Monoclate-P

Factor VIII:C is the coagulant portion of the Factor VIII complex circulating in plasma. It is noncovalently associated with the von Willebrand protein responsible for von Willebrand factor activity. These two proteins have distinct biochemical and immunological properties and are under separate genetic control. Factor VIII:C acts as a cofactor for Factor IX to activate Factor X in the intrinsic pathway of blood coagulation.8 Hemophilia A, a hereditary disorder of blood coagulation due to decreased levels of Factor VIII:C, results in profuse bleeding into joints, muscles or internal organs as a result of a trauma. Monoclate-P® provides an increase in plasma levels of AHF, thereby enabling temporary correction of Hemophilia A bleeding. Clinical evaluation of Monoclate-P® concentrate for its half-life characteristics in hemophilic patients showed it to be comparable to other commercially available Antihemophilic Factor (Human) concentrates. The mean half-life obtained from six patients was 17.5 hours with a mean recovery of 1.9 units/dl rise/U/kg.

The pasteurization process used in the manufacture of this concentrate has demonstrated in vitro inactivation of human immunodefi ciency virus (HIV) and several model viruses. In two separate studies, HIV was reduced by ≥ 7.0 log10 to an undetectable level and by 10.5 log10, respectively. In addition to HIV, studies were also performed using three lipid containing model viruses and one non-lipid, encapsulated model virus. Vesicular stomatitis (VSV) was reduced by ≥ 6.79 log10 to undetectable, Sindbis was reduced by ≥ 6.48 log10 to undetectable and Vaccinia was reduced by ≥ 5.36 log10 to undetectable. Murine encephalomyocarditis (EMC), a non-lipid, encapsulated model virus, was reduced by ≥ 7.1 log10 to undetectable.

Evidence of the capability of the purification and preparative steps used in the production of Monoclate-P® to reduce viral bioburden was obtained in studies involving the addition of known quantities of virus to cryoprecipitate. These studies were conducted using an earlier form of the concentrate which had not undergone liquid pasteurization (Antihemophilic Factor (Human), Monoclate®, Monoclonal Antibody Purified, Factor VIII:C, Heat-Treated). These studies provide evidence of the viral removal potential of the purification and preparative steps of the manufacturing process (exclusive of heat treatment) which are common to both concentrates. In one study, the viruses used were human immunodeficiency virus (HIV), Sindbis virus, vesicular stomatitis virus (VSV) and pseudorabies virus (PsRV). A comparison of the cumulative mean reductions for all viruses tested with the individual values obtained in each experiment indicates that the combined effects of the manufacturing steps, which purify the Factor VIII:C and prepare the concentrate in a fi nal sterile container as a lyophilized powder, contribute viral reduction capabilities of approximately 5 to 6 logs. In a separate study, aluminum hydroxide treatment followed by antibody affi nity chromatography reduced vaccinia virus infectivity by 4.81 logs. These studies indicate that the purifi cation and preparative steps of the manufacturing process are capable of providing a non-specific, viral reduction of approximately 5 to 6 logs, independent of the pasteurization process.

Monoclate-P® contains trace amounts of mouse protein9 ( ≤ 50 ng per 100 I.U. of AHF). In a study using an earlier form of the concentrate which had not undergone pasteurization (Monoclate®), a number of patients seronegative for Anti-HIV-1 were monitored to determine whether they would develop antibody or experience adverse reactions as a result of repeated exposure. These patients were treated on multiple occasions. Pre-study serum measurements of 27 patients for human anti-mouse IgG showed that, prior to treatment, 6 of them had either detectable antibody to mouse proteins or cross-reactive proteins. These patients continued to demonstrate similar or lower antibody levels during the study. Of the remaining 21 patients, 6 were shown to have low antibody levels on one or more occasions. In no case was observance of low antibody level associated with an anamnestic response or with any clinical adverse reaction. Patients were observed for time periods ranging from 2 to 30 months.

The viral safety of Monoclate-P® has been evaluated in two open-label studies using patients (aged 1 day to 20 years) with moderate to severe hemophilia A previously unexposed to blood or blood products. Thirty patients received Monoclate-P® therapy for 5 to 34 months as necessary according to the normal practices of the treatment center. These patients were followed for serum ALT elevations and a range of viral serologies. Six patients received another blood product prior to or during the study. Twenty-four patients were evaluable for assessment of viral safety of Monoclate-P®. No patients seroconverted to HIV, hepatitis nonA/nonB, or hepatitis B. Factor VIII:C inhibitors developed in 7 patients (23%) with 3 being high ( > 10 BU) titer.

REFERENCES

9. F. Feldman, S. Chandra, R. Kleszynski, C.C. Huang and R.L. Weeks, Measurement of Murine Protein Levels in Monoclonal Antibody Purifi ed Coagulation Factor, from the XVIII International Congress of the World Federation of Hemophilia, May 1988.

No drug interactions have been evaluated by the manufacturer. However, you should tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Not all drug interactions are known or reported and new drug interactions are continually being reported.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if Monoclate-P crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using Monoclate-P.

 

It is very important that your doctor check you or your child closely while you are receiving this medicine to make sure it is working properly. Blood tests may be needed.

This medicine may cause serious types of allergic reactions, including anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Check with your doctor right away if you or your child has a rash, itching, hoarseness, trouble breathing, trouble swallowing, lightheadedness or dizziness, or any swelling of your hands, face, or mouth after you receive this medicine.

It is recommended that you carry an identification (ID) card or letter stating that you have hemophilia A and the type of medicine you are using. If you have any questions about what kind of identification to carry, check with your doctor.

Check with your doctor right away if you have any symptoms of parvovirus infection: fever, chills, drowsiness, runny nose, and followed by a rash or joint pain.

Check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, unusual tiredness or weakness, or yellow eyes or skin. These could be symptoms of a serious liver problem.

This medicine is made from donated human blood. Some human blood products have transmitted certain viruses to people who have received them, although the risk is low. Human donors and donated blood are both tested for viruses to keep the transmission risk low. Talk with your doctor about this risk if you are concerned.

The stopper of the bottle (vial) contains dry natural rubber (a derivative of latex), which may cause allergic reactions in people who are sensitive to latex. Tell your doctor if you have a latex allergy before you start using this medicine.

Use Monoclate-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.
• If you will be giving yourself the shot, your doctor or nurse will 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.
• Use within 3 hours of making.
• 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.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Monoclate-P or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Monoclate-P. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Rx only

Monoclate-P® is indicated for treatment of classical hemophilia (Hemophilia A). Affected individuals frequently require therapy following minor accidents. Surgery, when required in such individuals, must be preceded by temporary corrections of the clotting abnormality. Surgical prophylaxis in severe AHF deficiency can be accomplished with an appropriately-dosed pre-surgical IV bolus of Monoclate-P® followed by intermittent maintenance doses (see DOSAGE AND ADMINISTRATION).

Monoclate-P® is not effective in controlling the bleeding of patients with von Willebrand's disease.

Monoclate-P® is for intravenous administration only. As a general rule 1 unit of AHF activity per kg will increase the circulating AHF level by 2%.10 The following formula10 provides a guide of dosage calculations for both adult and pediatric patients:

Number of AHF	=	Body weight	×	desired Factor VIII	×	0.5
I.U. Required		(in kg)		increase (% normal)

Although dosage must be individualized according to the needs of the patient (weight, severity of hemorrhage, presence of inhibitors), the following general dosages are suggested.11

1. MILD HEMORRHAGES - Minor hemorrhagic episodes will generally subside with a single infusion if a level of 30% or more is attained.
2. MODERATE HEMORRHAGE AND MINOR SURGERY - For more serious hemorrhages and minor surgical procedures, the patient's Factor VIII level should be raised to 30-50% of normal, which usually requires an initial dose of 15-25 I.U. per kg. If further therapy is required a maintenance dose is 10-15 I.U. per kg every 8-12 hours.
3. SEVERE HEMORRHAGE - In hemorrhages near vital organs (neck, throat, subperitoneal) it may be desirable to raise the Factor VIII level to 80-100% of normal which can be achieved with an initial dose of 40-50 I.U. per kg and a maintenance dose of 20-25 I.U. per kg every 8-12 hours.
4. MAJOR SURGERY - For surgical procedures a dose of AHF sufficient to achieve a level 80-100% of normal should be given an hour prior to surgery. A second dose, half the size of the priming dose, should be given five hours after the first dose. Factor VIII levels should be maintained at a daily minimum of at least 30% for a period of 10-14 days postoperatively. Close laboratory control to maintain AHF plasma levels deemed appropriate to maintain hemostasis is recommended.

Reconstitution

1. Warm both the diluent and Monoclate-P® in unopened vials to room temperature [not above 37°C (98°F)].
2. Remove the caps from both vials to expose the central portions of the rubber stoppers.
3. Treat the surface of the rubber stoppers with antiseptic solution and allow them to dry.
4. Using aseptic technique, insert one end of the double-end needle into the rubber stopper of the diluent vial. Invert the diluent vial and insert the other end of the double-end needle into the rubber stopper of the Monoclate-P® vial. Direct the diluent, which will be drawn in by vacuum, over the entire surface of the Monoclate-P® cake. (In order to assure transfer of all the diluent, adjust the position of the tip of the needle in the diluent vial to the inside edge of the diluent stopper.) Rotate the vial to ensure complete wetting of the cake during the transfer process.
5. Remove the diluent vial to release the vacuum, then remove the double-end needle, from the Monoclate-P® vial.
6. Gently swirl the vial until the powder is dissolved and the solution is ready for administration. The concentrate routinely and easily reconstitutes within one minute. To assure sterility, Monoclate-P® should be administered within three hours after reconstitution.
7. Parenteral drug preparations should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Administration

CAUTION: This kit contains two devices, a stainless steel 5 micron filter needle, individually labeled as a 5 micron filter needle and contained in a separate blister pack, and an all plastic 5 micron vented filter spike which is supplied with the four-item administration components blister pack, either of which may be used to withdraw the reconstituted product for administration. The withdrawal directions specific for each of these alternate devices must be followed exactly for whichever device is chosen for use as described below. Product loss or inability to withdraw product will result if the improper instructions are followed.

A. Administration using the stainless steel filter needle for withdrawal

(This item is individually packaged in a separate, labeled blister pack.)

Intravenous Injection

Plastic disposable syringes are recommended with Monoclate-P® solution. The ground glass surfaces of all-glass syringes tend to stick with solutions of this type.

1. Using aseptic technique, attach the filter needle to a sterile disposable syringe. 2. Draw air into the syringe equal to or greater than the contents of the vial. 3. Insert the filter needle into the stopper of the Monoclate-P® vial, invert the vial, position the filter needle above the level of the liquid and inject all of the air into the vial. 4. Pull the filter needle back down below the level of the liquid until the tip is at the inside edge of the stopper. 5. Withdraw the reconstituted solution into the syringe being careful to always keep the tip of the needle below the level of the liquid.   CAUTION: Failure to inject air into the vial, or allowing air to pass through the filter needle while filling the syringe with reconstituted solution, may cause the needle to clog. 6. Discard the filter needle. Perform venipuncture using the enclosed winged needle with microbore tubing. Attach the syringe to the luer end of the tubing.   CAUTION: Use of other winged needles without microbore tubing, although compatible with the concentrate, will result in a larger retention of solution within the winged infusion set. 7. Administer solution intravenously at a rate (approximately 2 mL/minute) comfortable to the patient.

B. Administration using the all plastic vented filter spike for withdrawal

(This spike is supplied in the four-item Administration Components pack.)

Intravenous Injection

Plastic disposable syringes are recommended with Monoclate-P® solution. The ground glass surfaces of all-glass syringes tend to stick with solutions of this type.

1. Using aseptic technique, attach the vented filter spike to a sterile disposable syringe.   CAUTION: DO NOT INJECT AIR INTO THE Monoclate-P® VIAL. The self-venting feature of the vented filter spike precludes the need to inject air in order to facilitate withdrawal of the reconstituted solution. The injection of air could cause partial product loss through the vent filter.   CAUTION: The use of other, non-vented filter needles or spikes without the proper procedure may result in an air lock and prevent the complete transfer of the concentrate. 2. Insert the vented filter spike into the stopper of the Monoclate-P® vial, invert the vial, and position the filter spike so that the orifice is at the inside edge of the stopper. 3. Withdraw the reconstituted solution into the syringe. 4. Discard the filter spike. Perform venipuncture using the enclosed winged needle with microbore tubing. Attach the syringe to the luer end of the tubing.   CAUTION: Use of other winged needles without microbore tubing, although compatible with the concentrate, will result in a larger retention of solution within the winged infusion set. 5. Administer solution intravenously at a rate (approximately 2 mL/minute) comfortable to the patient.

Hershman, R.J., Naconti, S.B., and Shulman, N.R. Prophylactic Treatment of Factor VIII Deficiency. Blood 35, (1970), p. 189.

Kasper, C.K. Dietrich, S.I. and Rapaport, S.K. Hemophilia Prophylaxis in Factor VIII Concentrate. Arch Int Med 125, (1970), p. 1004.

Biggs, R. ed. The Treatment of Hemophilia A and B and von Willebrands Disease. Oxford: Blackwell, 1978.

Fulcher, C.A., Zimmerman, T.S., Characterization of the Human Factor VIII Procoagulant Protein With A Heterologous Precipitating Antibody. Proc Natl Acad Sci 79 (1982), pp. 1648-1652.

Levine, P.H., Factor VIII C Purified from Plasma Via Monoclonal Antibodies Human Studies. Semin Hematol 25 (2 Suppl. 1), 1988, pp. 38-41.

Manufactured by:
CSL Behring LLC
Kankakee, IL 60901 USA
US License No. 1767

US Patent No. 5,605,884
US Patent No. 4,876,241

Revised January, 2007
12810-06