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Brought to you by the makers of
Find your True Identity at YourTrueID.com
Exercise your right to
choose the treatment
that's best for you
Please see ADVATE Detailed Important Risk Information on page 11.
Please see www.ADVATE.com/PI or your Baxter Representative for
ADVATE full Prescribing Information.
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identity FIND YOURS
You can reduce or prevent bleeds
Bleeds are a pain
When you have hemophilia, it may seem like bleeding is just
part of life. You may even think you’ve gotten used to the pain,
swelling, and stiffness. The truth is, with today’s options in
treatment, you can reduce or prevent most bleeds.
Men with severe hemophilia can bleed up to 100 times a year1
You should know:
• Bleeds don’t just cause pain — they
Most bleeds may be prevented interfere with daily living.3,12,13
Many people want to have zero bleeds. A good treatment plan including • Most bleeds can be prevented. 2,3,12,13
weight management and exercise can prevent most bleeds. Also, over
• Regular infusions (ie, prophylaxis) may
the last 30 years, researchers and clinicians have discovered that help prevent frequency of bleeds. 2,3,12,13
the infusion of factor on a regular basis (ie, prophylaxis) can actually
prevent most bleeds. 2,3,12,13 Today, prophylaxis is considered optimal
therapy for patients with severe hemophilia A. 4
There are different options available for managing and reducing
bleeds.5 You should work with your HTC to find the treatment
plan that works for you.
It's your treatment
Whether you want to address pain associated with bleeding, stay active, or be there with your family, your choices can have
an impact on your life. It’s never too late to assess your current treatment. Talk to your doctor about your options and if
prophylaxis is right for you.
It’s your life. It’s your treatment. You have a choice.
2
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Find what is right for you
Treat bleeds
For years, people have used factor treatment to treat bleeds. When
people infuse, they replace missing factor VIII (eight) in the blood.
Over time, factor levels drop according to half-life, the rate at which factor
is eliminated from the body. When factor levels are low, accidental bleeds
and spontaneous bleeds, as well as small, ongoing bleeds you may not
even notice, are more likely to occur.1,5,6 You should know:
Infusing when a bleed happens replaces missing factor, stops the bleed, • When factor levels are low, accidental
bleeds are more likely to occur.1,5
and eases pain in the process. The earlier factor treatment is infused, the
easier it is to control the bleed. That's why it's so important to recognize • Prophylaxis is used to prevent most
the signs of a bleed and treat right away. 2,5,7 bleeds before they happen.5
• Work with your HTC or hemophilia
Many people want zero bleeds. Work with your healthcare healthcare professional to determine a
professional to determine your goal. regimen that is right for you.
Prevent most bleeds with prophylaxis
Instead of only treating a bleed after it happens, infusing prophylactically
can keep factor levels up, which has been shown to prevent bleeds and
reduce annual bleed rates (ABRs), or the number of times you bleed in
1 year.3,12,13 Work with your HTC or hemophilia healthcare professional to
determine which regimen is right for you.
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Make a plan that is best for you
Creating a routine
A good plan helps you reduce bleeds and minimize pain associated with bleeding. A great plan will help you do it in a way that
works with your life. The key is to create a routine you can stick with over the long term. That way, it’s easier for you to realize
the benefits of reducing bleeds.
Work with your healthcare professional
To manage bleeds, you need a plan. Work with your healthcare professional to create a treatment regimen that works for you.*
Your plan should also focus on overall health. Keeping your joints and muscles strong now and in the future is also critical to
help prevent bleeds. Exercise and eating well are key to staying strong and reducing stress on joints by maintaining a healthy
weight.8,9 Fill out the Bleed Assessment Score Sheet (included on page 9) and take it to your healthcare professional to start
the conversation.
* Call your HTC or hemophilia healthcare professional if any unexpected bleeds occur.
Start today You should know:
Take the steps to better manage your hemophilia, your health, or other • Work with your HTC staff to create a
areas of your life. By knowing the facts, setting goals, and making good plan for reducing bleeds.
choices, you can minimize the impact of bleeds on your life. • Your plan will involve finding
a treatment regimen that works for you.
• Sticking with your plan is essential to
realizing the benefits of fewer bleeds.
4
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True Identity Tips
#1: Know your ABR
The first thing you can do to prevent, reduce, or eliminate bleeds is to know your annual bleed rate (ABR), which is
the number of times you bleed in a year. It's an important number — like knowing your weight or cholesterol levels.
• Calculate your ABR using the worksheet on page 9
• Talk with your healthcare professional about your current ABR
#2: Track your bleeds
Manage your bleeds over time to see how far you've come.
• Begin by tracking your bleeds for a month
• Set a goal for reducing your bleeds
• Talk with your healthcare professional about how to accomplish your goals
#3: Track your progress
On paper, on your smartphone, or online, create a simple tracking system that works for you.10
Track things like infusions, weight, bleeds, and successes.6
• Every month, take a look at your progress and successes.
• Check out the resources on pages 7–10 to help you manage bleeds.
Find more information about ABR, and tracking your bleeds and progress at YourTrueID.com
5
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Habits and Patterns
Your life today
When it comes to your health and your bleeds, what are you happy with? What would you like to change? Once you understand
where you are, you can then set goals to get you where you’d like to be.
General health:
• Track your weight. Has it changed by 5 to 10 pounds in the last month?
• In the last month, how often have you exercised?
• In the last year, how often have you been in contact with your health care provider?
Bleeds:
• Has your joint pain gotten worse over time? How?
• How often in the last month have you had to miss school, work, or other activities because of bleeds?
• How many bleeds did you have in the last year or month?
• How many fewer bleeds do you want to have?
• What motivators might help you achieve your goals?
• What obstacles might get in the way of achieving your goals?
• Your goal may be to have zero bleeds or fewer bleeds than you had last month or last year. Talk with
your healthcare professional to determine the appropriate and realistic goal for you.
6
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Sample goals
TODAY GOAL
Weight: 185 lbs 165 lbs
Exercise routine: 2 x week 5 x week
HTC visits: 0 x year 1 x year
Pain: Moderate Mild
Missed activities: 4 x month 0 x month
Bleeds: 35 x year 0 x year
Motivators: Schedule infusions on calendar Attend all of my child's games
Obstacles: Busy schedule Busy schedule
After reviewing the sample, take a moment to set your own goals:
Set your goals
TODAY GOAL
Weight:
Exercise routine:
HTC visits:
Pain:
Missed activities:
Bleeds:
Motivators:
Obstacles:
7
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Your success
While you’re tracking your progress toward your goals, also note your patterns. What do you need to do to achieve your goals?
What barriers are in the way? Write these down in the space below. Then think about key behaviors you can use to stay on the
right path.
Sticking to your plan
Keeping track of your infusions helps you notice any patterns. If you’re missing your infusions for recurring reasons, talk to your
healthcare professional about adjusting your treatment plan to better fit your needs.
Watching your weight
Remember that your weight is important for calculating your factor dose, which can change the effectiveness of your infusions.
If you lose or gain weight, contact your HTC to see if your dose needs to be adjusted.
Developing a fitness plan
Exercise is a great way to improve your health. Your HTC staff have great resources to help you develop a fitness plan that is
right for you.
Progress:
8
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Tracking bleeds
Your bleeds Calculate your ABR:
Keep track of your bleeds, and you can see how far you've Your annual bleed rate is an effective way to track your
come. Each month, mark any bleeds that occur in the chart bleeds over time. Start with counting your bleeds each
to the right. Over time, you can see your progress toward month (for example: ).
your goals. And remember:
Month 1
Common signs of a joint bleed 7
Month 2
• Tingling
• Pain Month 3
• Stiffness Month 4
• Heat
• Swelling Month 5
Month 6
Common signs of a muscle bleed11
• Pain Month 7
• Stiffness Month 8
• Warmth
• Swelling Month 9
• Tightness of skin Month 10
• Redness
• Numbness (this is a late sign) Month 11
Month 12
Annual Bleed Rate:
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Bleed assessment score sheet
Know your bleeds. Know your goal.
» Put a number (eg, 1, 2, 3) on the part of the body where you experienced a bleed.
» List the dates of your numbered bleeds below.
» Circle J for joint bleed, M for muscle bleed, or O for other bleed:
1. J M O 9. J M O
2. J M O 10. J M O
3. J M O 11. J M O
4. J M O 12. J M O
5. J M O 13. J M O
6. J M O 14. J M O
7. J M O 15. J M O
8. J M O
Factor Dose/Schedule:
Preventative (ie, prophylaxis)
Routine/minor bleeding
Major/life-threatening bleeding
Start date:
Adapted with permission from
End date: Sue Kovats-Bell, RN, BSN, and
Angela K. Tom, MS, FNP-C
Please call your HTC for:
• Persistent/recurrent bleeding
• Any invasive procedure
• Emergency or trauma
10Brought to you by the makers of
Find your True Identity at YourTrueID.com
Indication for ADVATE
ADVATE [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method] is a medicine used to replace clotting
factor VIII that is missing in people with hemophilia A (also called “classic” hemophilia). ADVATE is used to prevent and
control bleeding in adults and children (0-16 years) with hemophilia A. Your healthcare provider may give you ADVATE
when you have surgery. ADVATE can reduce the number of bleeding episodes in adults and children (0-16 years) when
used regularly (prophylaxis).
ADVATE is not used to treat von Willebrand Disease.
Detailed Important Risk Information for ADVATE
You should not use ADVATE if you are allergic to mice or hamsters or any ingredients in ADVATE.
You should tell your healthcare provider if you have or have had any medical problems, take any medicines, including
prescription and non-prescription medicines and dietary supplements, have any allergies, including allergies to mice or
hamsters, are nursing, are pregnant, or have been told that you have inhibitors to factor VIII.
You can have an allergic reaction to ADVATE. Call your healthcare provider right away and stop treatment if you get a
rash or hives, itching, tightness of the throat, chest pain or tightness, difficulty breathing, lightheadedness, dizziness,
nausea, or fainting.
Your body may form inhibitors to factor VIII. An inhibitor is part of the body’s normal defense system. If you form
inhibitors, it may stop ADVATE from working properly. Consult with your healthcare provider to make sure you are
carefully monitored with blood tests for the development of inhibitors to factor VIII.
Side effects that have been reported with ADVATE include: cough, sore throat, unusual taste, abdominal pain, diarrhea,
nausea/vomiting, headache, fever, dizziness, hot flashes, chills, sweating, joint swelling/aching, itching, hematoma,
swelling of legs, runny nose/congestion, and rash.
Call your healthcare provider right away about any side effects that bother you or if your bleeding does not stop after
taking ADVATE.
You are encouraged to report negative side effects of prescription drugs to the FDA.
Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.
Please see enclosed ADVATE full Prescribing Information.
References:
1. Severity of hemophilia. World Federation of Hemophilia Web site. http://www.wfh.org/en/page.aspx?pid=643. Accessed January 8, 2013.
2. Complications of hemophilia. In: All About Hemophilia: A Guide for Families. Montreal, Quebec, Canada: Canadian Hemophilia Society; 2010.
http://www.hemophilia.ca/files/Chapter%2008.pdf. Accessed January 8, 2013.
3. Aledort LM, Haschmeyer RH, Pettersson H. A longitudinal study of orthopaedic outcomes for severe factor-VIII-deficient haemophiliacs. The Orthopaedic Outcome Study Group.
J Intern Med 1994;236:391 -9.
4. National Hemophilia Foundation. MASAC recommendation concerning prophylaxis (regular administration of clotting factor concentrate to prevent bleeding). MASAC Document #179. November 2007.
5. Management of bleeds. In: All About Hemophilia: A Guide for Families. Montreal, Quebec, Canada: Canadian Hemophilia Society; 2010.
http://www.hemophilia.ca/files/Chapter%2004.pdf. Accessed January 8, 2013.
6. Clotting factor therapy. In: All About Hemophilia: A Guide for Families. Montreal, Quebec, Canada: Canadian Hemophilia Society; 2010.
http://www.hemophilia.ca/files/Chapter%2005.pdf. Accessed January 8, 2013.
7. Gilbert MS. Musculoskeletal complications of hemophilia: the joint. Haemophilia. 2000; 6(suppl 1):34-37.
8. LaFranco J, Delorm D. Making better food choices. HemAware Web site.
http://hemaware.org/health-wellness/fitness-nutrition/making-better-food-choices. Accessed May January 8, 2013.
9. Playing It Safe: Bleeding Disorders, Sports, and Exercise. New York, NY: National Hemophilia Foundation; 2005.
10. du Treil S. Quantifying adherence to treatment and its relationship to quality of life in a well-characterized haemophilia population. Haemophilia. 2007;13:493-501.
11. Butler RB, Crudder SO, Riske B, Toal S. Basic Concepts of Hemophilia. Atlanta, GA: Centers for Disease Control and Prevention; 2001.
12. Nilsson IM, Berntorp E, Lofqvist T, Pettersson H. Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B. J Intern Med 1992;232:25 -32.
13. Schimpf K, Fischer B, Rothmann P. Hemophilia A prophylaxis with factor VIII concentrate in a home-treatment program: a controlled study. Scand J Haematol Suppl. 1977; 30:79-80.
Baxter, Advate and True Identity are trademarks of Baxter International Inc.
©Copyright (December 2012), Baxter Healthcare Corporation. All rights reserved. HYL8266HIGHLIGHTS OF PRESCRIBING INFORMATION
DOSAGE FORMS AND STRENGTHS
These highlights do not include all the information needed to use ADVATE
ADVATE with 5 mL of Sterile Water for Injection, USP is available as a
safely and effectively. See full prescribing information for ADVATE.
lyophilized powder in single-use vials containing nominally 250, 500, 1000,
1500, 2000, 3000 or 4000 IU.
ADVATE ADVATE with 2 mL of Sterile Water for Injection, USP is available as a
[Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method] lyophilized powder in single-use glass vials containing nominally 250, 500,
For Intravenous Use, Lyophilized Powder for Reconstitution 1000 or 1500 IU. (3)
Initial U.S. Approval: 2003
CONTRAINDICATIONS
RECENT MAJOR CHANGES Known anaphylaxis to mouse or hamster protein or other constituents of the
Indications and Usage (1.3) 12/2011 product. (4)
Dosage and Administration (2.3) 12/2011 WARNINGS and PRECAUTIONS
INDICATIONS AND USAGE • Anaphylaxis and severe hypersensitivity reactions may occur. Patients may
ADVATE is an Antihemophilic Factor (Recombinant) indicated for: develop hypersensitivity to mouse or hamster protein, which is present
in trace amounts in the product. Should symptoms occur, discontinue
• Control and prevention of bleeding episodes in adults and children (0-16 treatment with ADVATE and administer appropriate treatment. (5.1)
years) with Hemophilia A. (1.1)
• Perioperative management in adults and children (0-16 years) with • Development of activity-neutralizing antibodies has been detected in
Hemophilia A. (1.2) patients receiving Factor VIII-containing products, including ADVATE. If
expected plasma Factor VIII activity levels are not attained, or if bleeding is
• Routine prophylaxis to prevent or reduce the frequency of bleeding not controlled with an appropriate dose, perform an assay that measures
episodes in adults and children (0-16 years) with Hemophilia A. (1.3) Factor VIII inhibitor concentration. (5.2)
ADVATE is not indicated for the treatment of von Willebrand disease. (1)
ADVERSE REACTIONS
DOSAGE AND ADMINISTRATION
The serious adverse drug reactions are hypersensitivity and Factor VIII
For intravenous use after reconstitution only. (2) inhibitors. (6.1)
• Each vial of ADVATE contains the labeled amount of recombinant Factor
VIII in International Units (IU). (2) The most common adverse drug reactions observed in ≥ 10% of patients
are pyrexia, headache, cough, nasopharyngitis, vomiting, arthralgia, limb
• The required dosage is determined using the following formulas: injury. (6.1)
Desired increment in Factor VIII concentration (IU/dL or % of
normal)=[Total Dose (IU)/body weight (kg) x 2 [IU/dL]/[IU/kg] To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare
Corporation at 1-866-888-2472 or FDA at 1-800-FDA-1088 or
OR www.fda.gov/medwatch.
Required Dose (IU) = body weight (kg) x Desired Factor VIII Rise
(IU/dL or % of normal) x 0.5 (IU/kg per IU/dL). (2) USE IN SPECIFIC POPULATIONS
• Frequency of intravenous injection of the reconstituted product is • Pregnancy: No human or animal data. Use only if clearly needed. (8.1)
determined by the type of bleeding episode and the recommendation of
the treating physician. (2.1, 2.2) • Pediatric Use: Because clearance (based on per kg body weight) has been
• For prophylaxis regimen to prevent or reduce frequency of bleeding demonstrated to be higher in the pediatric population, larger or more frequent
episodes, dose between 20 to 40 IU per kg every other day (3 to 4 times dosing based on per kg body weight may be needed in this population. (8.4)
weekly). Alternatively, an every third day dosing regimen targeted to See 17 for PATIENT COUNSELING INFORMATION and FDA-approved
maintain FVIII trough levels ≥ 1% may be employed. (2.3) patient labeling.
FULL PRESCRIBING INFORMATION: CONTENTS
1 INDICATIONS AND USAGE 3 DOSAGE FORMS AND STRENGTHS 8.3 Nursing Mothers 14 CLINICAL STUDIES
1.1 Control and Prevention of Bleeding 4 CONTRAINDICATIONS 8.4 Pediatric Use 14.1 Original Safety and Efficacy Study
Episodes 8.5 Geriatric Use 14.2 Continuation Study
1.2 Perioperative Management 5 WARNINGS AND PRECAUTIONS 14.3 Perioperative Management Study
5.1 Anaphylaxis and Hypersensitivity 10 OVERDOSAGE
1.3 Routine Prophylaxis 14.4 Routine Prophylaxis Study
Reactions 11 DESCRIPTION
2 DOSAGE AND ADMINISTRATION 5.2 Neutralizing Antibodies 15 REFERENCES
2.1 Control and Prevention of Bleeding 12 CLINICAL PHARMACOLOGY
5.3 Monitoring Laboratory Tests 16 HOW SUPPLIED/STORAGE
Episodes 12.1 Mechanism of Action
6 ADVERSE REACTIONS AND HANDLING
2.2 Perioperative Management 12.2 Pharmacodynamics
6.1 Clinical Trial Experience 16.1 How Supplied
2.3 Routine Prophylaxis 12.3 Pharmacokinetics
6.2 Post Marketing Experience 16.2 Storage and Handling
2.4 Instruction for Use 13 NONCLINICAL TOXICOLOGY
2.5 Preparation and Reconstitution 7 DRUG INTERACTIONS 17 PATIENT COUNSELING INFORMATION
13.1 Carcinogenesis, Mutagenesis, Impairment and FDA-approved patient labeling
2.6 Administration of Fertility
8 USE IN SPECIFIC POPULATIONS * Sections or subsections omitted from the
8.1 Pregnancy full prescribing information are not listed
8.2 Labor and Delivery
Revised: July 2012FULL PRESCRIBING INFORMATION
ADVATE [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method]
1. INDICATIONS AND USAGE 2.3 Routine Prophylaxis
For prevention of bleeding episodes, doses between 20 to 40 International Units of Factor VIII per kg
1.1 Control and Prevention of Bleeding Episodes body weight every other day (3 to 4 times weekly) may be utilized. Alternatively, an every third day
ADVATE [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method] is an Antihemophilic dosing regimen targeted to maintain FVIII trough levels ≥ 1% may be employed. Adjust dose based on
Factor (Recombinant) indicated for control and prevention of bleeding episodes in adults and children the patient’s clinical response.1,2
(0-16 years) with Hemophilia A.
2.4 Instruction for Use
1.2 Perioperative Management Administer ADVATE by intravenous (IV) injection after reconstitution. Ask patients to follow the specific
ADVATE is indicated in the perioperative management in adults and children (0-16 years) with Hemophilia A. preparation and administration procedures provided by their physicians.
1.3 Routine Prophylaxis For instructions, ask patients to follow the recommendations in the FDA-approved patient labeling. [See
FDA-approved patient labeling (17)]
ADVATE is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in
adults and children (0-16 years) with Hemophilia A. Perform reconstitution, product administration, and handling of the administration set and needles with
caution. Percutaneous puncture with a needle contaminated with blood can transmit infectious viruses
ADVATE is not indicated for the treatment of von Willebrand disease. including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs. Place needles
in a sharps container after single use. Discard all equipment, including any reconstituted ADVATE, in an
appropriate container.
2. DOSAGE AND ADMINISTRATION 2.5 Preparation and Reconstitution
For Intravenous Use After Reconstitution Only
The procedures below are provided as general guidelines for the preparation and reconstitution
• Initiate treatment with ADVATE under the supervision of a physician experienced in the treatment of of ADVATE. Always work on a clean surface and wash your hands before performing the following
Hemophilia A. procedures:
• Each vial of ADVATE has the recombinant Factor VIII potency in International Units stated on the 1. Bring the ADVATE (dry factor concentrate) and Sterile Water for Injection, USP (diluent) to room
label. The expected in vivo peak increase in Factor VIII level expressed as IU/dL of plasma or percent temperature.
normal can be estimated by multiplying the dose administered per kg body weight (IU/kg) by 2.
2. Remove caps from the factor concentrate and diluent vials.
• The 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 3. Cleanse stoppers with germicidal solution and allow to dry prior to use. Place the vials on a flat
is especially important in cases of major surgery or life-threatening bleeding episodes. [See Dosage surface.
and Administration (2.1) and (2.2)] 4. Open the BAXJECT II device package by peeling away the
The expected in vivo peak increase in Factor VIII level expressed as IU/dL (or % of normal) can be lid, without touching the inside (Figure A). Do not remove
estimated using the following formulas: the device from the package.
IU/dL (or % of normal)=[Total Dose (IU)/body weight (kg)] x 2 [IU/dL]/[IU/kg] 5. Turn the package over. Press straight down to fully insert
the clear plastic spike through the diluent vial stopper
OR (Figure B).
Dose (International Unit) = body weight (kg) x Desired Factor VIII Rise 6. Grip the BAXJECT II package at its edge and pull the
(IU/dL or % of normal) x 0.5 (IU/kg per IU/dL) package off the device (Figure C). Do not remove the
Examples (assuming patient’s baseline Factor VIII level is < 1% of normal): blue cap from the BAXJECT II device. Do not touch the
1. A dose of 1750 IU ADVATE administered to a 70 kg patient should be expected to result in a peak exposed white plastic spike.
post-infusion Factor VIII increase of 1750 IU x {[2 IU/dL]/[IU/kg]}/[70 kg] = 50 IU/dL (50% of normal). 7. Turn the system over so that the diluent vial is on top.
2. A peak level of 70% is required in a 40 kg child. In this situation, the appropriate dose would be 40 Quickly insert the white plastic spike fully into the ADVATE
kg x 70 IU/dL/{[2 IU/dL]/[IU/kg]} = 1400 IU. vial stopper by pushing straight down (Figure D). The
vacuum will draw the diluent into the ADVATE vial.
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 8. Swirl gently until ADVATE is completely dissolved. Do not
you can estimate the dose by the calculations above, whenever possible, perform appropriate refrigerate after reconstitution.
laboratory tests including serial Factor VIII activity assays. [See Warnings and Precautions (5.4) and 2.6 Administration
Clinical Pharmacology (12.3)]
ADVATE is for intravenous use after reconstitution only.
2.1 Control and Prevention of Bleeding Episodes • Inspect parenteral drug products for particulate matter and discoloration prior to administration,
A guide for dosing in the treatment of bleeding episodes is provided in Table 1. The careful control of whenever solution and container permit. The solution should be clear and colorless in appearance. If
treatment dose is especially important in cases of life-threatening bleeding episodes. not, do not use the solution and notify Baxter immediately.
Table 1 • Administer ADVATE at room temperature within 3 hours of reconstitution.
ADVATE Dosing for Treatment of Bleeding Episodes in Adults and Children • Use plastic syringes with this product because proteins in the product tend to stick to the surface of
Required Peak Post-infusion Dosage and Frequency
glass syringes.
Type of Bleeding Episodes Factor VIII Activity in the Blood Necessary to Maintain the 1. Use aseptic technique.
(as % of Normal or IU/dL) Therapeutic Plasma Level 2. Remove the blue cap from the BAXJECT II device.
10-20 International Units per kga Connect the syringe to the BAXJECT II device (Figure E).
Minor
Early hemarthrosis, mild muscle Repeat infusions every 12 to 24 hours (8 to 24 Do not inject air.
20-40 hours for patients under the age of 6) for one to
bleeding, or mild oral bleeding 3. Turn the system upside down (factor concentrate vial
episode. three days until the bleeding episode is resolved (as
indicated by relief of pain) or healing is achieved. now on top). Draw the factor concentrate into the syringe
15-30 International Units per kga by pulling the plunger back slowly (Figure F).
Moderate 4. Disconnect the syringe; attach a suitable needle and
Moderate bleeding into muscles, Repeat infusions every 12 to 24 hours (8 to
bleeding into the oral cavity, 30-60 24 hours for patients under the age of 6) for inject intravenously as instructed under Administration by Bolus Infusion. If a patient is to receive
definite hemarthroses, and three days or more until the bleeding episode is more than one vial of ADVATE, the contents of multiple vials may be drawn into the same syringe.
known trauma. resolved (as indicated by relief of pain) or healing Please note that the BAXJECT II device is intended for use with a single vial of ADVATE and
is achieved. Sterile Water for Injection, USP only; therefore, reconstituting and withdrawing a second vial
Major into the syringe requires a second BAXJECT II device.
Significant gastrointestinal bleeding, Initial dose 30-50 International Units per kga
intracranial, intra-abdominal or 5. Administer ADVATE over a period of ≤ 5 minutes (maximum infusion rate 10 mL/min). Determine
intrathoracic bleeding, central Repeat dose 30-50 International Units per kg the pulse rate before and during administration of ADVATE. Should a significant increase in pulse
60-100 every 8 to 24 hours (6 to 12 hours for patients rate occur, reducing the rate of administration or temporarily halting the injection usually allows the
nervous system bleeding,
bleeding in the retropharyngeal or under the age of 6) until resolution of the symptoms to disappear promptly.
retroperitoneal spaces or iliopsoas bleeding episode has occurred.
sheath, fractures, head trauma.
a
Dose (IU/kg) = Desired Factor VIII Rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL)
3. DOSAGE FORMS AND STRENGTHS
2.2 Perioperative Management ADVATE with 5 mL of Sterile Water for Injection, USP is available as a lyophilized powder in single-use glass
A guide for dosing in perioperative management is provided in Table 2. The careful control of dose and vials containing nominally 250, 500, 1000, 1500, 2000, 3000 or 4000 International Units (IU). ADVATE with 2
duration of treatment is especially important in cases of major surgery. mL of Sterile Water for Injection, USP is available as a lyophilized powder in single-use glass vials containing
Table 2 nominally 250, 500, 1000 or 1500 IU.
ADVATE Dosing for Perioperative Management in Adults and Children Reconstitute using Sterile Water for Injection, USP (sWFI) provided in the kit.
Required Peak Post-infusion Each vial of ADVATE is labeled with the recombinant Antihemophilic Factor (rAHF) activity expressed in
Type of Surgery Factor VIII Activity in the Blood Frequency of Infusion International Units per vial. This potency assignment employs a Factor VIII concentrate standard that is
(% of Normal or IU/dL) referenced to a WHO (World Health Organization) International Standard for Factor VIII concentrates and is
A single bolus infusion (30-50 International Units/kga) evaluated by appropriate methodology to ensure accuracy of the results.
beginning within one hour of the operation. Optional
Minor
60-100 additional dosing every 12 to 24 hours as needed to control
Including tooth extraction
bleeding. For dental procedures, adjunctive therapy may
be considered. 4. CONTRAINDICATIONS
Major Preoperative bolus infusion: 40-60 International Units/ Known anaphylaxis to mouse or hamster protein or other constituents of the product.
Examples include kga. Verify 100% activity has been achieved prior to
80-120
intracranial, surgery. Maintenance bolus infusion (40-60 International
(pre- and
intra-abdominal, or Units/kga) repeat infusions every 8 to 24 hours (6 to 24
post-operative)
intrathoracic surgery, joint hours for patients under the age of 6), depending on the
replacement surgery desired level of Factor VIII and state of wound healing.
a
Dose (IU/kg) = Desired Factor VIII Rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL)5. WARNINGS AND PRECAUTIONS IMMUNOGENICITY
The development of Factor VIII inhibitors with the use of ADVATE was evaluated in clinical studies with
5.1 Anaphylaxis and Hypersensitivity Reactions pediatric PTPs (50 Factor VIII exposures) and PTPs (≥10 years of age with
Allergic-type hypersensitivity reactions, including anaphylaxis, are possible and have been reported with > 150 Factor VIII exposures). Of 198 subjects who were treated for at least 10 exposure days or on
ADVATE. Symptoms have manifested as dizziness, paresthesias, rash, flushing, face swelling, urticaria, study for a minimum of 120 days, 1 adult developed a low-titer inhibitor (2.0 [BU] in the Bethesda
dyspnea, and pruritus. [See Patient Counseling Information (17)] assay) after 26 exposure days. Eight weeks later, the inhibitor was no longer detectable, and in vivo
ADVATE contains trace amounts of mouse immunoglobulin G (MuIgG): maximum of 0.1 ng/IU ADVATE, recovery was normal at 1 and 3 hours after infusion of another marketed recombinant Factor VIII
and hamster proteins: maximum of 1.5 ng/IU ADVATE. Patients treated with this product may develop concentrate. This single event results in a Factor VIII inhibitor frequency in PTPs of 0.51% (95% CI 0.03
hypersensitivity to these non-human mammalian proteins. to 2.91% for the risk of any Factor VIII inhibitor development).3,4 No Factor VIII inhibitors were detected in
the 53 treated pediatric PTPs.
Discontinue ADVATE if hypersensitivity symptoms occur and administer appropriate emergency treatment.
In clinical studies that enrolled previously untreated subjects (defined as having had up to 3 exposures
5.2 Neutralizing Antibodies to a Factor VIII product at the time of enrollment), 5 (20%) of 25 subjects who received ADVATE
Carefully monitor patients treated with AHF products for the development of Factor VIII inhibitors developed inhibitors to Factor VIII.3 Four patients developed high titer (> 5 BU) and one patient
by appropriate clinical observations and laboratory tests. Inhibitors have been reported following developed low-titer inhibitors. Inhibitors were detected at a median of 11 exposure days (range 7 to 13
administration of ADVATE predominantly in previously untreated patients (PUPs) and previously exposure days) to investigational product.
minimally treated patients (MTPs). If expected plasma Factor VIII activity levels are not attained, or if Immunogenicity also was evaluated by measuring the development of antibodies to heterologous
bleeding is not controlled with an expected dose, perform an assay that measures Factor VIII inhibitor proteins. 182 treated subjects were assessed for anti-Chinese hamster ovary (CHO) cell protein
concentration. [See Warnings and Precautions (5.3)] antibodies. Of these patients, 3 showed an upward trend in antibody titer over time and 4 showed
repeated but transient elevations of antibodies. 182 treated subjects were assessed for muIgG protein
5.3 Monitoring Laboratory Tests antibodies. Of these, 10 showed an upward trend in anti-muIgG antibody titer over time and 2 showed
The clinical response to ADVATE may vary. If bleeding is not controlled with the recommended dose, repeated but transient elevations of antibodies. Four subjects who demonstrated antibody elevations
determine the plasma level of Factor VIII and administer a sufficient dose of ADVATE to achieve a reported isolated events of urticaria, pruritus, rash, and slightly elevated eosinophil counts. All of these
satisfactory clinical response. If the patient’s plasma Factor VIII level fails to increase as expected or subjects had numerous repeat exposures to the study product without recurrence of the events and a
if bleeding is not controlled after the expected dose, suspect the presence of an inhibitor (neutralizing causal relationship between the antibody findings and these clinical events has not been established.
antibodies) and perform appropriate tests as follows: Of the 181 subjects who were treated and assessed for the presence of anti-human von Willebrand
• Monitor plasma Factor VIII activity levels by the one-stage clotting assay to confirm the adequate Factor (VWF) antibodies, none displayed laboratory evidence indicative of a positive serologic response.
Factor VIII levels have been achieved and maintained when clinically indicated. [See Dosage and
Administration (2)] 6.2 Post-Marketing Experience
• Perform the Bethesda assay to determine if Factor VIII inhibitor is present. If expected Factor VIII The following adverse reactions have been identified during post-approval use of ADVATE. Because
activity plasma levels are not attained, or if bleeding is not controlled with the expected dose of these reactions are reported voluntarily from a population of uncertain size, it is not always possible to
ADVATE, use Bethesda Units (BU) to titer inhibitors. reliably estimate their frequency or establish a causal relationship to drug exposure.
– If the inhibitor titer is less than 10 BU per mL, the administration of additional Antihemophilic Among patients treated with ADVATE, cases of serious allergic/hypersensitivity reactions including
Factor concentrate may neutralize the inhibitor and may permit an appropriate hemostatic anaphylaxis have been reported and Factor VIII inhibitor formation (observed predominantly in PUPs).
response. Table 4 represents the most frequently reported post-marketing adverse reactions as MedDRA
Preferred Terms.
– 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 Table 4
VIII. The treatment or prevention of bleeding in such patients requires the use of alternative Post-Marketing Experience
therapeutic approaches and agents.
Organ System [MedDRA Primary SOC] Preferred Term
Anaphylactic reactiona
Immune system disorders
6. ADVERSE REACTIONS Hypersensitivitya
The serious adverse drug reactions (ADRs) seen with ADVATE are hypersensitivity reactions and the Blood and lymphatic system disorders Factor VIII inhibition
development of high-titer inhibitors necessitating alternative treatments to Factor VIII. Injection site reaction
The most common ADRs observed in clinical trials (frequency ≥ 10% of subjects) were pyrexia, headache, Chills
cough, nasopharyngitis, vomiting, arthralgia, limb injury. General disorders and administration site conditions Fatigue/Malaise
Chest discomfort/pain
6.1 Clinical Trial Experience
Less-than-expected therapeutic effect
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 a
These reactions have been manifested by dizziness, paresthesias, rash, flushing, face swelling, urticaria, and/or pruritus.
may not reflect the rates observed in clinical practice.
ADVATE has been evaluated in five completed studies in previously treated patients (PTPs) and one
ongoing study in previously untreated patients (PUPs) with severe to moderately severe Hemophilia A 7. DRUG INTERACTIONS
(Factor VIII ≤ 2% of normal). A total of 234 subjects have been treated with ADVATE as of March 2006. There are no known drug interactions reported with ADVATE. Drug interaction studies have not
Total exposure to ADVATE was 44,926 infusions. The median duration of participation per subject was been performed.
370.5 (range: 1 to 1,256) days and the median number of exposure days to ADVATE per subject was
128.0 (range: 1 to 598).3
The summary of adverse reactions (ADRs) with a frequency ≥5% (defined as adverse events occurring
within 24 hours of infusion or any event causally related occurring within study period) is shown in Table 3. 8. USE IN SPECIFIC POPULATIONS
No subject was withdrawn from a study due to an ADR. There were no deaths in any of the clinical studies. 8.1 Pregnancy
Table 3 Pregnancy Category C. Animal reproduction studies have not been conducted with ADVATE. It is not
Summary of Adverse Reactions (ADRs)a with a Frequency ≥ 5% in 234 Treated Subjectsb known whether ADVATE can cause fetal harm when administered to a pregnant woman or whether it
can affect reproductive capacity. Prescribe ADVATE only if clinically needed.
MedDRAc MedDRA Number Number of Percent of
System Organ Class Preferred Term of ADRs Subjects Subjects 8.2 Labor and Delivery
General disorders and There are no adequate and well-controlled human studies that have investigated the effects of ADVATE
Pyrexia 78 50 21
administration site conditions during labor and delivery. Prescribe ADVATE only if clinically needed.
Nervous system disorders Headache 104 49 21
Respiratory, thoracic and mediastinal disorders Cough 75 44 19 8.3 Nursing Mothers
Infections and infestations Nasopharyngitis 61 40 17 It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
Gastrointestinal disorders Vomiting 35 27 12 human milk, caution should be exercised when ADVATE is administered to a nursing woman. Prescribe
Musculoskeletal and connective tissue disorders Arthralgia 44 27 12 ADVATE only if clinically needed.
Injury, poisoning and procedural complications Limb injury 55 24 10
8.4 Pediatric Use
Upper respiratory
Infections and infestations 24 20 9 In comparison to adults, children present with higher Factor VIII clearance (based on per kg body weight) values
tract infection
Pharyngolaryngeal and thus lower half-life and recovery of Factor VIII. This may be explained by differences in body composition
Respiratory, thoracic and mediastinal disorders 23 20 9 and should be taken into account when dosing or following Factor VIII levels in the pediatric population.5
pain
Respiratory, thoracic and mediastinal disorders Nasal congestion 24 19 8 Because clearance (based on per kg body weight) has been demonstrated to be higher in the pediatric
Gastrointestinal disorders Diarrhea 24 18 8 population, larger or more frequent dosing based on per kg body weight may be needed in this population.
Gastrointestinal disorders Nausea 21 17 8 [See Clinical Pharmacology (12.3)] In the ADVATE Routine Prophylaxis Clinical Study, 3 children aged 7 toFULL PRESCRIBING INFORMATION
ADVATE [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method]
10. OVERDOSAGE 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
No symptoms of overdose with ADVATE have been reported. 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.
11. DESCRIPTION See the description of the clinical study results for a discussion of the effect of long-term exposure on
ADVATE [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method] is a purified glycoprotein the pharmacokinetic properties of ADVATE. [See Clinical Studies (14.2)]
consisting of 2,332 amino acids that is synthesized by a genetically engineered CHO cell line. In culture, In an analysis of data from 58 unique subjects with 65 surgical procedures in the perioperative
the CHO cell line expresses rAHF into the cell culture medium. The rAHF is purified from the culture management study, the target Factor VIII level was met or exceeded in all cases following a single
medium using a series of chromatography columns. The purification process includes an immunoaffinity loading dose ranging from 29 to 104 IU/kg.
chromatography step in which a monoclonal antibody directed against Factor VIII is employed to selectively Pharmacokinetic parameters calculated from interim pharmacokinetic data for 51 subjects ≤ 16 years
isolate the rAHF from the medium. The cell culture and purification processes used in the manufacture of age (per-protocol analysis) are available for 0 neonates, 3 infants, 21 children, and 27 adolescents
of ADVATE employ no additives of human or animal origin. The production process includes a dedicated, as shown in Table 7. The clearance of ADVATE in infants, children, older children, and adolescents
viral inactivation solvent-detergent treatment step. The rAHF synthesized by the CHO cells has the same was 26%, 23%, 42%, and 23% higher than adults (0.031 dL/hr/kg). The half-life of ADVATE in infants,
biological effects on clotting as human Antihemophilic Factor [hAHF]. Structurally the recombinant protein children, older children, and adolescents was 27%, 15%, 10%, and 3% lower than adults (12.08 hours).
has a similar combination of heterogeneous heavy and light chains as found in AHF (Human). The extent to which these differences may be clinically significant is not known.
ADVATE is formulated as a sterile, non-pyrogenic, white to off-white powder for intravenous injection.
When reconstituted with the provided Sterile Water for Injection, USP, the product contains the following Table 7
stabilizers and excipients in targeted amounts: Pharmacokinetic Parameters (Mean ± SD) of ADVATE by Age Group
(N = 51; Intent to Treat Analysis)
Table 5
Approximate Concentration of Stabilizer and Excipient after Reconstitution Infants (N = 3) Children Older Children Adolescents
Parameters (1 month to (N = 8) (N = 13) (N = 27)
5 mL Reconstitution < 2 yrs) (2 to < 5 yrs) (5 to < 12 yrs) (12 to < 16 yrs)
2 mL Reconstitution (for 250,
Stabilizer and Excipient (for 250, 500, 1000, 1500, 2000,
500, 1000, 1500 IU) Target AUC (IU hr/dL) 1385 ± 476 1545 ± 616 1282 ± 509 1447 ± 528
3000, 4000 IU) Target
Cmax (IU/dL) 98.0 ± 10.5 104.6 ± 34.5 111.8 ± 25.7 113.3 ± 21.7
Tris (hydroxymethyl) aminomethane 10 mM 25 mM MRT (hrs) 11.6 ± 3.0 12.8 ± 2.3 13.1 ± 3.5 15.0 ± 5.6
CL (dL/hr/kg) 0.039 ± 0.015 0.038 ± 0.016 0.044 ± 0.012 0.038 ± 0.012
Calcium Chloride 1.7 mM 4.2 mM
Half-life (hrs) 8.86 ± 1.78 10.27 ± 1.94 10.89 ± 1.60 11.70 ± 3.72
Mannitol 3.2% (w/v) 8% (w/v) Vss (dL/kg)a 0.43 ± 0.08 0.46 ± 0.12 0.54 ± 0.07 0.53 ± 0.08
Recoveryb IU/dL/IU/kg 1.96 ± 0.21 2.05 ± 0.62 2.21 ± 0.44 2.26 ± 0.42
Sodium Chloride 90 mM 225 mM
a
Volume of distribution at steady state
α, α-Trehalose 0.8% (w/v) 2% (w/v) b
Incremental recovery at Cmax calculated as (Cmax – baseline Factor VIII) divided by the dose in IU/kg, where Cmax is the maximal post-infusion
Factor VIII measurement
Histidine 10 mM 25 mM
In a crossover pharmacokinetic study of rAHF-PFM reconstituted in 2 mL versus 5 mL Sterile Water for
Glutathione (Reduced) 0.08 mg/mL 0.2 mg/mL 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,
Polysorbate 80 0.01% (w/v) 0.025% (w/v) indicating that the two formulations are pharmacokinetically equivalent.
ADVATE is available in single-dose vials that contain nominally 250, 500, 1000, 1500, 2000, 3000 or 4000
International Units (IU) per vial. The product contains the following stabilizers and excipients: mannitol, 13. NONCLINICAL TOXICOLOGY
trehalose, sodium chloride, histidine, Tris, calcium chloride, polysorbate 80, and glutathione. VWF is co- Single doses, several-fold higher than the recommended clinical dose (related to body weight), did not
expressed with Factor VIII and helps to stabilize it in culture. The final product contains no more than 2 ng demonstrate any acute or toxic effect for ADVATE in laboratory animals (mouse, rat, rabbit, and dog).
VWF/IU rAHF, which will not have any clinically relevant effect in patients with von Willebrand disease. The Multiple dose studies were not performed with ADVATE but were performed with the related product,
product contains no preservative. RECOMBINATE, and with formulation buffers of ADVATE.
Each vial of ADVATE is labeled with the rAHF activity expressed in International Units per vial. Biological
potency is determined by an in vitro assay, which employs a Factor VIII concentrate standard that is 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
referenced to a WHO International Standard for Factor VIII concentrates. One International Unit, as defined No studies have been conducted with the active ingredient in ADVATE to assess its mutagenic or
by the WHO standard for blood coagulation Factor VIII, human, is approximately equal to the level of Factor carcinogenic potential. The CHO cell line employed in the production of ADVATE is derived from that used
VIII activity found in 1 mL of fresh pooled human plasma. The specific activity of ADVATE is 4000 to 10000 in the biosynthesis of RECOMBINATE [Antihemophilic Factor (Recombinant)]. ADVATE has been shown
International Units per milligram of protein. to be comparable to RECOMBINATE with respect to its biochemical and physicochemical properties, as
well as its non-clinical in vivo pharmacology.
RECOMBINATE was tested for mutagenicity at doses considerably exceeding plasma concentrations
12. CLINICAL PHARMACOLOGY 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
12.1 Mechanism of Action in bone marrow polychromatic erythrocytes. Studies in animals have not been performed to evaluate
ADVATE temporarily replaces the missing coagulation Factor VIII that is needed for effective hemostasis. carcinogenic potential.
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
14. CLINICAL STUDIES
normalizes the aPTT over the effective dosing period. 14.1 Original Safety and Efficacy Study
12.3 Pharmacokinetics The original safety and efficacy study evaluated the pharmacokinetics (double-blinded, randomized,
cross-over), safety, immunogenicity, and hemostatic efficacy (open-label) of ADVATE in 111 subjects.
A randomized, crossover pharmacokinetic study of ADVATE produced at Orth, Austria (test) and
The study was conducted with 103 Caucasian; 7 Black and 1 Asian US and European previously treated
RECOMBINATE [Antihemophilic Factor (Recombinant)] (reference) was conducted in 56 non-bleeding
subjects (PTPs with ≥ 150 exposure days) diagnosed with moderate to severe hemophilia A (FVIII level
subjects. The subjects received either of the products as an IV infusion (50 ± 5 IU/kg body weight) and
≤ 2% of normal), who were ≥ 10 years of age (20 were 10 to 16 years) good, fair, or none, based on the quality of hemostasis achieved with ADVATE produced in the Orth
facility for the treatment of each new bleeding episode. A total of 510 bleeding episodes were reported,
RECOMBINATE (n = 20)a ADVATE (n = 20)a with a mean (± SD) of 6.1 ± 8.2 bleeding episodes per subject. Of these 510 episodes, 439 (86%) were
Parameter
Mean ± SD Mean ± SD rated excellent or good in their response to treatment with ADVATE, 61 (12%) were rated fair, 1 (0.2%)
AUC0-48h (IU·hrs/dL)b 1638 ± 357 1644 ± 338 was rated as having no response, and for 9 (2%), the response to treatment was unknown. A total of
In vivo recovery (IU/dL/IU/kg)c 2.74 ± 0.56 2.57 ± 0.53 411 (81%) bleeding episodes were managed with a single infusion, 62 (12%) required 2 infusions,
Half-life (hrs) 11.16 ± 2.50 12.03 ± 4.15 15 (3%) required 3 infusions, and 22 (4%) required 4 or more infusions of ADVATE for satisfactory
Cmax (IU/dL) 136 ± 29 128 ± 28
resolution. A total of 162 (32%) bleeding episodes occurred spontaneously, 228 (45%) were the result of
antecedent trauma, and for 120 (24%) bleeding episodes, the etiology was unknown.4
MRT (hrs) 14.68 ± 3.82 15.81 ± 5.91
The rate of new bleeding episodes during the protocol-mandated 75 exposure day prophylactic regimen
Vss (dL/kg) 0.43 ± 0.10 0.44 ± 0.10
(≥ 25 IU/kg body weight 3-4 times per week) was calculated as a function of the etiology of bleeding
CL (dL/hr/kg) 0.03 ± 0.01 0.03 ± 0.01 episodes for 107 evaluable subjects (n = 274 new bleeding episodes).4 These rates are presented in
a
56 subjects were enrolled in the clinical study. The per-protocol analysis included 30 patients (20 adults and 10 children). The PK parameters in Table 8.
the table are calculated for adult subjects only.
b
Area under the plasma Factor VIII concentration x time curve from 0 to 48 hours post-infusion.
c
Calculated as (Cmax – baseline Factor VIII) divided by the dose in IU/kg, where Cmax is the maximal post-infusion Factor VIII measurement.Table 8 14.4 Routine Prophylaxis Study
Rate of New Bleeding Episodes During Prophylaxis
In a multicenter, open-label, prospective, randomized, controlled postmarketing clinical study of the relative
Bleeding Episode Etiology Mean (± SD) New Bleeding Episodes/Subject/Month efficacy of ADVATE use in 2 prophylactic treatment regimens compared to that of on-demand treatment,
Spontaneous 0.34 ± 0.49 53 PTPs with severe to moderately severe Hemophilia A (FVIII level ≤ 2 IU/dL) were analyzed in the per-
Post-traumatic 0.39 ± 0.46 protocol group. Subjects were initially treated for 6 months of on-demand therapy and then randomized to
Unknowna 0.33 ± 0.34 12 months of either a standard prophylaxis regimen (20-40 IU/kg every 48 hours) or PK-driven prophylaxis
Overall 0.52 ± 0.71 regimen (20-80 IU/kg every 72 hours). All subjects had a history of at least 8 joint hemorrhages per year
a
Etiology was indeterminate
upon entering the study. Each subject in the per-protocol group was adherent to > 90% of the prescribed
number of prophylactic infusions; no subject in the study surpassed the upper boundary of 110% of the
The pharmacokinetic properties of ADVATE were investigated at the beginning of treatment in a multicenter prescribed number of prophylactic infusions.
study of previously treated subjects and at the end of treatment in a subset of subjects (N=13) who had The median annual bleed rate during the on-demand therapy period was 44 bleeds per subject per year
completed at least 75 exposure days of treatment with ADVATE. Post-infusion levels and clearance of Factor compared to 1 bleed per subject per year while on either prophylaxis regimen, which was a statistically
VIII during the perioperative period were examined in an interim analysis of subjects enrolled in a surgery significant difference (p12y: Major: 22 Caucasian: 55
4 IU·kg-1·h-1; initial rate subjects Minor: 35 Black: 3 Any Prophylaxis On-Demand
5-12y: 5 IU·kg-1·h-1 for; then Orthopedic: 40 Asian: 1 Age Category Percentage of Percentage of
investigator-determined Dental: 8 N Min Med Max Subjects With N Min Med Max Subjects With
3. Home Replacement Therapy 7 toFULL PRESCRIBING INFORMATION
ADVATE [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method]
15. REFERENCES 17. PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Patient Information and Instructions for Use)
1. Fischer K, Collins P, Björkman S, Blanchette V, Oh M, Fritsch S, Schroth P, Spotts G, Ewenstein B. • Advise patients to report any adverse reactions or problems following ADVATE administration to their
Trends in bleeding patterns during prophylaxis for severe haemophilia: observations from a series of physician or healthcare provider.
prospective clinical trials. Haemophilia 2011 17(3):433-8. • Allergic-type hypersensitivity reactions have been reported with ADVATE. Warn patients of the early
2. Collins PW, Blanchette VS, Fischer K, Björkman S, Oh M, Fritsch S, Schroth P, Astermark J, Spotts G, signs of hypersensitivity reactions, including hives, pruritus, generalized urticaria, angioedema,
Ewenstein B, The rAHF-PFM Study Group. Break-through bleeding in relation to predicted factor VIII hypotension, shock, anaphylaxis and acute respiratory distress. Advise patients to discontinue use of
levels in patients receiving prophylactic treatment for severe haemophilia A. J Thromb Haemost 2009 the product if these symptoms occur and seek immediate emergency treatment with resuscitative
7(3):413-20. measures such as the administration of epinephrine and oxygen.
3. Shapiro A, Gruppo R, Pabinger I et al. Integrated analysis of safety and efficacy of a plasma- and • Inhibitor formation may occur with the treatment of a patient with Hemophilia A. Advise patients
albumin-free recombinant factor VIII (rAHF-PFM) from six clinical studies in patients with hemophilia A. to contact their physician or treatment center for further treatment and/or assessment if they
Expert Opin Biol Ther 2009 9:273-283. experience a lack of clinical response to Factor VIII replacement therapy, as this may be a
4. Tarantino MD, Collins PW, Hay PW et al. Clinical evaluation of an advanced category antihaemophilic manifestation of an inhibitor.
factor prepared using a plasma/albumin-free method: pharmacokinetics, efficacy, and safety in • Advise patients to consult with their physicians or healthcare provider prior to travel.
previously treated patients with haemophilia A. Haemophilia 2004 10:428-437. • While traveling advise patients to bring an adequate supply of ADVATE based on their current
5. Björkman S, Blanchette VS, Fischer K, Oh M, Spotts G, Schroth P, Fritsch S, Patrone L, Ewenstein BM, regimen of treatment.
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.
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.
7. White II GC, Courter S, Bray GL et al. A multicenter study of recombinant factor VIII (Recombinate) in
previously treated patients with hemophilia A. Thromb Haemost 1997 77:660-667.
8. Lee CA, Owens D, Bray G et al. Pharmacokinetics of recombinant factor VIII (Recombinate) using one-
stage clotting and chromogenic factor VIII assay. Thromb Haemost 1999 82:1644-1647.
16. HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
ADVATE is available in single-dose vials that contain the following nominal product strengths:
Nominal Factor VIII NDC (Includes NDC (Includes
Strength Potency Range 5 mL sWFI Diluent) 2 mL sWFI Diluent)
250 IU 200–400 IU per vial 0944-2960-10 0944-2921-02
500 IU 401–800 IU per vial 0944-2961-10 0944-2922-02
1000 IU 801–1200 IU per vial 0944-2962-10 0944-2923-02
1500 IU 1201–1800 IU per vial 0944-2963-10 0944-2924-02
2000 IU 1801–2400 IU per vial 0944-2964-10
3000 IU 2401–3600 IU per vial 0944-2965-10
4000 IU 3601–4800 IU per vial 0944-2948-10
Actual Factor VIII activity in International Units is stated on the label of each ADVATE carton and vial.
16.2 Storage and Handling
ADVATE is packaged with 5 mL or 2 mL of Sterile Water for Injection, USP, a BAXJECT II Needleless
Transfer Device, one Terumo Microbore Infusion set (2 mL only), one full prescribing physician insert,
and one patient insert.
ADVATE should be refrigerated (2° - 8°C [36° - 46°F]) in powder form.
ADVATE may be stored at room temperature (up to 30°C [86°F]) for a period of up to 6 months not to
exceed the expiration date.
The date that ADVATE is removed from refrigeration should be noted on the carton.
Do not use beyond the expiration date printed on the vial or six months after date noted on the carton,
whichever is earlier. After storage at room temperature, the product must not be returned to the
refrigerator. Avoid freezing to prevent damage to the diluent vial.
To enroll in the confidential, industry-wide Patient Notification System, call 1-888-873-2838.
Baxter, Advate, Baxject and Recombinate are trademarks of Baxter International Inc. Baxter, Advate and Baxject are
registered in the U.S. Patent and Trademark Office.
Patented under U.S. Patent Numbers: 5,733,873; 5,854,021; 5,919,766; 5,955,448; 6,313,102; 6,586,573; 6,649,386;
7,087,723; and 7,247,707. Made according to the method of U.S. Patent Numbers: 5,470,954; 6,100,061; 6,475,725;
6,555,391; 6,936,441; 7,094,574; 7,253,262; and 7,381,796.
Baxter Healthcare Corporation, Westlake Village, CA 91362 USA
U.S. License No. 140
Printed in USA
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