].
Perioperative Management
A guide for dosing ADVATE during surgery (perioperative management) is provided in Table 2. The goal of treatment is to maintain a plasma factor VIII activity level at or above the plasma level (in % of normal or in IU/dL) outlined in Table 2.
| Type of Surgery | Factor VIII Level Required (% of normal or IU/dL) | Dose*
(IU/kg) | Frequency of Doses (hours) | Duration of Therapy (days) |
|---|---|---|---|---|
|
||||
| Minor
Including tooth extraction | 60 to 100 | 30 to 50 | Single dose within 1 hour of the operation. | Single dose or repeat until bleeding is resolved. |
| 12 to 24 (as needed to control bleeding) | For dental procedures, adjunctive therapy may be considered. | |||
| Major
Intracranial, intra-abdominal, or intrathoracic surgery, joint replacement surgery | 80 to 120 (pre- and postoperative) | 40 to 60 | One dose preoperative to achieve 100% activity. Every 8 to 24 to keep factor VIII activity in desired range. (Every 6 to 24 hours for patients under the age of 6) | Until healing is complete. |
2.3 Administration
For intravenous injection after reconstitution only.
- Inspect parenteral drug products for particulate matter and discoloration prior to administration. The solution should be clear and colorless in appearance. If not, do not use the solution and notify Takeda Pharmaceuticals U.S.A., Inc. immediately.
- Administer ADVATE at room temperature within 3 hours of reconstitution.
- Use plastic syringes with this product because proteins in the product tend to stick to the surface of glass syringes.
- Use aseptic technique.
- Remove the blue cap from the housing. Connect the syringe to the system (Figure D). Do not inject air into the ADVATE.
- Turn the system upside down (factor concentrate vial now on top). Draw the factor concentrate into the syringe by pulling the plunger back slowly (Figure E).
- Disconnect the syringe, attach a suitable needle, and inject intravenously as instructed. If a patient is to receive more than one ADVATE-BAXJECT III system or a combination of an ADVATE-BAXJECT II and an ADVATE-BAXJECT III system, the contents may be drawn into the same syringe.
- Administer ADVATE over a period of ≤5 minutes (maximum infusion rate 10 mL/min). Determine the pulse rate before and during administration of ADVATE. Should a significant increase in pulse rate occur, reducing the rate of administration or temporarily halting the injection usually allows the symptoms to disappear promptly.
| Figure D | Figure E |
 |  |
3. Dosage Forms and Strengths
ADVATE is available as a lyophilized white to off-white powder in single-use vials containing nominally 250, 500, 1000, 1500, 2000, 3000, or 4000 International Units (IU, unit). The 250 to 1500 IU strengths come with 2 mL Sterile Water for Injection (sWFI); the 2000 to 4000 IU strengths come with 5 mL of sWFI.
Each ADVATE is labeled on the housing with the recombinant antihemophilic factor (rAHF) activity expressed in IU per system. This 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.
4. Contraindications
ADVATE is contraindicated in patients who have life-threatening hypersensitivity reactions, including anaphylaxis, to mouse or hamster protein or other constituents of the product (mannitol, trehalose, sodium chloride, histidine, Tris, calcium chloride, polysorbate 80, and/or glutathione).
5. Warnings and Precautions
5.1 Hypersensitivity Reactions
Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with ADVATE. Symptoms include dizziness, paresthesia, rash, flushing, facial swelling, urticaria, dyspnea, pruritus, and vomiting.
ADVATE contains trace amounts of mouse immunoglobulin G (MuIgG) ≤0.1 ng/IU ADVATE, and hamster proteins ≤1.5 ng/IU ADVATE. Patients treated with this product may develop hypersensitivity to these nonhuman mammalian proteins.
Discontinue ADVATE if hypersensitivity symptoms occur and administer appropriate emergency treatment.
5.2 Neutralizing Antibodies
Neutralizing antibodies (inhibitors) have been reported following administration of ADVATE predominantly in previously untreated patients (PUPs) and previously minimally treated patients (MTPs). Monitor all patients for the development of factor VIII inhibitors by appropriate clinical observation and laboratory testing. If expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an expected dose, perform an assay that measures factor VIII inhibitor concentration [see Warnings and Precautions (5.3)].
5.3 Monitoring Laboratory Tests
- Monitor plasma factor VIII activity levels by the one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained when clinically indicated [see Dosage and Administration (2.1)].
- Monitor for development of factor VIII inhibitors. Perform the Bethesda 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 ADVATE, use Bethesda Units (BU) to titer inhibitors.
- If the inhibitor titer is less than 10 BU per mL, the administration of additional antihemophilic factor concentrate may neutralize the inhibitor and may permit an appropriate hemostatic response.
- If the inhibitor titer is above 10 BU per mL, adequate hemostasis may not be achieved. The inhibitor titer may rise following ADVATE infusion as a result of an anamnestic response to factor VIII. The treatment or prevention of bleeding in such patients requires the use of alternative therapeutic approaches and agents.
6. Adverse Reactions/Side Effects
Serious adverse reactions seen with ADVATE are hypersensitivity reactions, including anaphylaxis, and the development of high-titer inhibitors necessitating alternative treatments to factor VIII.
The most common adverse reactions observed in clinical trials (frequency greater than 5% of subjects) were pyrexia, headache, cough, nasopharyngitis, arthralgia, vomiting, upper respiratory tract infection, limb injury, nasal congestion, and diarrhea.
6.1 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 clinical practice.
ADVATE has been evaluated in 11 clinical trials in previously treated patients (PTPs) and one trial in previously untreated patients (PUPs) with severe to moderately severe hemophilia A (factor VIII ≤2% of normal). A total of 418 subjects have been treated with ADVATE as of January 2012. Total exposure to ADVATE was 63,188 infusions. The median duration of participation per subject was 397 (min-max: 2−1620) days and the median number of exposure days to ADVATE per subject was 97 (min-max: 1−709).
The summary of adverse reactions with a frequency >5% are shown in Table 3 below.
No subject was withdrawn from a clinical trial due to an adverse reaction.
| MedDRA‡ System Organ Class | MedDRA Preferred Term | Number of Adverse Reactions | Number of Subjects | Percent of Subjects |
|---|---|---|---|---|
|
||||
| General Disorders and Administration Site Conditions | Pyrexia | 110 | 66 | 16 |
| Nervous System Disorders | Headache | 114 | 56 | 13 |
| Respiratory, Thoracic and Mediastinal Disorders | Cough | 86 | 54 | 13 |
| Infections and Infestations | Nasopharyngitis | 72 | 49 | 12 |
| Musculoskeletal and Connective Tissue Disorders | Arthralgia | 49 | 32 | 8 |
| Gastrointestinal Disorders | Vomiting | 41 | 31 | 7 |
| Infections and Infestations | Upper Respiratory Tract Infection | 35 | 29 | 7 |
| Injury, Poisoning and Procedural Complications | Limb Injury | 56 | 25 | 6 |
| Respiratory, Thoracic and Mediastinal Disorders | Nasal Congestion | 32 | 25 | 6 |
| Gastrointestinal Disorders | Diarrhea | 29 | 24 | 6 |
| Injury, Poisoning and Procedural Complications | Procedural Pain | 26 | 22 | 5 |
| Respiratory, Thoracic and Mediastinal Disorders | Oropharyngeal Pain | 25 | 22 | 5 |
| Infections and Infestations | Ear Infection | 30 | 21 | 5 |
6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of ADVATE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Table 4 represents the most frequently reported postmarketing adverse reactions as MedDRA Preferred Terms.
| Organ System [MedDRA Primary SOC] | Preferred Term |
|---|---|
| Immune System Disorders | Anaphylactic reaction Hypersensitivity |
| General Disorders and Administration Site Conditions | Injection site reaction Chills Fatigue/Malaise Chest discomfort/pain Decreased therapeutic effect |
8. Use In Specific Populations
8.4 Pediatric Use
Pharmacokinetic studies in children have demonstrated higher clearance, a shorter half-life and lower recovery of factor VIII compared to adults [see Clinical Pharmacology (12.3)]. This may be explained by differences in body composition and should be taken into account when dosing or following factor VIII levels in the pediatric population.4 Because clearance (based on per kg body weight) has been demonstrated to be higher in the pediatric population, dose adjustment or more frequent dosing based on per kg body weight may be needed in this population [see Clinical Pharmacology (12.3)]. In the ADVATE routine prophylaxis clinical trial, 3 children aged 7 to <12 and 4 adolescents aged 12 to <16 were included in the per-protocol analysis. The reductions in annualized bleeding rate per subject per year during any prophylaxis regimen as compared to during on-demand therapy were similar among children, adolescents, and adults [see Clinical Studies (14)].
8.5 Geriatric Use
Clinical trials of ADVATE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease and other drug therapy.
11. Advate Description
ADVATE [Antihemophilic Factor (Recombinant)] is a purified glycoprotein consisting of 2,332 amino acids that is synthesized by a genetically engineered Chinese hamster ovary (CHO) cell line but does not contain plasma or albumin. The CHO cell line employed in the production of ADVATE is derived from that used in the biosynthesis of RECOMBINATE [Antihemophilic Factor (Recombinant)]. ADVATE has been shown to be comparable to RECOMBINATE with respect to its biochemical and physicochemical properties, as well as its nonclinical in vivo pharmacology.
In culture, the CHO cell line expresses the recombinant antihemophilic factor (rAHF) into the cell culture medium. The rAHF 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 rAHF from the medium. The cell culture and purification processes used in the manufacture of ADVATE employ no additives of human or animal origin. The production process includes a dedicated, viral inactivation solvent-detergent treatment step. The rAHF synthesized by the CHO cells has the same biological effects on clotting as human antihemophilic factor (hAHF). Structurally, the recombinant protein has a similar combination of heterogeneous heavy and light chains as found in AHF (Human).
ADVATE is formulated as a sterile, nonpyrogenic, white to off-white powder for intravenous injection. ADVATE in a single-use vial contains nominally 250, 500, 1000, 1500, 2000, 3000, or 4000 International Units (IU). The product contains the following stabilizers and excipients: mannitol, trehalose, sodium chloride, histidine, Tris, calcium chloride, polysorbate 80, and glutathione. Von Willebrand factor (VWF) is co-expressed with factor VIII and helps to stabilize it in culture. The final product contains no more than 2 ng VWF/IU rAHF, which will not have any clinically relevant effect in patients with von Willebrand disease.
The product contains no preservative. When reconstituted with the provided Sterile Water for Injection, USP, the final solution contains the following stabilizers and excipients in targeted amounts:
| Stabilizer and Excipient | 2 mL Reconstitution (for 250, 500, 1000, 1500 IU) Target | 5 mL Reconstitution (for 2000, 3000, 4000 IU) Target |
|---|---|---|
| Tris (hydroxymethyl) aminomethane | 25 mM | 10 mM |
| Calcium Chloride | 4.2 mM | 1.7 mM |
| Mannitol | 8% (w/v) | 3.2% (w/v) |
| Sodium Chloride | 225 mM | 90 mM |
| α, α-Trehalose | 2% (w/v) | 0.8% (w/v) |
| Histidine | 25 mM | 10 mM |
| Glutathione (Reduced) | 0.2 mg/mL | 0.08 mg/mL |
| Polysorbate 80 | 0.025% (w/v) | 0.01% (w/v) |
Each ADVATE housing is labeled with the rAHF activity expressed in international units. Biological potency is determined by an in vitro assay, which employs a factor VIII concentrate standard that is referenced to a WHO international standard for factor VIII concentrates. One international unit, 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. The specific activity of ADVATE is 4000 to 10000 International Units per milligram of protein.
12. Advate - Clinical Pharmacology
12.1 Mechanism of Action
ADVATE temporarily replaces the missing coagulation factor VIII that is needed for effective hemostasis.
12.2 Pharmacodynamics
The activated partial thromboplastin time (aPTT) is prolonged in patients with hemophilia. Determination of aPTT is a conventional in vitro assay for biological activity of factor VIII. Treatment with ADVATE normalizes the aPTT over the effective dosing period.
12.3 Pharmacokinetics
A randomized, crossover pharmacokinetic trial of ADVATE (test) and RECOMBINATE [Antihemophilic Factor (Recombinant)] (reference) was conducted in 56 nonbleeding subjects. The subjects received either of the products as an IV infusion (50 ± 5 IU/kg body weight) and there was a washout period of 72 hours to 4 weeks between the two infusions. The pharmacokinetic parameters were calculated from factor VIII activity measurements in blood samples obtained up to 48 hours following each infusion.3 The per-protocol analysis included 30 patients (20 adults and 10 children). Pharmacokinetic parameters for the 20 adults for each trial are presented in Table 6.
| Parameter | RECOMBINATE (N=20) | ADVATE (N=20) |
|---|---|---|
|
||
| AUC0-48h (IU∙hrs/dL)* | 1638 ± 357 | 1644 ± 338 |
| In vivo recovery (IU/dL/IU/kg)† | 2.7 ± 0.6 | 2.6 ± 0.5 |
| Half-life (hrs) | 11.2 ± 2.5 | 12.0 ± 4.2 |
| Cmax (IU/dL) | 136 ± 29 | 128 ± 28 |
| MRT (hrs) | 14.7 ± 3.8 | 15.8 ± 5.9 |
| Vss (dL/kg) | 0.4 ± 0.1 | 0.4 ± 0.1 |
| CL (mL/kg*hr) | 3 ± 1 | 3 ± 1 |
The 90% confidence intervals for the ratios of the mean AUC(0-48h) and in vivo recovery values for the test and control products were within the pre-established limits of 0.80 and 1.25. In addition, in vivo recoveries at the onset of treatment and after 75 exposure days were compared for 62 subjects. Results of this analysis indicated no significant change in the in vivo recovery at the onset of treatment and after ≥75 exposure days.
In an analysis of data from 58 subjects with 65 surgical procedures in the perioperative management trial, the target factor VIII level was met or exceeded in all cases following a single loading dose ranging from 29 to 104 IU/kg.
Pharmacokinetic parameters calculated from 98 subjects less than 16 years of age (intent-to-treat analysis) are available for 7 infants (1 month to less than 2 years), 32 children (2 to less than 5 years), 24 older children (5 to less than 12 years), and 35 adolescents (12 to less than 16 years), as shown in Table 7. The mean clearance (based on body weight) of ADVATE in infants, children, older children, and adolescents was higher than adults (3.6 mL/kg*hr). The mean half-life of ADVATE in infants, children, older children, and adolescents was lower than adults (12 hours). The extent to which these differences may be clinically significant is not known.
| PK Parameter | Infants (N=7) (1 month to <2 yrs) | Children (N=32) (2 to <5 yrs) | Older Children (N=24) (5 to <12 yrs) | Adolescents (N=35) (12 to <16 yrs) |
|---|---|---|---|---|
|
||||
| AUC0-inf (IU*hr/dL) | 1240 ± 330 | 1164 ± 424 | 1396 ± 506 | 1300 ± 469 |
| Incremental Recovery at Cmax* (IU/dL per IU/kg) | 2.1 ± 0.5 | 1.8 ± 0.4 | 2.1 ± 0.6 | 2.1 ± 0.5 |
| Half-Life (hr) | 8.7 ± 1.4 | 9.5 ± 1.8 | 11.2 ± 3.5 | 12.0 ± 2.9 |
| Maximum Plasma Concentration Postinfusion (IU/dL) | 104 ± 27 | 91 ± 19 | 105 ± 34 | 103 ± 25 |
| Mean Residence Time (hr) | 10.4 ± 2.5 | 11.8 ± 2.8 | 14.3 ± 4.3 | 14.9 ± 4.6 |
| Volume of Distribution at Steady State (dL/kg) | 0.4 ± 0.1 | 0.5 ± 0.1 | 0.6 ± 0.2 | 0.6 ± 0.1 |
| Clearance (mL/kg*hr) | 4.3 ± 1.0 | 4.8 ± 1.5 | 4.1 ± 1.5 | 4.2 ± 1.2 |
In a crossover pharmacokinetic trial of recombinant antihemophilic factor, plasma/albumin free method (rAHF-PFM) reconstituted in 2 mL vs 5 mL Sterile Water for Injection, USP (sWFI) in previously treated severe hemophilia A adult and adolescent patients, the AUCs of the two formulations were comparable and the 90% confidence interval ranged from 90.4 to 102.6, indicating that the two formulations are pharmacokinetically equivalent.
13. Nonclinical Toxicology
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No studies have been conducted with the active ingredient in ADVATE to assess its mutagenic or carcinogenic potential.
RECOMBINATE was tested for mutagenicity at doses considerably exceeding plasma concentrations in vitro, and at doses up to ten times the expected maximal clinical dose in vivo. At that concentration, it did not cause reverse mutations, chromosomal aberrations, or an increase in micronuclei formation in bone marrow polychromatic erythrocytes. Studies in animals have not been performed to evaluate carcinogenic potential.
15. References
- Fischer K, Collins P, Björkman S, Blanchette V, Oh M, Fritsch S, Schroth P, Spotts G, Ewenstein B. Trends in bleeding patterns during prophylaxis for severe haemophilia: observations from a series of prospective clinical trials. Haemophilia 2011 17(3):433-8.
- Collins PW, Blanchette VS, Fischer K, Björkman S, Oh M, Fritsch S, Schroth P, Astermark J, Spotts G, Ewenstein B, The rAHF-PFM Study Group. Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe haemophilia A. J Thromb Haemost 2009 7(3):413-20.
- Tarantino MD, Collins PW, Hay PW et al. Clinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin-free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia A. Haemophilia 2004 10:428-437.
- Björkman S, Blanchette VS, Fischer K, Oh M, Spotts G, Schroth P, Fritsch S, Patrone L, Ewenstein BM, Collins PW, ADVATE Clinical Program Group. Comparative pharmacokinetics of plasma- and albumin-free recombinant factor VIII in children and adults: the influence of blood sampling schedule on observed age-related differences and implications for dose tailoring. J Thromb Haemost 2010 8(4):730-6.
- Negrier C, Shapiro A, Berntorp E et al. Surgical evaluation of a recombinant factor VIII prepared using a plasma/albumin-free method: efficacy and safety of ADVATE in previously treated patients. Thromb.Haemost 2008 100:217-223.
17. Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
- Advise patients to report any adverse reactions or problems following ADVATE administration to their physician or healthcare provider.
- Allergic-type hypersensitivity reactions have been reported with ADVATE. Warn patients of the early signs of hypersensitivity reactions, including hives, pruritus, generalized urticaria, angioedema, hypotension, shock, anaphylaxis and acute respiratory distress. Advise patients to discontinue use of the product if these symptoms occur and seek immediate emergency treatment.
- Inhibitor formation may occur with the treatment of a patient with hemophilia A. Advise patients to contact their physician or treatment center if they experience a lack of clinical response to factor VIII replacement therapy, as this may be a manifestation of an inhibitor.
- Advise patients to consult with their physicians or healthcare provider prior to travel. While traveling, advise patients to bring an adequate supply of ADVATE based on their current regimen of treatment.
To enroll in the confidential, industry-wide Patient Notification System, call 1-888-873-2838.
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| ADVATE
antihemophilic factor (recombinant) kit |
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| ADVATE
antihemophilic factor (recombinant) kit |
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| Labeler - Takeda Pharmaceuticals America, Inc. (039997266) |
| Establishment | |||
| Name | Address | ID/FEI | Business Operations |
|---|---|---|---|
| Baxalta US INC | 009471603 | MANUFACTURE, API MANUFACTURE | |
| Establishment | |||
| Name | Address | ID/FEI | Business Operations |
|---|---|---|---|
| Baxalta Manufacturing Sarl | 482124943 | MANUFACTURE, API MANUFACTURE | |
| Establishment | |||
| Name | Address | ID/FEI | Business Operations |
|---|---|---|---|
| Takeda Manufacturing Austria AG | 300434670 | MANUFACTURE | |
| Establishment | |||
| Name | Address | ID/FEI | Business Operations |
|---|---|---|---|
| Takeda Manufacturing Singapore Pte. Ltd. | 659910011 | API MANUFACTURE | |
| Establishment | |||
| Name | Address | ID/FEI | Business Operations |
|---|---|---|---|
| Siegfried Hameln GmbH | 315869123 | MANUFACTURE | |
