Humate-P

You should not use this medication if you have ever had a severe allergic reaction to antihemophilic factor in the past.

Your body may develop antibodies to antihemophilic factor, making it less effective. Call your doctor if this medicine seems to be less effective in controlling your bleeding.

Carefully follow all instructions about how to store this medicine. Each brand of antihemophilic and von Willebrand factor complex may have specific storage instructions.

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended. Always check the strength of the medicine on the label to be sure you are using the correct potency.

Antihemophilic and von Willebrand factor complex is injected into a vein through an IV. You may be shown how to use an IV at home. Do not give yourself this medicine if you do not understand how to use the injection and properly dispose of needles, IV tubing, and other items used.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Always wash your hands before preparing and giving your injection.

Antihemophilic and von Willebrand factor complex is a powder medicine that must be mixed with a liquid (diluent) before using it. If you are using the injections at home, be sure you understand how to properly mix and store the medicine.

After mixing the medicine with a diluent, store at room temperature and use it within 3 hours. Do not refrigerate or freeze.

Do not shake the mixed medicine. Prepare your dose in a syringe only when you are ready to give yourself an injection. A single-use vial is for one use only. After measuring your dose, throw this vial away, even if there is medicine left in it.

Do not use antihemophilic and von Willebrand factor complex if it has changed colors or has particles in it. Call your pharmacist for new medicine.

Use a disposable needle and syringe only once. Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

While using this medicine, you may need frequent blood tests.

Your body may develop antibodies to antihemophilic factor, making it less effective. Call your doctor if this medicine seems to be less effective in controlling your bleeding.

Carefully follow all instructions about how to store this medicine. Each brand of antihemophilic and von Willebrand factor complex may have specific storage instructions.

Store the medicine and diluent at room temperature, away from moisture and heat. Throw away any medicine not used before the expiration date on the medicine label.

The Wilate brand of this medicine should be stored in the original container in the refrigerator. Do not freeze. Before preparing your dose, take these items of the refrigerator and allow them to reach room temperature.

If you store this medicine at room temperature, do not return it to the refrigerator.

Wear a medical alert tag or carry an ID card stating that you have hemophilia or von Willebrand disease. Any medical care provider who treats you should know that you have a bleeding or blood-clotting disorder.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Use Humate-P as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as a shot into a vein.
• This medicine may be given at home.
• Your doctor may teach you how to give the shot.
• Follow how to use as you have been told by the doctor or read the package insert.
• Wash your hands before and after use.
• This medicine needs to be mixed before use. Follow how to mix as you were told by the doctor.
• Do not shake.
• Do not use if the solution is cloudy, leaking, or has particles.
• Do not use if solution changes color.
• Throw away any part of opened vial not used after use.
• Throw away needles in a needle/sharp disposal box. Do not reuse needles or other items. When the box is full, follow all local rules for getting rid of it. Talk with a doctor or pharmacist if you have any questions.
• Use within 3 hours of making.

What do I do if I miss a dose?

• Skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.
• If you are not sure what to do if you miss a dose, call your doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Upset stomach.
• Dizziness.
• Feeling tired or weak.
• Headache.
• Back pain.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Hemophilia A

Humate-P, Antihemophilic Factor/von Willebrand Factor Complex (Human), is indicated for treatment and prevention of bleeding in adults with hemophilia A (classical hemophilia).

Von Willebrand Disease (VWD)

Humate-P is also indicated in adult and pediatric patients with von Willebrand disease (VWD) for:

Controlled clinical studies to evaluate the safety and efficacy of prophylactic dosing with Humate-P to prevent spontaneous bleeding have not been conducted in VWD subjects. Adequate data are not presently available on which to evaluate or to base dosing recommendations in this setting.

Treatment of Bleeding Episodes in VWD

Clinical efficacy of Humate-P in the control of bleeding in subjects with VWD was determined by a retrospective review of clinical safety and efficacy data obtained from 97 Canadian VWD subjects who received product under an Emergency Drug Release Program. The dosage schedule and duration of therapy were determined by the medical practitioner.

There were 514 requests for product use for surgery, bleeding, or prophylaxis in the 97 subjects. Of these, Humate-P was not used in 151 cases, and follow-up safety and/or efficacy information was available for 303 (83%) of the remaining 363 requests. In many cases, Humate-P from a single request was used for several treatment courses in one subject. Therefore, there are more reported treatment courses than requests.

Humate-P was administered to 97 subjects in 530 treatment courses: 73 for surgery, 344 for treatment of bleeding, and 20 for prophylaxis of bleeding. The majority of the 93 "other" uses involved dental procedures, diagnostic procedures, prophylaxis prior to a procedure, or test doses.

Table 9 summarizes the dosing information (all subjects) for bleeding episodes.

Prevention of Excessive Bleeding During and After Surgery in VWD

Two prospective, open-label, non-controlled, multicenter clinical studies, one in the US and one in Europe, investigated the safety and hemostatic efficacy of Humate-P in subjects with VWD undergoing surgery.

• US clinical study – The primary objective of this study was to demonstrate the safety and hemostatic efficacy of Humate-P in preventing excessive bleeding in adult and pediatric subjects with VWD undergoing surgery. The 35 subjects (21 female and 14 male) ranged in age from 3 to 75 years (mean 32.9); seven were age 15 or younger and two were age 65 or older. Twelve subjects had type 1 VWD, two had type 2A, three had type 2B, five had type 2M, and 13 had type 3. Twenty-eight of the surgical procedures were classified as major (e.g., orthopedic joint replacement, intracranial surgery, multiple tooth extractions, laparoscopic cholecystectomy), four as minor (e.g., placement of intravenous access device), and three subjects had oral surgery3. Seven of the 13 subjects with type 3 VWD had major surgery.

The first 15 subjects received a loading dose of Humate-P corresponding to 1.5 times the "full dose" (defined as the dose predicted to achieve a peak VWF:RCo level of 100 International Units (IU)/dL as determined by each subject's calculated IVR and baseline VWF:RCo level); the loading dose did not vary with the type of surgery performed (i.e., major, minor, or oral). The remaining 20 subjects were dosed based on individual pharmacokinetic assessments and target peak VWF:RCo levels of 80 to 100 International Units (IU)/dL for major surgery and 50 to 60 International Units (IU)/dL for minor or oral surgery, respectively. All 35 subjects received initial maintenance doses corresponding to 0.5 times the full dose at intervals of 6, 8, or 12 hours after surgery as determined by their individual half-lives for VWF:RCo; subsequent maintenance doses were adjusted based on regular measurements of trough VWF:RCo and FVIII:C levels. The median duration of treatment was 1 day (range: 1 to 2 days) for oral surgery, 5 days (range: 3 to 7 days) for minor surgery, and 5.5 days (range: 2 to 26 days) for major surgery.

• European clinical study –The primary objective of this study was to assess the ability of Humate-P to effectively correct the coagulation defect in subjects with VWD undergoing elective surgery, as demonstrated by an increase in VWF:RCo and FVIII, a shortening of the prolonged bleeding time, and the prevention and/or cessation of excessive bleeding. This study did not have a pre-stated hypothesis to evaluate hemostatic efficacy. The 27 subjects (18 females and nine males) ranged in age from 5 to 81 years (median age: 46 years); one was age 5, and five were older than 65. Ten subjects had type 1 VWD, nine had type 2A, one had type 2M, and seven had type 3. Sixteen of the surgical procedures were classified as major (orthopedic joint replacement, hysterectomy, multiple tooth extractions, laparoscopic adnexectomy, laparoscopic cholecystectomy, and basal cell carcinoma excision). Six of the seven subjects with type 3 VWD had major surgery.

Dosing was individualized based on a pharmacokinetic assessment performed before surgery. The median duration of treatment was 3.5 days (range: 1 to 17 days) for minor surgery and 9 days (range: 1 to 17 days) for major surgery.

In both studies, assessments of the hemostatic efficacy of Humate-P in preventing excessive bleeding were performed at the end of surgery, 24 hours after the last infusion of Humate-P, and at the end of the study (14 days following surgery).

Table 10 summarizes the end-of-surgery hemostatic efficacy assessments in subjects participating in either the US or European study.

Table 11 summarizes the overall hemostatic efficacy assessments in subjects participating in either the US or European study. Humate-P was effective in preventing excessive bleeding during and after surgery.

In the US study, all efficacy assessments were reviewed by an independent Data Safety Monitoring Board (DSMB). The DSMB agreed with the investigators' assessments of the overall hemostatic efficacy for all but two subjects (neither of whom had type 3 VWD). Based on this, the DSMB judged hemostatic efficacy as "effective" in 33 (94.3%) (95% CI: 81.1% to 99.0%) of the 35 subjects.

In the US study, the median actual estimated blood loss did not exceed the median expected blood loss, regardless of the type of surgery. Table 12 shows the median expected and actual estimated blood loss during surgery in the US study.

In the US study, four subjects received transfusions, three due to adverse events and one due to pre-existing anemia. In the European study, one subject received transfusions to treat pre-existing anemia.

Virus Transmission Studies

Clinical evidence of the absence of virus transmission in Humate-P was obtained in additional studies.

In one study, none of the evaluable subjects (31 of 67) who received Humate-P developed HBV infection or showed clinical signs of non-A, non-B (NANB) hepatitis infection.

In another study, 32 lots of Humate-P were administered to 26 subjects with hemophilia or VWD who had not previously received any blood products. No subject developed any signs of an infectious disease, and the 10 subjects not previously vaccinated remained seronegative for markers of infection with HBV, HAV, cytomegalovirus (CMV), Epstein-Barr virus, and HIV.

In a retrospective study, 155 subjects evaluated remained negative for the presence of HIV-1 antibodies for time periods ranging from 4 months to 9 years from the initial administration of Humate-P. All 67 of the subjects tested for HIV-2 antibodies remained seronegative.

1. Levine PH, Brettler DB. Clinical aspects and therapy for hemophilia A. In: Hoffman R, Benz JB, Shattil SJ, Furie B, Cohen HJ, eds. Hematology: Basic Principles and Practice. New York: Churchill Livingstone Inc.; 1991:1296-1297.
2. Scott JP, Montgomery RT. Therapy of von Willebrand disease. Semin Thromb Hemost. 1993;19:37-47.
3. Mannucci, PM. Venous Thromboembolism in Von Willebrand Disease. Thromb Haemostas. 2002;88:378-379.
4. Markis M, Colvin B, Gupta V, Shields ML, Smith MP. Venous thrombosis following the use of intermediate purity FVIII concentrate to treat patients with von Willebrand's disease. Thromb Haemostas. 2002;88:387-388.
5. Berntorp E, Nilsson IM. Biochemical and in vivo properties of commercial virus-inactivated factor VIII concentrates. Eur J Haematol. 1988;40:205-214.
6. Berntorp E. Plasma product treatment in various types of von Willebrand's disease. Haemostasis. 1994;24:289-297.
7. Hoyer LW. The factor VIII complex: structure and function. Blood. 1981;58:1-13.
8. Meyer D, Girma J-P. von Willebrand factor: structure and function. Thromb Haemostas. 1993;70:99-104.

Humate-P is supplied in a single-dose vial containing the labeled amount of VWF:RCo and FVIII activity expressed in International Units (IU). Each package contains a vial of Humate-P, a vial of diluent containing sterile water (meets USP chemistry requirements Sterile Water for Injection, except for pH), a Mix2Vial filter transfer set, and two alcohol swabs.

The components used in the packaging for Humate-P contain no latex.

Approximate potencies are shown below; check each carton/vial for the actual potency prior to reconstitution:

When stored at temperatures up to 25°C (77°F), Humate-P is stable for 24 months up to the expiration date printed on its label. Do not freeze.

This product does not contain a preservative and should be used within 3 hours after reconstitution.

Applies to antihemophilic factor / von willebrand factor: intravenous powder for solution

Along with its needed effects, antihemophilic factor / von willebrand factor may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking antihemophilic factor / von willebrand factor:

• Difficulty with breathing or swallowing
• dizziness
• fast heartbeat
• fever
• hives or welts
• itching
• nausea
• reddening of the skin, especially around the ears
• shortness of breath
• skin rash
• swelling of the face, throat, or tongue
• unusual tiredness or weakness

• Cough
• tightness in the chest
• vomiting
• wheezing