Bebulin VH

Bebulin VH® (coagulation factor ix (human)) , is indicated for the prevention and control of bleeding in Factor IX deficiency, also known as Hemophilia B or Christmas disease.

Bebulin VH® (coagulation factor ix (human)) is not indicated in the treatment or prophylaxis of Hemophilia A patients with inhibitors to Factor VIII.

Bebulin VH® (coagulation factor ix (human)) , contains non-detectable levels of Factors II, VII and X ( < 0. 0025 IU per Factor IX unit using standard coagulation assays) and is, therefore, not indicated for replacement therapy of these clotting factors. Bebulin VH® (coagulation factor ix (human)) is also not indicated in the treatment or reversal of coumarin-induced anticoagulation or in a hemorrhagic state caused by hepatitis-induced lack of production of liver dependent coagulation factors.

Bebulin VH® (coagulation factor ix (human)) is intended for intravenous administration only. It should be reconstituted with the volume of Sterile Water for Injection, USP supplied with the lot, and administered within three hours of reconstitution. Do not refrigerate after reconstitution. After administration, any unused solution and the administration equipment should be discarded.

As a general rule, 1 IU of Factor IX activity per kg can be expected to increase the circulating level of Factor IX by 1% [IU/dL] of normal. The following formula provides a guide to dosage calculations:

Number of Factor IX required (IU) = Body Weight (in kg) x desired Factor IX increase (% or IU/dL normal) x 1.0 IU/kg IU [per IU/dL]

The amount of Bebulin VH® (coagulation factor ix (human)) to be infused, as well as the frequency of infusions, will vary with each patient and with the clinical situation. ^11,12

As a general rule, the level of Factor IX required for treatment of different conditions is as follows:

Recovery of the loading dose varies from patient to patient. Doses administered should be titrated to the patient's response. Bebulin VH® (coagulation factor ix (human)) administered in doses of ≥ 75 IU/kg were well tolerated (see CLINICAL PHARMACOLOGY).

In the presence of an inhibitor to Factor IX, higher doses of Bebulin VH® (coagulation factor ix (human)) might be necessary to overcome the inhibitor (see PRECAUTIONS). No data on the treatment of patients with inhibitors to Factor IX with Bebulin VH® (coagulation factor ix (human)) are available.

For information on rate of administration, see Rate of Administration, below.

Reconstitution

1. Warm both the diluent and Coagulation Factor IX (Human), Bebulin VH® (coagulation factor ix (human)) , 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 dilu-ent vial. Invert the diluent vial and insert the other end of the double-end needle into the rubber stopper of the Bebulin VH® (coagulation factor ix (human)) vial. Direct the diluent, which will be drawn in by vacuum, over the entire surface of the Bebulin VH® (coagulation factor ix (human)) 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 Bebulin VH® (coagulation factor ix (human)) 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, Bebulin VH® (coagulation factor ix (human)) should be administered within three hours after reconstitution.
7. Product should be filtered prior to use as described under Administration. Parenteral drug preparations should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Administration

Intravenous Injection

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Plastic disposable syringes are recommended with Bebulin VH® (coagulation factor ix (human)) solution. The ground glass surfaces of all-glass syringes tend to stick with solutions of this type. Please note, this concentrate is supplied with a SELF-VENTING filter spike.

1. Using aseptic technique, attach the vented filter spike to a sterile diposable syringe.
   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.
   CAUTION: DO NOT INJECT AIR INTO THE Bebulin VH® (coagulation factor ix (human)) 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.
2. Insert the vented filter spike into the stopper of the Bebulin VH® (coagulation factor ix (human)) 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.

Rate of Administration

The rate of administration should be determined by the response and comfort of the patient; intravenous dosage administration rates of up to 225 IU/minute have been regularly tolerated without incident. When reconstituted as directed, i. e. , to approximately 100 IU/mL, Bebulin VH® (coagulation factor ix (human)) should be administered at a rate of approximately 2. 0 mL per minute.

Storage

When stored at refrigerator temperature, 2-8°C (36-46°F), Bebulin VH® (coagulation factor ix (human)) is stable for the period indicated by the expiration date on its label. Within this period, Bebulin VH® (coagulation factor ix (human)) may be stored at room temperature not to exceed 25°C (77°F), for up to one month.

Avoid freezing, which may damage container for the diluent.

Known hypersensitivity to mouse protein is a contraindication to Bebulin VH® (coagulation factor ix (human)).

WARNINGS

Bebulin VH® is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. Because Bebulin VH® is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current viral infections and by inactivating and/or removing certain viruses during manufacture (see DESCRIPTION section for virus reduction measures). The manufacturing procedure for Bebulin VH® (coagulation factor ix (human)) includes processing steps designed to reduce further the risk of virus transmission. Stringent procedures, utilized at plasma collection centers, plasma testing laboratories, and fractionation facilities are designed to reduce the risk of virus transmission. The primary virus reduction step of the Bebulin VH® (coagulation factor ix (human)) manufacturing process is the use of two sequential virus retentive ultrafilter membranes designed to separate viruses from Factor IX. In addition, the purification procedure (several chromatography steps) used in the manufacture of Bebulin VH® (coagulation factor ix (human)) also provides virus reduction capacity. Despite these measures, such products may still potentially contain human pathogenic agents, including those not yet known or identified. Thus the risk of transmission of infectious agents cannot be totally eliminated. Any infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to ZLBBehring at 800-504-5434 (in the U. S. and Canada). The physician should discuss the risks and benefits of this product with the patient.

Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections, particularly nonA, nonB hepatitis. (See INFORMATION FOR PATIENTS.)

Since the use of Factor IX Complex concentrates has historically been associated with the development of thromboembolic complications, the use of Factor IX-containing products may be potentially hazardous in patients with signs of fibrinolysis and in patients with disseminated intravascular coagulation (DIC).

Hypersensitivity and allergic type hypersensitivity reactions, including anaphylaxis, have been reported for all factor IX products. Frequently, these events have occurred in close temporal association with the development of factor IX inhibitors. Patients should be informed of the early symptoms and signs of hypersensitivity reactions, including hives, generalized urticaria, angioedema, chest tightness, dyspnea, wheezing, faint-ness, hypotension, tachycardia, and anaphylaxis. Patients should be advised to discontinue use of product and contact their physician and/or seek immediate emergency care, depending on the severity of the reac-tion, if any of these symptoms occur.

Preliminary information suggests a relationship may exist between the presence of major deletion mutations in the factor IX gene and an increased risk of inhibitor formation and of acute hypersensitivity reactions. Patients known to have major deletion mutations of the factor IX gene should be observed closely for signs and symptoms of acute hypersensitivity reactions, particularly during the early phases of initial exposure to product.

Nephrotic syndrome has been reported following attempted immune tolerance induction with factor IX products in Hemophilia B patients with factor IX inhibitors and a history of severe allergic reactions to factor IX. The safety and efficacy of using Bebulin VH® (coagulation factor ix (human)) in attempted immune tolerance induction has not been established.

PRECAUTIONS

Extensive clinical experience suggests that there is a lower risk of thromboembolic complications with the use of Bebulin VH® (coagulation factor ix (human)) than with prothrombin complex concentrates. However, as with all products containing Factor IX, caution should be exercised when administering Bebulin VH® (coagulation factor ix (human)) to patients with liver disease, to patients post-operatively, to neonates, or to patients at risk of thromboembolic phenomena or DIC. ^{8, 9} In each of these situations, the potential benefit of treatment with Bebulin VH® (coagulation factor ix (human)) should be weighed against the potential risk of these complications.

Coagulation Factor IX (Human), Bebulin VH® (coagulation factor ix (human)) , should be administered intravenously at a rate that will permit observation of the patient for any immediate reaction. Rates of infusion of up to 225 IU per minute have been regularly tolerated with no adverse reactions. If any reaction takes place that is thought to be related to the administration of Bebulin VH® (coagulation factor ix (human)) , the rate of infusion should be decreased or the infusion stopped, as dictated by the response of the patient. The infusion should be stopped promptly and appropriate countermeasures and supportive therapy should be administered should evidence of an acute hypersensitivity reaction be observed. Patients known to have major deletion mutations of the factor IXgene may be at increased risk for inhibitor formation and acute hypersensitivity reactions. (See WARNINGS.)

During the course of treatment, determination of daily Factor IX levels is advised to guide the dose to be administered and the frequency of repeated infusions. Individual patients may vary in their response to Bebulin VH® (coagulation factor ix (human)) , achieving different levels of in vivo recovery and demonstrating different half-lives.

The use of high doses of Factor IX Complex concentrates has been reported to be associated with instances of myocardial infarction, disseminated intravascular coagulation, venous thrombosis and pulmonary embolism. Generally a Factor IX level of 25-50% [IU/dL] is considered adequate for hemostasis, including major hemorrhages and surgery. Attempting to maintain Factor IX levels of > 75-100% [IU/dL] during treatment is not routinely recommended nor required. To achieve Factor IX levels that will remain above 25% [IU/dL] between once a day administrations, each daily dose should attempt to raise the 30-minute post-infusion Factor IX level to 50-60% [IU/dL] (see DOSAGE AND ADMINISTRATION).

No controlled studies have been available regarding the use of ε-amino caproic acid or other antifibrinolyt-ic agents following an initial infusion of Bebulin VH® (coagulation factor ix (human)) for the prevention or treatment of oral bleeding following trauma or dental procedures such as extractions.

Pregnancy Category C

Animal reproduction studies have not been conducted with Bebulin VH® (coagulation factor ix (human)). It is also not known whether Bebulin VH® (coagulation factor ix (human)) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Bebulin VH® (coagulation factor ix (human)) should be given to a pregnant woman only if clearly needed.

Pediatric Use

Evaluation of the safety and effectiveness of Bebulin VH® (coagulation factor ix (human)) treatment in 51 pediatric patients between the ages of 1 day and 20 years, as a part of virus safety trials and trials for surgery, trauma or spontaneous bleeding, showed that excellent hemostasis was achieved with no thrombotic complications. ¹⁰ Included in the experience with patients aged birth to 20 years are two long-term virus safety studies demonstrating lack of virus transmission. Dosing in children is based on body weight and is generally based on the same guidelines as for adults (see DOSAGE AND ADMINISTRATION).

Geriatric Use

Clinical studies of Bebulin VH® (coagulation factor ix (human)) did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. As for all patients, dosing for geriatric patients should be appropriate to their overall situation.

REFERENCES

8. Aledort LM: Factor IX and Thrombosis. Scand J Haematology Suppl. 30:40, 1977.

9. Cederbaum AI, Blatt PM, Roberts HR. Intravascular coagulation with useof human prothrombin complex concentrates. Ann Intern Med 84:683-687, 1976.

10. Kurczynski E, Lusher JM, Pitel P, Shapiro AD, Bergman GE, the Bebulin VH® (coagulation factor ix (human)) StudyGroup. Safetyand efficacyofmonoclonal antibody-purified factor IX concentrate for management of bleeding and surgical prophylaxis in previously treated children with hemophilia B. Int J Ped Hemat/Oncol 2:211-216, 1995.

As with the intravenous administration of other plasma-derived products, the following reactions may be observed following administration: headache, fever, chills, flushing, nausea, vomiting, tingling, lethargy, hives, stinging or burning at the infusion site or manifestations of allergic reactions. In a clinical study with Bebulin VH® (coagulation factor ix (human)) in previously untreated hemophilia Bpatients, five patients experienced ALTelevations. Serologic tests for hepatitis A, hepatitis B, hepatitis C, Cytomegalovirus, and Epstein-Barr virus were negative.

The following adverse reactions have been spontaneously reported during post-marketing use of Bebulin VH® (coagulation factor ix (human)) as well as other Factor IX products:anaphylaxis, angioedema, cyanosis, dyspnea, hypotension, thrombosis, inadequate therapeutic response, and inhibitor development.

There is a potential risk of thromboembolic episodes following the administration of Bebulin VH® (see WARNINGS and PRECAUTIONS).

The patient should be monitored closely during the infusion of Bebulin VH® (coagulation factor ix (human)) to observe for the development of any reaction. If any reaction takes place that is thought to be related to the administration of Bebulin VH® (coagulation factor ix (human)) , the rate of infusion should be decreased or the infusion stopped, as dictated by the response of the patient. Should evidence of an acute hypersensitivity reaction be observed, the infusion should be stopped promptly and appropriate countermeasures and supportive therapy should be administered.

No information provided.