Thromboembolic Complications

Thromboembolic events (deep vein thrombosis, pulmonary embolism, thrombotic stroke) as well as DIC have been reported with BEBULIN. The risk of thromboembolic complications including disseminated intravascular coagulation (DIC) and hyperfibrinolysis is present when patients with congenital or acquired coagulation disorders are  treated with BEBULIN, particularly with repeated dosing. Monitor patients closely for signs and symptoms of intravascular coagulation or thrombosis when administering BEBULIN.

The Factor IX level should not be raised more than necessary to achieve a sufficient clinical response in patients predisposed to thrombosis. Closely monitor patients when administering BEBULIN because of the risk of thromboembolic complications in:

• patients with a history of coronary artery disease,
• patients with liver disease,
• pre- or postoperative patients,
• neonates, or
• other patients at risk for thromboembolic events or DIC.

The infusion should be stopped immediately and appropriate diagnostic and therapeutic measures initiated at the first signs or symptoms of thrombosis or embolism.

In each of these situations, the potential benefit of treatment should be weighed against the risk of these complications.

Anaphylaxis and Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions have been reported with BEBULIN. In the event of an anaphylactic/anaphylactoid reaction, the infusion must be stopped immediately and adequate medical treatment and provisions should be available for immediate use. Manifestations of hypersensitivity or allergic reactions include: anaphylactic shock, hypotension, hypertension, chest tightness, dizziness, paresthesia, lethargy, restlessness, vomiting, urticaria, erythema, pyrexia, chills. Mild reactions (transient discomfort that resolves spontaneously or with minimal intervention), such as rash, can be managed with antihistamines. Evaluate patients experiencing allergic reactions for the presence of an inhibitor.

Development of Inhibitor

Formation of circulating antibodies inhibiting Factor IX has been reported with the administration of BEBULIN. If such an inhibitor occurs, the condition will manifest itself as a poor clinical response. Nephrotic syndrome has been reported following attempted immune tolerance induction in hemophilia B with Factor IX inhibitor.

Transmission of Infectious Agents

BEBULIN is made from human plasma. The risk of transmitting infectious agents (e.g., viruses, and theoretically, the agent that causes Creutzfeldt-Jakob disease in human) cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens. No cases of transmission of viral diseases or CJD have ever been identified for BEBULIN. The risk of transmitting 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 viruses. The standard measures taken (including vapor heating and nanofiltration) are considered effective for inactivation/removal of enveloped viruses such as HIV, HBV, and HCV and for the nonenveloped viruses HAV and parvovirus B19.

Appropriate vaccination (hepatitis A and B) must be considered for patients in regular/repeated receipt of human plasma-derived products.

All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Baxter Healthcare Corporation at 1-800-423-2862 (in the U.S.) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Discuss the risks and benefits of this product with the patient.

Interference with Heparin Sensitivity Laboratory Testing

The heparin content of BEBULIN must be taken into account when performing clotting tests that are sensitive to heparin.

Information for Patients

Some viruses, such as parvovirus B19, are particularly difficult to remove or inactivate at this time. Parvovirus B19 most seriously affects pregnant women or immune-compromised individuals. Symptoms of parvovirus B19 infection include fever, drowsiness, chills, and runny nose followed about two weeks later by a rash, and joint pain.

Inform patients of all signs and symptoms of immediate hypersensitivity reactions such as fever, urticaria/hives, rashes, nausea, retching, angioedema/swelling of face or other body areas, laryngeal edema, stridor, dysphonia, bronchospasm/wheezing, hypotension, dizziness, lightheadedness, or loss of consciousness. Advise patients to discontinue use of the product and contact their physician if these symptoms occur. Patients should seek emergency care immediately for serious symptoms.

Drug Interactions

No drug interaction studies were performed. Factor IX complex products may overcome the effect of vitamin K antagonist treatment.

Pregnancy

Pregnancy Category C - Animal reproduction studies have not been conducted with BEBULIN It is also not known whether BEBULIN can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. BEBULIN should be given to a pregnant woman only if clearly needed.

Pediatric Use

The safety and efficacy of the use of BEBULIN in pediatric patients have not been established in Baxter clinical trials; however, the use of BEBULIN in the pediatric population is referenced in the medical literature.

Post-marketing Adverse Reactions

Because adverse reactions are reported voluntarily post-approval from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure.

The following adverse reactions have been reported during post-marketing use of BEBULIN (Table 2).

In addition to events listed above, myocardial infarction has been identified in the published literature with other Partial Coagulation Complex (PCC) and Factor IX products.

Management of Specific Types of Bleeding 5-8

Approximate Factor IX levels, typical initial doses, and the average duration of treatment are suggested in the table below. For minor bleeding a single dose will usually be sufficient, otherwise a second dose may be given after 24 hours. More severe hemorrhage will require the administration of several doses at approximately 24 hours intervals. For maintenance therapy, usually two thirds of the initial dose is infused (Table 3).

Management of Surgical Procedures 5-8

Dosage guidelines for surgical procedures are suggested below. Administer preoperative loading dose one hour prior to surgery. Depending on the type of surgery, replacement therapy has to be continued over one to several weeks until adequate wound healing is achieved. The average treatment interval will initially be 12 hours, while in the later postoperative period 24 hours is adequate (Table 4).

For tooth extraction the same initial dose as for minor surgery is recommended and one infusion should be sufficient. In case of extraction of several teeth, replacement therapy for up to one week may be necessary using the same doses as for minor surgery. 4-6

Reconstitution

Administer BEBULIN within 3 hours after reconstitution. The solution does not contain a preservative.

For reconstitution proceed as follows:

1. Warm both diluent and concentrate in unopened vials to room temperature (not above 37 °C, 98 °F).
2. Remove caps from both vials to expose central portions of the rubber stoppers.
3. Cleanse exposed surface of the rubber stoppers with germicidal solution and allow to dry.
4. Using aseptic technique, remove protective covering from one end of the double-ended needle and insert the exposed end through the diluent vial stopper.
5. Remove protective covering from the other end of the double-ended needle. Do not touch the exposed end. Invert diluent vial over the concentrate vial, then insert free end of the needle through the concentrate vial stopper. Diluent will be drawn into the concentrate vial by vacuum.
6. Disconnect the two vials by removing needle from the concentrate vial stopper.
   Gently agitate or rotate the concentrate vial until all material is dissolved.

Do not refrigerate after reconstitution!

Administration

Parenteral drug products should be inspected for particulate matter and discoloration prior to administration. The appearance of the reconstituted product should be colorless to slightly yellowish and clear to slightly turbid solution. Do not administer if particulate matter or discoloration is found and notify Baxter immediately.

Do not mix BEBULIN with other medicinal products or solvents, other than the enclosed sterilized water for injection.

Record the name of the patient and batch number of the product in order to maintain a link between the patient and the batch of the product.

Intravenous Injection

1. After reconstituting the concentrate as described above, attach the enclosed filter needle to a sterile disposable syringe using aseptic technique. Insert filter needle through the concentrate vial stopper.
2. Inject air and withdraw solution into the syringe.
3. Remove and discard filter needle. Attach a suitable intravenous needle or infusion set with winged adapter.
4. Administer the solution intravenously at a rate comfortable to the patient. The infusion rate should not exceed 2 mL per minute.