Advate

The serious adverse drug reactions (ADRs) seen with ADVATE are hypersensitivity reactions and the development of high-titer inhibitors necessitating alternative treatments to Factor VIII.

The most common ADRs observed in clinical trials (frequency ≥ 10% of subjects) were pyrexia, headache, cough, nasopharyngitis, vomiting, arthralgia, limb injury.

Clinical Trial 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 five completed studies in previously treated patients (PTPs) and one ongoing study in previously untreated patients (PUPs) with severe to moderately severe Hemophilia A (Factor VIII ≤ 2% of normal). A total of 234 subjects have been treated with ADVATE as of March 2006. Total exposure to ADVATE was 44,926 infusions. The median duration of participation per subject was 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.

No subject was withdrawn from a study due to an ADR. There were no deaths in any of the clinical studies.

Table 3: Summary of Adverse Reactions (ADRs)a with a Frequency ≥ 5% in 234 Treated Subjectsb

The development of Factor VIII inhibitors with the use of ADVATE was evaluated in clinical studies with pediatric PTPs ( < 6 years of age with > 50 Factor VIII exposures) and PTPs ( ≥ 10 years of age with > 150 Factor VIII exposures). Of 198 subjects who were treated for at least 10 exposure days or on study for a minimum of 120 days, 1 adult developed a low-titer inhibitor (2.0 [BU] in the Bethesda assay) after 26 exposure days. Eight weeks later, the inhibitor was no longer detectable, and in vivo recovery was normal at 1 and 3 hours after infusion of another marketed recombinant Factor VIII concentrate. This single event results in a Factor VIII inhibitor frequency in PTPs of 0.51% (95% CI 0.03 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.

In clinical studies that enrolled previously untreated subjects (defined as having had up to 3 exposures to a Factor VIII product at the time of enrollment), 5 (20%) of 25 subjects who received ADVATE developed inhibitors to Factor VIII.3 Four patients developed high titer ( > 5 BU) and one patient developed low-titer inhibitors. Inhibitors were detected at a median of 11 exposure days (range 7 to 13 exposure days) to investigational product.

Immunogenicity also was evaluated by measuring the development of antibodies to heterologous proteins. 182 treated subjects were assessed for anti-Chinese hamster ovary (CHO) cell protein 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 antibodies. Of these, 10 showed an upward trend in anti-muIgG antibody titer over time and 2 showed repeated but transient elevations of antibodies. Four subjects who demonstrated antibody elevations reported isolated events of urticaria, pruritus, rash, and slightly elevated eosinophil counts. All of these subjects had numerous repeat exposures to the study product without recurrence of the events and a causal relationship between the antibody findings and these clinical events has not been established. Of the 181 subjects who were treated and assessed for the presence of anti-human von Willebrand Factor (VWF) antibodies, none displayed laboratory evidence indicative of a positive serologic response.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval 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.

Among patients treated with ADVATE, cases of serious allergic/hypersensitivity reactions including anaphylaxis have been reported and Factor VIII inhibitor formation (observed predominantly in PUPs). Table 4 represents the most frequently reported post-marketing adverse reactions as MedDRA Preferred Terms.

Table 4: Post-Marketing Experience

ADVATE
(ad-vate)
[Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method] for Intravenous Injection

This leaflet summarizes important information about ADVATE. Please read it carefully before using this medicine. This information does not take the place of talking with your healthcare provider, and it does not include all of the important information about ADVATE. If you have any questions after reading this, ask your healthcare provider.

What is the most important information I need to know about ADVATE?

Do not attempt to do an infusion to yourself unless you have been taught how by your healthcare provider or hemophilia center.

You must carefully follow your healthcare provider's instructions regarding the dose and schedule for infusing ADVATE so that your treatment will work best for you.

What is ADVATE?

ADVATE is a medicine used to replace clotting factor (Factor VIII or Antihemophilic Factor) that is missing in people with Hemophilia A (also called “classic” hemophilia). Hemophilia A is an inherited bleeding disorder that prevents blood from clotting normally.

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.

Who should not use ADVATE?

You should not use ADVATE if you

• are allergic to mice or hamsters.
• are allergic to any ingredients in ADVATE.

Tell your healthcare provider if you are pregnant or breastfeeding because ADVATE may not be right for you.

How should I use ADVATE?

ADVATE is given directly into the bloodstream.

You may infuse ADVATE at a hemophilia treatment center, at your healthcare provider's office or in your home. You should be trained on how to do infusions by your healthcare provider or hemophilia treatment center. Many people with Hemophilia A learn to infuse their ADVATE by themselves or with the help of a family member.

Your healthcare provider will tell you how much ADVATE to use based on your weight, the severity of your Hemophilia A, and where you are bleeding.

You may have to have blood tests done after getting ADVATE to be sure that your blood level of Factor VIII is high enough to clot your blood.

Call your healthcare provider right away if your bleeding does not stop after taking ADVATE.

What should I tell my healthcare provider before I use ADVATE?

You should tell your healthcare provider if you

• have or have had any medical problems.
• take any medicines, including prescription and nonprescription medicines, such as over-the-counter medicines, supplements or herbal remedies.
• have any allergies, including allergies to mice or hamsters.
• are breastfeeding. It is not known if ADVATE passes into your milk and if it can harm your baby.
• are pregnant or planning to become pregnant. It is not known if ADVATE may harm your unborn baby.
• have been told that you have inhibitors to Factor VIII (because ADVATE may not work for you).

What are the possible side effects of ADVATE?

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.

Side effects that have been reported with ADVATE include:

cough
headache
joint swelling/aching
sore throat
fever
itching
unusual taste
dizziness
hematoma
abdominal pain
hot flashes
swelling of legs
diarrhea
chills
runny nose/congestion
nausea/vomiting
sweating
rash

Tell your healthcare provider about any side effects that bother you or do not go away.

These are not all the possible side effects with ADVATE. You can ask your healthcare provider for information that is written for healthcare professionals.

What are the ADVATE dosage strengths?

ADVATE comes in seven different dosage strengths: 250 International Units (IU), 500 IU, 1000 IU, 1500 IU, 2000 IU*, 3000 IU* and 4000 IU*. The actual strength will be imprinted on the label and on the box. The seven different strengths are color coded, as follows:

Dosage strength of approximately 250 International Units per vial (200-400 IU/vial)

Dosage strength of approximately 500 International Units per vial (401-800 IU/vial)

Dosage strength of approximately 1000 International Units per vial (801-1200 IU/vial)

Dosage strength of approximately 1500 International Units per vial (1201-1800 IU/vial)

Dosage strength of approximately 2000 International Units per vial (1801-2400 IU/vial) (*available only with 5 mL sWFI)

Dosage strength of approximately 3000 International Units per vial (2401-3600 IU/vial) (*available only with 5 mL sWFI)

Dosage strength of approximately 4000 International Units per vial (3601-4800 IU/vial) (*available only with 5 mL sWFI)

Always check the actual dosage strength printed on the label to make sure you are using the strength prescribed by your healthcare provider. Always check the expiration date printed on the box. Do not use the product after the expiration date printed on the box.

How do I store ADVATE?

Do not freeze ADVATE.

Store ADVATE vials containing powdered product (without sterile diluent added) in a refrigerator (2° to 8°C [36° to 46°F]) or at room temperature (up to 30°C [86°F]) for up to 6 months.

If you choose to store ADVATE at room temperature:

• note the date that the product is removed from refrigeration on the box.
• do not use after 6 months from this date or the expiration date listed on the vial, whichever is earlier.
• do not return the product back to the refrigerator.

Store vials in their original box and protect them from extreme exposure to light.

Reconstituted product (after mixing dry product with wet diluent) must be used within 3 hours and cannot be stored or refrigerated. Discard any ADVATE left in the vial at the end of your infusion.

What else should I know about ADVATE and Hemophilia A?

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.

Medicines are sometimes prescribed for purposes other than those listed here. Do not use ADVATE for a condition for which it is not prescribed. Do not share ADVATE with other people, even if they have the same symptoms that you have.

Resources at Baxter available to the patients:

For more product information on ADVATE, please visit www.advate.com or call 1-888-423-8283.

For information on patient assistance programs that are available to you, including the Baxter CARE Program, please contact the Baxter Insurance Assistance Helpline at 1-888-229-8379.

For information on additional Baxter patient resources, please visit www.advate.com.

Instructions For Use

ADVATE
[Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method] (For intravenous use only)

Do not attempt to do an infusion to yourself unless you have been taught how by your healthcare provider or hemophilia center.

See below for step-by-step instructions for reconstituting ADVATE at the end of this leaflet.

Always follow the specific instructions given by your healthcare provider. The steps listed below are general guidelines for using ADVATE. If you are unsure of the procedures, please call your healthcare provider before using.

Call your healthcare provider right away if bleeding is not controlled after using ADVATE.

Your healthcare provider will prescribe the dose that you should take.

Your healthcare provider may need to take blood tests from time to time.

Talk to your healthcare provider before traveling. Plan to bring enough ADVATE for your treatment during this time.

Dispose of all materials, including any leftover reconstituted ADVATE product, in an appropriate container.

ADVATE with 5 mL Diluent

1. Prepare a clean flat surface and gather all the materials you will need for the infusion. Check the expiration date, and let the vials with the ADVATE concentrate and the Sterile Water for Injection, USP (diluent) warm up to room temperature. Wash your hands and put on clean exam gloves. If infusing yourself at home, the use of gloves is optional. If you are using more than one vial of ADVATE, make sure you mix each vial of ADVATE with the Sterile Water for Injection, USP that is provided in the box.

ADVATE with 2 mL Diluent

a. When ADVATE is provided with 5 mL of Sterile Water for Injection, USP, the drug product and its diluent are provided in an orange box; the 5 mL diluent vial has a grey cap.

b. When ADVATE is provided with 2 mL of Sterile Water for Injection, USP, the drug product and its diluent are provided in a purple box; the 2 mL diluent vial has a transparent cap.

2. Remove caps from the ADVATE concentrate and diluent vials to expose the centers of the rubber stoppers.

3. Disinfect the stoppers with an alcohol swab (or other suitable solution suggested by your healthcare provider or hemophilia center) by rubbing the stoppers firmly for several seconds and allow them to dry prior to use. Place the vials on a flat surface.

4. Open the BAXJECT II device package by peeling away the lid, without touching the inside of the package. Do not remove the BAXJECT II device from the package.

5. Turn the package with the BAXJECT II device upside down and place it over the top of the diluent vial. Fully insert the clear plastic spike of the device into the center of the diluent vial's stopper by pushing straight down. Grip the package at its edge and lift it off the device. Be careful not to touch the white plastic spike. Do not remove the blue cap from the BAXJECT II device.

The diluent vial now has the BAXJECT II device connected to it and is ready to be connected to the ADVATE vial.

6. To connect the diluent vial to the ADVATE vial, turn the diluents vial over and place it on top of the vial containing ADVATE concentrate. Fully insert the white plastic spike into the ADVATE vial's stopper by pushing straight down. Diluent will flow into the ADVATE vial. This should be done right away to keep the liquid free of germs.

7. Swirl the connected vials gently and continuously until the ADVATE is completely dissolved. Do not shake. The ADVATE solution should look clear and colorless. If not, do not use it and notify Baxter immediately.

8. Take off the blue cap from the BAXJECT II device and connect the syringe. Be careful to not inject air.

9. Turn over the connected vials so that the ADVATE vial is on top. Draw the ADVATE solution into the syringe by pulling back the plunger slowly. Disconnect the syringe from the vials. Attach the infusion needle to the syringe using a winged (butterfly) infusion set, if available. Point the needle up and remove any air bubbles by gently tapping the syringe with your finger and slowly and carefully pushing air out of the syringe and needle.

10. If you are using more than one vial of ADVATE, the contents of more than one vial may be drawn into the same syringe. Make sure you mix each vial of ADVATE with the Sterile Water for Injection, USP that is provided in the box (Following Steps 1-9). You will need a separate BAXJECT II device to mix each additional vial of ADVATE.

Apply a tourniquet and get the injection site ready by wiping the skin well with an alcohol swab (or other suitable solution suggested by your healthcare provider or hemophilia center).

11. Insert the needle into the vein and remove the tourniquet. Slowly infuse the ADVATE. Do not infuse any faster than 10 mL per minute.

12. Take the needle out of the vein and use sterile gauze to put pressure on the infusion site for several minutes.

Do not recap the needle. Place it with the used syringe in a hard-walled Sharps container for proper disposal.

Remove the peel-off label from the ADVATE vial and place it in your logbook. Clean any spilled blood with a freshly prepared mixture of 1 part bleach and 9 parts water, soap and water, or any household disinfecting solution.

13. Dispose of the used vials and BAXJECT II system in your hardwalled  Sharps container without taking them apart. Do not dispose of these supplies in ordinary household trash.

Important: Contact your healthcare provider or local hemophilia treatment center if you experience any problems.

Advate is a prescription medication used to prevent bleeding episodes in children and adults with hemophilia A (cogenital factor VIII deficiency). 

Advate belongs to a group of drugs called clotting factors. It works by replacing a protein in the blood that is needed to control bleeding that people with hemophilia A are missing.

This medication comes in an injectable form to be given directly into a vein (IV) by a healthcare professional.

Common side effects of Advate include fever, headache, cough, and infection of the nose and throat.

Advate is a prescription medication used to prevent and control bleeding in adults and children with hemophilia A, a genetic disorder that increases bleeding and is caused by a missing or defective protein called factor VIII clotting factor. This medication is approved to prevent bleeding during surgery. Advate is also approved to prevent or reduce the frequency of bleeding episodes.

This medication is not approved to treat von Willebrand disease. 

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Advate, there are no specific foods that you must exclude from your diet when receiving this medication.

In the U.S.

• Advate
• Adynovate
• Afstyla
• Eloctate
• Helixate FS
• Hemofil-M
• Hyate:C
• Koate DVI
• Kogenate FS
• Monarc-M
• Monoclate-P
• Obizur
• Xyntha

Available Dosage Forms:

• Powder for Solution

Therapeutic Class: Antihemophilic Agent

• If you have an allergy to Advate (antihemophilic factor (recombinant) (advate)) or any part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are allergic to hamsters, talk with the doctor.
• If you are allergic to mouse proteins, talk with the doctor.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Advate with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

The most serious adverse drug reactions (ADRs) seen with Advate are hypersensitivity reactions and the development of high-titer inhibitors necessitating alternative treatments of Factor VIII..

The most common ADRs observed in clinical trials (frequency > 2% of subjects) were: Factor VIII inhibitor formation (observed predominantly in PUPs) and headache.(6.1)

Clinical Trial 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 five completed studies in previously treated patents (PTPs) and one ongoing study in PUPs with severe to moderately severe Hemophilia A (Factor VIII ≤ 2% of normal). A total of 234 subjects have been treated with Advate as of March 2006. Total exposure to Advate was 44,926 infusions. The median duration of participation per subject was 370.5 (range: 1 to 1,256) days and the median exposure to Advate per subject was 128.0 (range: 1 to 598) days.

There were 2,507 adverse events (AEs) reported in 215 subjects. None of the subjects withdrew from the studies due to adverse events. There were no deaths. Nineteen treated subjects reported no AEs during their participation. The most common AEs (product-related and unrelated, according to the investigator's opinion) occurring in at least 5% if subjects who received at least 1 Advate study infusion as shown in Table 3.

The majority of the events in Table 3 appear to have been related to trauma, intercurrent mild respiratory or gastrointestinal disease or well-described complications of hemophilia.

Fifty-six ADRs were reported in 27 subjects. Nearly all (53/56) were isolated events or occurred once in one subject with numerous subsequent infusions without reoccurrence. The most common ADRs with a frequency greater than or equal to 2% are shown in Table 4. Of all ADRs, none were reported in neonates, 16 were reported in infants, 7 were reported in children, 8 were reported in adolescents, and 25 were reported in adults.

Immunogenicity

The development of Factor VIII inhibitors with the use of Advate was evaluated in clinical studies with pediatric PTPs (<6 years of age with >50 Factor VIII exposures) and PTPs (>10 years of age with >150 Factor VIII exposures). Of 198 subjects who were treated for at least 10 exposure days or on study for a minimum of 120 days, 1 adult developed a low-titer inhibitor (2.0 [BU] in the Bethesda assay) after 26 exposure days. Eight weeks later, the inhibitor was no longer detectable, and in vivo recovery was normal at 1 and 3 hours after infusion of another marketed recombinant Factor VIII concentrate. This single event results in a Factor VIII inhibitor frequency in PTPs of 0.51% (95% CI of 0.03 and 2.91% for the risk of any Factor VIII inhibitor development). No factor VIII inhibitors were detected in the 53 treated pediatric PTPs.

In clinical studies that enrolled previously untreated subjects (defined as having had up to 3 exposures to a Factor VIII product at the time of enrollment, 5 (20%) of 25 subjects who received Advate developed inhibitors to Factor VIII. Four patients developed high titer ( > 5 BU) and one patient developed low-titer inhibitors. Inhibitors were detected at a median of 11 exposure days (range 7 to 13 exposure days) to investigational product.

Immunogenicity was also evaluated by measuring the development of antibodies to heterologous proteins. 182 treated subjects were assessed for anti-chinese hamster ovary cell protein 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 muIgGl protein antibodies. Of these 10 showed an upward trend in anti-mu IgG antibody titer over time and 2 showed repeated but transient elevations of antibodies. Four subjects who demonstrated antibody elevations reported isolated events of urticaria, pruritus, rash, and slightly elevated eosinophil counts. All of these subjects had numerous repeat exposures to the study product without recurrence of the events and a causal relationship between the antibody findings and these clinical events has not been established.

Of the 181 subjects who were treated and assessed for the presence of anti-human von Willebrand Factor (VWF) antibodies, none displayed laboratory evidence indicative of a positive serologic response.

Post Marketing Experience

The following adverse reactions have been identified during post approval 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.

Among patients treated with Advate, cases of serious allergic/hypersensitivity reactions including anaphylaxis have been reported and Factor VIII inhibitor formation (observed predominantly in PUPs).

Table 5 represents the most frequently reported post-marketing adverse reactions as MedDRA Preferred Terms.

How Supplied

Advate [Antihemophilic factor (recombinant) plasma /Albumin Free Method] is available in single-dose vials that contain the following nominal product strengths:

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

Storage and Handling

Advate is packaged with 5 mL of Sterile Water for Injection, USP, a BAXJECT II Needleless Transfer Device, 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.

See Patient Product Information (PPI) 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 with resuscitative measures such as the administration of epinephrine and oxygen.
• Inhibitor formation may occur with the treatment of a patient with hemophilia A. Advise patients to contact their physician or treatment center for further treatment and/or assessment, 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 UPDATE U (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.

U.S. Patent Numbers:

4,757,006; 5,198,349; 5,250,421; 5,733,873; 5,919,766; 4,891,319; 5,955,448; 6,313,102; 5,891,873; 6,034,080; 6,649,386; 5,854,021; 5,470,954; 6,555,391; 6,936,441; 7,094,574; 6,100,061; 6,475,725; 6,586,573; 7,087,7236,475,725; 6,100,061; 6,586,573; 6,555,391; 5,198,349; 4,757,006; 5,470,954

Baxter Healthcare Corporation
Westlake Village, CA 91362 USA
U.S. License No. 140
Printed in USA

FDA-Approved Patient Labeling – Patient Product Information (PPI)

Advate (ad-vate)
[Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method]

This leaflet summarizes important information about Advate. Please read it carefully before using this medicine. This information does not take the place of talking with your healthcare provider, and it does not include all of the important information about Advate. If you have any questions after reading this, ask your healthcare provider.

What is the most important information I need to know about Advate?

Do not attempt to do an infusion to yourself unless you have been taught how by your doctor or hemophilia center.

You must carefully follow your doctor's or other healthcare provider's instructions regarding the dose and schedule for infusing Advate so that your treatment will work best for you.

What is Advate?

Advate is a medicine used to replace clotting factor (Factor VIII or antihemophilic factor) that is missing in people with hemophilia A (also called "classic" hemophilia). Hemophilia A is an inherited bleeding disorder that prevents blood from clotting normally.

Advate is used to prevent and control bleeding in people with hemophilia A.

Advate is not used to treat von Willebrand's Disease.

Who should not use Advate?

You should not use Advate if you

• are allergic to mouse or hamster proteins.
• are allergic to any ingredients in Advate.

Tell your healthcare provider if you are pregnant or breast-feeding because Advate many not be right for you.

How should I use Advate?

Advate is given directly into the blood stream.

You may infuse Advate at a hemophilia treatment center, at your healthcare provider's office or in your home. You should be trained on how to do infusions by your hemophilia treatment center or healthcare provider. Many people with hemophilia A learn to infuse their Advate by themselves or with the help of a family member.

Your healthcare provider will tell you how much Advate to use based on your weight, the severity of your hemophilia A, and where you are bleeding.

You may have to have blood tests done after getting Advate to be sure that your blood level of Factor VIII is high enough to clot your blood.

Call your healthcare provider right away if your bleeding does not stop after taking Advate.

What should I tell my healthcare provider before I use Advate?

You should tell your healthcare provider if you

• have or have had any medical problems.
• take any medicines, including non-prescription medicines and dietary supplements.
• have any allergies, including allergies to mouse or hamster proteins.
• are nursing.
• are pregnant.
• have been told that you have inhibitors to Factor VIII (because Factor VIII may not work for you).

What are the possible side effects of Advate?

You could have an allergic reaction to Advate.

Call your healthcare provider right away and stop treatment with Advate if you get a rash or hives, itching, tightness of the throat, chest pain or tightness, difficulty breathing, light-headed, dizziness, nausea or fainting.

Side effects that have been reported with Advate include:

These are not all the possible side effects with Advate.

What are the Advate dosage strengths?

Advate comes in six different dosage strengths. The actual strength will be imprinted on the label and on the box. The six different strengths are coded, as follows:

Always check the potency printed on the label to make sure you are using the strength prescribed by your doctor. Always check the expiration date printed on the box. You should not use the product after the expiration date printed on the box.

How do I store Advate?

Do not freeze Advate.

Advate vials containing powdered product (without sterile diluent added) should be stored in a refrigerator (2° to 8°C [36° to 46°F]) or at room temperature (up to 30°C [86°F]) for up to 6 months.

If you choose to store Advate at room temperature:

• note the date that the product is removed from refrigeration on the box.
• do not use after six months from this date or the expiration date listed on the vial, whichever is earlier.

Store vials in their original box and protect them from extreme exposure to light.

Reconstituted product (after mixing dry product with wet diluent) must be used within 3 hours and cannot be stored or refrigerated. Any Advate left in the vial at the end of your infusion should be discarded.

What else should I know about Advate and hemophilia A?

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.

Medicines are sometimes prescribed for purposes other than those listed here. Do not use Advate for a condition for which it is not prescribed. Do not share Advate with other people, even if they have the same symptoms that you have.

Resources at Baxter available to the patients:

For more product information on Advate, please visit www.Advate.com or call 1-888-4Advate (1-888-423-8283).

For information on patient assistance programs that are available to you, including the Baxter CARE Program, please contact the Baxter Insurance Assistance Helpline at 1-888-BAXTER9 (1-888-229-8379).

For information on additional Baxter patient resources, please visit www.Advate.com.

INSTRUCTIONS FOR USE

Advate
[Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method]
(For intravenous use only)

Do not attempt to do an infusion to yourself unless you have been taught how by your doctor or hemophilia center.

See the step-by-step instructions for reconstituting Advate at the end of this leaflet.

You should always follow the specific instructions given by your healthcare provider. The steps listed below are general guidelines for using Advate. If you are unsure of the procedures, please call your healthcare provider before using.

Call your healthcare provider right away if bleeding is not controlled after using Advate.

Your healthcare provider will prescribe the dose that you should take.

Your healthcare provider may need to take blood tests from time to time.

Talk to your healthcare provider before traveling. You should plan to bring enough Advate for your treatment during this time.

Dispose of all materials, including any leftover reconstituted Advate product, in an appropriate container.

1. In a quiet place, prepare a clean flat surface and gather all the materials you will need for the infusion. Check the expiration date, and let the vial with the Advate concentrate and the Sterile Water for Injection, USP (diluent) warm up to room temperature. Wash your hands and put on clean exam gloves. If infusing yourself at home, the use of gloves is optional.
   
2. Remove caps from the Advate concentrate and diluent vials to expose the centers of the rubber stoppers.
   
3. Disinfect the stoppers with an alcohol swab (or other suitable solution suggested by your doctor or hemophilia center) by rubbing the stoppers firmly for several seconds, and allow them to dry prior to use. Place the vials on a flat surface.
   
4. Open the BAXJECT II device package by peeling away the lid, without touching the inside of the package. Do not remove the BAXJECT II device from the package.
   
5. Turn the package with the BAXJECT II device upside down, and place it over the top of the diluent vial. Fully insert the clear plastic spike of the device into the center of the diluent vial's stopper by pushing straight down. Grip the package at its edge and lift it off the device. Be careful not to touch the white plastic spike. Do not remove the blue cap from the BAXJECT II device.
   
   The diluent vial now has the BAXJECT II device connected to it and is ready to be connected to the Advate vial.
   
6. To connect the diluent vial to the Advate vial, turn the diluent vial over and place it on top of the vial containing Advate concentrate. Fully insert the white plastic spike into the Advate vial's stopper by pushing straight down. Diluent will flow into the Advate vial. This should be done right away to keep the liquid free of germs.
   
7. Swirl the connected vials gently and continuously until the Advate is completely dissolved. Do not shake. The Advate solution should look clear and colorless. If not, do not use it and notify Baxter immediately.
   
8. Take off the blue cap from the BAXJECT II device and connect the syringe. BE CAREFUL TO NOT INJECT AIR.
   
9. Turn over the connected vials so that the Advate vial is on top. Draw the Advate solution into the syringe by pulling back the plunger slowly. Disconnect the syringe from the vials. Attach the infusion needle to the syringe using a winged (butterfly) infusion set, if available. Point the needle up and remove any air bubbles by gently tapping the syringe with your finger and slowly and carefully pushing air out of the syringe and needle.
   
10. If you are using more than one vial of Advate, the contents of more than one vial may be drawn into the same syringe. However, you will need a separate diluent and BAXJECT II device to mix each additional vial of Advate.
    
    Apply a tourniquet, and get the injection site ready by wiping the skin well with an alcohol swab (or other suitable solution suggested by your doctor or hemophilia center).
    
11. Insert the needle into the vein, and remove the tourniquet. Slowly infuse the Advate. Do not infuse any faster than 10 mL per minute.
    
12. Take the needle out of the vein and use sterile gauze to put pressure on the infusion site for several minutes.
    
    Do not recap the needle. Place it with the used syringe in a hard-walled Sharps container for proper disposal.
    
    Remove the peel-off label from the Advate vial and place it in your logbook. Clean any spilled blood with a freshly prepared mixture of 1 part bleach and 9 parts water, soap and water, or any household disinfecting solution.
    
13. Dispose of the used vials and BAXJECT II system in your hard-walled Sharps container, without taking them apart. Do not dispose of these supplies in ordinary household trash.

Important: Contact your doctor or local Hemophilia Treatment Center if you experience any problems.

BAXTER, Advate, BAXJECT, and CARE are trademarks of Baxter International Inc. registered in the U.S. Patent and Trademark Office.

U.S. Patent Numbers:

4,757,006; 5,198,349; 5,250,421; 5,733,873; 5,919,766; 4,891,319; 5,955,448; 6,313,102; 5,891,873; 6,034,080; 6,649,386; 5,854,021; 5,470,954; 6,555,391; 6,936,441; 7,094,574; 6,100,061; 6,475,725; 6,586,573; 7,087,7236,475,725; 6,100,061; 6,586,573; 6,555,391; 5,198,349; 4,757,006; 5,470,954

Baxter Healthcare Corporation
Westlake Village, CA 91362 USA
U.S. License No. 140
Printed in USA
Issued Oct, 2009

The serious adverse drug reactions (ADRs) seen with ADVATE are hypersensitivity reactions and the development of high-titer inhibitors necessitating alternative treatments to Factor VIII.

The most common ADRs observed in clinical trials (frequency ≥ 10% of subjects) were pyrexia, headache, cough, nasopharyngitis, vomiting, arthralgia, limb injury.

Clinical Trial 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 five completed studies in previously treated patients (PTPs) and one ongoing study in previously untreated patients (PUPs) with severe to moderately severe Hemophilia A (Factor VIII ≤ 2% of normal). A total of 234 subjects have been treated with ADVATE as of March 2006. Total exposure to ADVATE was 44,926 infusions. The median duration of participation per subject was 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.

No subject was withdrawn from a study due to an ADR. There were no deaths in any of the clinical studies.

Table 3: Summary of Adverse Reactions (ADRs)a with a Frequency ≥ 5% in 234 Treated Subjectsb

The development of Factor VIII inhibitors with the use of ADVATE was evaluated in clinical studies with pediatric PTPs ( < 6 years of age with > 50 Factor VIII exposures) and PTPs ( ≥ 10 years of age with > 150 Factor VIII exposures). Of 198 subjects who were treated for at least 10 exposure days or on study for a minimum of 120 days, 1 adult developed a low-titer inhibitor (2.0 [BU] in the Bethesda assay) after 26 exposure days. Eight weeks later, the inhibitor was no longer detectable, and in vivo recovery was normal at 1 and 3 hours after infusion of another marketed recombinant Factor VIII concentrate. This single event results in a Factor VIII inhibitor frequency in PTPs of 0.51% (95% CI 0.03 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.

In clinical studies that enrolled previously untreated subjects (defined as having had up to 3 exposures to a Factor VIII product at the time of enrollment), 5 (20%) of 25 subjects who received ADVATE developed inhibitors to Factor VIII.3 Four patients developed high titer ( > 5 BU) and one patient developed low-titer inhibitors. Inhibitors were detected at a median of 11 exposure days (range 7 to 13 exposure days) to investigational product.

Immunogenicity also was evaluated by measuring the development of antibodies to heterologous proteins. 182 treated subjects were assessed for anti-Chinese hamster ovary (CHO) cell protein 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 antibodies. Of these, 10 showed an upward trend in anti-muIgG antibody titer over time and 2 showed repeated but transient elevations of antibodies. Four subjects who demonstrated antibody elevations reported isolated events of urticaria, pruritus, rash, and slightly elevated eosinophil counts. All of these subjects had numerous repeat exposures to the study product without recurrence of the events and a causal relationship between the antibody findings and these clinical events has not been established. Of the 181 subjects who were treated and assessed for the presence of anti-human von Willebrand Factor (VWF) antibodies, none displayed laboratory evidence indicative of a positive serologic response.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval 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.

Among patients treated with ADVATE, cases of serious allergic/hypersensitivity reactions including anaphylaxis have been reported and Factor VIII inhibitor formation (observed predominantly in PUPs). Table 4 represents the most frequently reported post-marketing adverse reactions as MedDRA Preferred Terms.

Table 4: Post-Marketing Experience

Read the entire FDA prescribing information for Advate ([Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method] for Intravenous Injection)