Prescription Drugs

CLINICAL PHARMACOLOGY Profilnine is a mixture of the vitamin K-dependent clotting factors IX, II, X, and low levels of VII. The administration of Profilnine temporarily increases the plasma levels of factor IX, thus enabling a temporary correction of the factor deficiency. A clinical study that evaluated twelve subjects with hemophilia B indicated that, following administration of Profilnine, the factor IX in vivo half-life was 24.68 ± 8.29 hours and recovery was 1.15 ± 0.16 units/dL per unit infused per kg body weight. Administration of Factor IX Complex can result in higher than normal levels of factor II due to the significantly longer half-life of factor II5. REFERENCES 5. Sorensen, B., Spahn, D.R., Innerhofer, P., Spannagl, M., Rossaint, R. Clinical review: prothrombin complex concentrates-evaluation of safety and thrombogenicity. Critical Care 15: 201-209, 2011.

CLINICAL PHARMACOLOGY BEBULIN is a combination of vitamin K-dependent clotting factors (Factor IX, II, X) and found in normal plasma. The administration of BEBULIN provides an increase in plasma levels of Factor IX and can temporarily correct the coagulation defect of patients with Factor IX deficiency. Plasma levels of Factors II and X will also be increased. However, no clinical studies have been conducted to show benefit from this product for treating deficiencies other than Factor IX deficiency. In vivo recovery of BEBULIN was determined using the former International Standard, WHO 72/32 and was found to be 53.3% ±9.6%, 57.5% ±21.8%, and 53.24% ±16.95%, respectively. In the same studies, using different methodologies, half-lives were determined to be 19.4 hrs ±3.8 hrs, 24.6 hrs ±3.2 hrs, and 19.97 hrs ±8.24 hrs, respectively.1 REFERENCES 1. T. Abe et al.: Clinical Study with BENOBIL TIM 4, Steam-Treated Factor IX Complex, Single Administration. Jap. Pharm. & Ther., 14, 1986, 1, pp. 19-31.

Find Lowest Prices on Profilnine® (Factor IX Complex) for Intravenous Administration DESCRIPTION Profilnine®, Factor IX Complex, is a solvent/detergent treated, nanofiltered, sterile, lyophilized concentrate of coagulation factors IX, II, X, and low levels of factor VII. The factor II content is not more than (NMT) 150 units* per 100 factor IX units, the factor X content is NMT 100 units per 100 factor IX units, and the factor VII content is NMT 35 units per 100 factor IX units. Profilnine does not contain heparin and contains no preservatives. Profilnine contains few, if any, activated factors based on results from the non-activated partial thromboplastin time (NAPTT) test1,2. Profilnine is intended for intravenous administration only. Each vial is a single-dose container and is labeled with the factor IX potency expressed in International Units. Profilnine is prepared from pooled human plasma and purified by diethylaminoethyl (DEAE) cellulose adsorption. The risk of transmission of infective agents by Profilnine has been substantially reduced by donor selection procedures and virus screening of individual donations and plasma pools by serological and nucleic acid testing. In addition, virus elimination steps such as nanofiltration3 and solvent/detergent (tri-n-butyl phosphate) treatment4 have been incorporated into the Profilnine manufacturing process. Additional removal of some viruses occurs during the DEAE cellulose product purification step. The ability of the manufacturing process to eliminate virus from Profilnine was evaluated in the laboratory by intentionally adding virus to product just prior to the elimination step and monitoring virus removal. Table 1 shows the amounts of virus that can be removed by solvent/detergent treatment, nanofiltration, and purification by DEAE chromatography when vesicular stomatitis virus (VSV), human immunodeficiency virus-1 and 2 (HIV-1, HIV-2), parvovirus, West Nile virus (WNV), bovine viral diarrhea virus (BVDV), hepatitis A virus (HAV), and pseudorabies virus (PRV) were evaluated in these virus spiking studies. The results indicate that the solvent/detergent treatment step inactivates enveloped viruses and the nanofiltration step removes both enveloped and non-enveloped viruses. Table 1: Virus Reduction Virus Virus Type Model For: Virus Reduction (log10) 1st DEAE Chromatography Process Step Solvent- Detergent Nanofiltration Sindbis Env Hepatitis C 1.4 ≥ 5.3 NT VSV Env Robust enveloped viruses NT ≥ 4.9 NT HIV-1 Env HIV-1 NT ≥ 12.2 ≥ 6.2 HIV-2 Env HIV-2 NT ≥ 6.0 NT WNV Env WNV NT NT ≥ 6.6 BVDV Env Hepatitis C NT NT ≥ 4.9 Parvo* Non-Env Parvovirus B19 NT NT ≥ 6.1 HAV Non-Env HAV NT NT ≥ 5.8 PRV Env Hepatitis B NT NT ≥ 5.3 * Porcine, NT=Not tested, Env=Enveloped REFERENCES * Unit refers to International Unit in the labeling of Profilnine. 1. Menache, D., Roberts, H.R. Summary report and recommendations of the task force members and consultants. Thromb Diath Haemorrh 33:645-647, 1975. 2. Kingdon, H.S., Lundblad, R.L., Veltkamp, J.J., Aronson, D.L. Potentially thrombogenic materials in Factor IX Concentrates. Thromb Diath Haemorrh 33:617- 631, 1975. 3. Burnouf T, Radosevich M. Nanofiltration of plasma-derived biopharmaceutical products. Haemophilia : the official journal of the World Federation of Hemophilia. 2003;9:24-37. 4. Dichtelmüller HO, Biesert L, Fabbrizzi F, Gajardo R, Gröner A, von Hoegen I, Jorquera JI, Kempf C, Kreil TR, Pifat D, Osheroff W, Poelsler G. Robustness of solvent/detergent treatment of plasma derivatives: a data collection from Plasma Protein Therapeutics Association member companies. Transfusion 49:1931-1943, 2009.

BEBULIN (Factor IX Complex), Nanofiltered and Vapor Heated Lyophilized Powder for Intravenous Administration DESCRIPTION BEBULIN (Factor IX Complex), Nanofiltered and Vapor Heated is a purified, sterile, freeze-dried concentrate of the Coagulation Factor IX (Christmas Factor) as well as Factor II (Prothrombin) and Factor X (Stuart-Prower Factor) and low amounts of Factor VII. In addition, the product contains small amounts of heparin ( ≤ 0.15 IU heparin per IU Factor IX). BEBULIN is standardized in terms of Factor IX content and each vial is labeled for the Factor IX content indicated in International Units (IU). One International Unit of Factor IX (according to the current International Standard for Human Blood Coagulation Factors II, IX, and X in concentrates) corresponds to the activity of Factor IX in 1 mL of fresh normal human plasma. BEBULIN is manufactured from large plasma pools of human plasma. Screening against potentially infectious agents begins with the donor selection process and continues throughout plasma collection and plasma preparation. Each individual plasma donation used in the manufacture of BEBULIN is collected only at FDA approved blood establishments and is tested by FDA licensed serological tests for Hepatitis B Surface Antigen (HBsAg), for antibodies to Human Immunodeficiency Virus (HIV-1/HIV-2) and Hepatitis C Virus (HCV) in accordance with U.S. regulatory requirements. As an additional safety measure, mini-pools of the plasma are tested for the presence of HIV-1 and HCV by FDA licensed Nucleic Acid Testing (NAT) and found negative. Validated virus removal/inactivation steps have been integrated into the manufacturing process, namely 35 nm nanofiltration1 and a vapor heat treatment process2 [10 hours at 60°C and subsequent 1 hour at 80°C under the condition of 7-8% (w/v) residual moisture]. In addition, DEAE-Sephadex adsorption contributes to the virus safety profile of BEBULIN. Despite these measures, this product can still potentially transmit disease3 (see WARNINGS). In vitro spiking studies have been used to validate the capability of the manufacturing process to remove and inactivate viruses. To establish virus clearance capacity of the manufacturing process, these virus clearance studies were performed in accordance with good laboratory practices under extreme conditions (e.g. at minimum incubation times and temperatures below specifications for vapor-heat treatment). The in vitro viral reduction studies performed on nanofiltered BEBULIN are summarized in Table 1. Table 1: Mean log10 Reduction Factors (RFs) For Each Virus and Manufacturing Step* Virus Type Enveloped RNA Enveloped DNA Non- enveloped RNA Non- enveloped DNA Virus Family Retro- viridae Flavi- viridae Herpes- viridae Picorna- viridae Parvo- viridae** Virus* HIV-1 BVDV PRV HAV MMV DEAE Sephadex Adsorption n.d. n.d. n.d. 1.4 1.3 35 nm Nanofiltration‡ > 6.4 2.0 > 6.0 1.7 ≤ 1.0 Vapor-Heat Treatment > 6.8 > 7.1 > 7.4 > 4.5 ≤ 1.0 Overall log reduction factor (ORF) > 13.2 > 9.1 > 13.4 > 7.6 1.3 n.d.: Not done * Reduction factors < 1 log are not used for calculation of the overall reduction factor. HIV-1, Human Immunodeficiency Virus Type 1 BVDV, Bovine Viral Diarrhea Virus (model for Hepatitis C Virus and other lipid enveloped RNA viruses) PRV, Pseudorabies Virus (model for lipid enveloped DNA viruses including Hepatitis B Virus) HAV, Hepatitis A Virus MMV, Mice Minute Virus (model for non-lipid enveloped DNA viruses, including human parvovirus B19 [B19V]) ** Studies on B19V, which are considered experimental in nature, have demonstrated a virus reduction factor of not more than 3.6 log10 and 4.6 log10 >by DEAE-Sephadex adsorption and vapor-heat treatment, respectively. ‡ Studies on West Nile Virus (WNV) have demonstrated a virus reduction factor of 3.1 log10 by the 35 nm nanofiltration step. REFERENCES 1. T. Abe et al.: Clinical Study with BENOBIL TIM 4, Steam-Treated Factor IX Complex, Single Administration. Jap. Pharm. & Ther., 14, 1986, 1, pp. 19-31. 2. Vapor Heating is described in: World Health Organization (WHO) Technical Report, Series No. 924, 2004, Annex 4, Guidelines on viral inactivation and removal, procedures intended to assure the viral safety, of human blood plasma products. 3. D.U. Preiss, B. Eberspächer, D. Abdullah, I. Rosner: Safety of Vapour Heated Prothrombin Complex Concentrate (PCC) Prothromplex S-TIM4. Thrombosis Research, 63, 1991, pp. 651-659.

INDICATIONS Profilnine, Factor IX Complex, is indicated for the prevention and control of bleeding in patients with factor IX deficiency (hemophilia B). Profilnine contains non-therapeutic levels of factor VII and is not indicated for use in the treatment of factor VII deficiency. DOSAGE AND ADMINISTRATION Dose Each vial of Profilnine is labeled with total units expressed as International Units (IU). According to the WHO International Standard, one unit approximates the activity in one mL of normal plasma. A 1% increase in factor IX (0.01 units) per unit administered per kg body weight can be expected1. The amount of Profilnine required to establish hemostasis will vary with each patient and circumstance. Use the following formula and example as guides in determining the number of units to be administered: Body weight (in kg) x Desired increase in Plasma Factor IX/ Plasma Factor IX (Percent) x 1 Units/kg = Number of Factor IX Units Required Example: 50 kg X 25 (% increase) X 1 Units/kg = 1,250 Units of factor IX Due to variability among patients and their clinical condition, monitor the factor IX level of each patient frequently during replacement therapy. Table 2 below provides treatment guidelines for hemorrhagic events and surgery in patients with factor IX deficiency. Table 2: Treatment Guidelines Type of Bleeding or Surgical Procedure Factor IX Level Required, % of Normal (Dose) Frequency of Doses Duration of Therapy (Days) Minor to Moderate Hemorrhages 20-30% (20-30 IU FIX/kg) until hemorrhage stops and healing has been achieved. Every 16-24 hrs Minor: 1-2 days Moderate: 2-7 days Major Hemorrhages 30-50% (30-50 IU FIX/kg). Every 16-24 hrs 3-10 days Surgery Following this treatment period, maintain FIX levels at 20% (20 IU FIX/kg) until healing has been achieved. Prior to surgery, 30-50% (30-50 IU FIX/kg). For dental extractions, bring FIX levels to 50% immediately prior to the procedure. Maintain FIX levels at 30-50% (30-50 IU FIX/kg) until healing has been achieved. Every 16-24 hrs 7-10 days Dosing requirements and frequency of dosing are calculated on the basis of an initial response of 1% FIX increase achieved per IU of FIX infused per kg body weight and an average half-life for FIX of 24 hours. If dosing studies reveal that a particular patient exhibits a lower response, monitor blood levels and adjust the dose accordingly. Reconstitution Use Aseptic Technique Ensure that concentrate (Profilnine) and diluent (Sterile Water for Injection, USP) are at room temperature (but not above 37° C) before reconstitution. Remove the plastic flip off cap from the diluent vial. Gently swab the exposed stopper surface with a cleansing agent such as alcohol. Avoid leaving any excess cleansing agent on the stopper. Open the Mix2Vial® package by peeling away the lid (Figure 1). Leave the Mix2Vial in the clear outer packaging. Place the diluent vial upright on an even surface, hold the vial tightly, and pick up the Mix2Vial in its clear outer packaging. While holding the diluent vial securely, push the blue end of the Mix2Vial vertically down through the diluent vial stopper (Figure 2). While holding onto the diluent vial, carefully remove the clear outer packaging from the Mix2Vial set, ensuring the Mix2Vial remains attached to the diluent vial (Figure 3). Place the product vial upright on an even surface, invert the diluent vial with the Mix2Vial attached. While holding the product vial securely on a flat surface, push the clear end of the Mix2Vial set vertically down through the product vial stopper (Figure 4). The diluent will automatically transfer out of its vial into the product vial. NOTE: If the Mix2Vial is connected at an angle, the vacuum may be released from the product vial and the diluent will not transfer into the product vial. With the diluent and product vials still attached to the Mix2Vial, gently swirl the product vial to ensure the product is fully dissolved (Figure 5). Reconstitution requires less than 10 minutes. Do not shake the vial. Disconnect the Mix2Vial into two separate pieces (Figure 6) by holding each vial adapter and twisting counterclockwise. After separating, discard the diluent vial with the blue end of the Mix2Vial. Draw air into an empty, sterile syringe. Keeping the product vial upright with the clear end of the Mix2Vial attached, screw the disposable syringe onto the luer lock portion of the Mix2Vial device by pressing and twisting clockwise. Inject air into the product vial. While keeping the syringe plunger depressed, invert the system upside down and draw the reconstituted product into the syringe by pulling the plunger back slowly (Figure 7). When the reconstituted product has been transferred into the syringe, firmly hold the barrel of the syringe and the clear vial adapter (keeping the syringe plunger facing down) and unscrew the syringe from the Mix2Vial (Figure 8). Hold the syringe upright and push the plunger until no air is left in the syringe. Attach the syringe to a venipuncture set. NOTE: If the same patient is to receive more than one vial of concentrate, the contents of two vials may be drawn into the same syringe through a separate unused Mix2Vial set before attaching to the venipuncture set. After reconstitution, inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. When reconstitution procedure is strictly followed, a few small particles may occasionally remain. The Mix2Vial set will remove particles and the labeled potency will not be reduced. Do not refrigerate after reconstitution. The reconstituted product is stable for 3 hours at room temperature; use as soon as possible within 3 hours after reconstitution. Figure 1 to 6 Administration For intravenous administration only, Inspect the final solution visually for particulate matter and discoloration prior to administration. Administer the prepared drug at room temperature within three hours after reconstitution. Prompt administration is recommended to avoid ill effects of any inadvertent bacterial contamination occurring during reconstitution. Administer by intravenous injection (plastic disposable syringe only) or infusion at a rate not exceeding 10 mL/minute. Discard any unused Profilnine vial contents. Discard administration equipment into the appropriate safety container after single use. Do not resterilize components. Do not reuse components. HOW SUPPLIED Profilnine is supplied in sterile lyophilized form in single-dose vials accompanied by a suitable volume of diluent (Sterile Water for Injection, USP), according to factor IX potency. Each vial is labeled with the factor IX potency expressed in International Units which is referenced to the WHO International Standard. Profilnine is packaged with a Mix2Vial filter transfer set for use in administration. The product is available in several potencies, with carton and vial label color coded based upon assay as follows: Potency Carton NDC Assay Color Code 500 units FIX/5 mL 68516-3201-1 500 units FIX Range - blue 1000 units FIX/10 mL 68516-3202-2 1000 units FIX Range - red 1500 units FIX/10 mL 68516-3203-2 1500 units FIX Range - black The diluent vial stopper contains natural rubber latex. All other components of the kit are not made with natural rubber latex. Storage Profilnine is stable for three years, up to the expiration date printed on its label, provided that the storage temperature does not exceed 25 °C (77 °F). Do not freeze. REFERENCES 1. Menache, D., Roberts, H.R. Summary report and recommendations of the task force members and consultants. Thromb Diath Haemorrh 33:645-647, 1975. Manufactured by: Grifols Biologicals Inc. 5555 Valley Boulevard, Los Angeles, CA 90032, U.S.A. Revised: Jul 2015

INDICATIONS BEBULIN is indicated for the prevention and control of bleeding episodes in adult patients with hemophilia B (congenital Factor IX deficiency or Christmas disease). BEBULIN is not indicated for use in the treatment of Factor VII deficiency. No clinical studies have been conducted to show benefit from this product for treating deficiencies other than Factor IX deficiency. DOSAGE AND ADMINISTRATION For intravenous administration only One International Unit (IU) of Factor IX activity/kg will increase the plasma level of Factor IX by 0.8%. Accordingly, the following formula is provided for dosage calculations: Number of Factor IX IU required = bodyweight (kg) x desired Factor IX increase (% of normal) x 1.2. The response to treatment will vary from patient to patient. Exact dosage determination should be based on localization and extent of hemorrhage, and the level of Factor IX to be achieved. Close laboratory monitoring of the Factor IX level is required to determine proper dosage, particularly with severe hemorrhage and major surgery. Larger doses than those derived from the above formula may be required, particularly if treatment is delayed. Management Of Bleeding7-11 Approximate desired Factor IX levels, typical initial doses, and the average duration of treatment are suggested in Table 3. 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 several doses at approximately 24-hour intervals. For maintenance therapy, usually two thirds of the initial dose is infused. Table 3. Management of Specific Types of Bleeding Type of Bleeding Approximate Desired Factor IX Level (% Normal) Typical Initial Dose (International Units/kg) Average Duration of Treatment (Days) Minor Early hemarthrosis, minor epistaxis, and gingival bleeding, mild hematuria 20 25-35 1 Moderate Severe joint bleeding, early hematoma, major open bleeding, minor trauma, minor hemoptysis, hematemesis, melena, and major hematuria 40 50-65 2 or until adequate wound healing Major Severe hematoma, major trauma, severe hemoptysis, hematemesis, and melena > 60* 75-90 2-3 or until adequate wound healing * For patients predisposing to thrombosis see PRECAUTIONS section. Management Of Surgical Procedures 7-11 Dosage guidelines for surgical procedures are suggested in Table 4. Administer preoperative loading dose one hour prior to surgery. Depending on the type of surgery, continue replacement therapy 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: Management of Surgical Procedures Type of Surgery Day of Operation Init. Postop. Period (1st to 2nd Week) Late Postop. Period (from 3rd Week Onwards) Approx. Level Factor IX (% Normal) Dose (IU/kg) Approx. Level Factor IX (% Normal) Dose (IU/kg) Approx. Level Factor IX (% Normal) Dose (IU/kg) Minor 40-60 50-75 20-40 25-65 N/A N/A Major ≥ 60* 75-90 20-60 25-75 20 25-35 * For patients predisposing to thrombosis see PRECAUTIONS section. N/A: Not Applicable. 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.8-11 Reconstitution Do not mix BEBULIN with other medicinal products or solvents, other than the enclosed sterilized water for injection. Administer BEBULIN within 3 hours after reconstitution as the solution does not contain a preservative. Do not refrigerate after reconstitution. Warm unopened vials of both diluent and concentrate to room temperature (not to exceed 37°C, 98°F). Remove caps from both vials to expose central portions of the rubber stoppers. Cleanse exposed surface of the rubber stoppers with germicidal solution and allow to dry. Using aseptic technique, remove protective covering from one end of the double-ended needle and insert the exposed end through the diluent vial stopper. 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. Disconnect the two vials by removing needle from the concentrate vial stopper. Gently agitate or rotate the concentrate vial until all material is dissolved. Administration For Intravenous Administration Only. Parenteral drug products should be inspected for particulate matter and discoloration prior to administration. 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. 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. 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. Inject air and withdraw solution into the syringe. Remove and discard filter needle. Attach a suitable intravenous needle or infusion set with winged adapter. Administer the solution intravenously at a rate comfortable to the patient. The infusion rate should not exceed 2 mL per minute. HOW SUPPLIED BEBULIN is supplied in single dose vials (NDC 64193-445-02) with Sterile Water for Injection, U.S.P., double-ended needle, and filter needle for reconstitution and withdrawal. Factor IX activity in international units is stated on the label of each vial. Storage Store at refrigerated temperature (2°C-8°C, 35°F-46°F). Do not use BEBULIN past the expiration date printed on the unit carton. Do not freeze. To enroll in the confidential, Industry-wide Patient Notification System, call 1-888-873-2838. REFERENCES 7. P. H. Levine: Clinical Manifestations and Therapy of Hemophilias A and B. In: R. W. Colman, J. Hirsh, V. J. Marder, E. W. Salzman (Eds.): Hemostasis and Thrombosis. Philadelphia: J. B. Lippincott Company, 1987, pp. 97-111.5. 8. C. R. Rizza, P. Jones: Management of patients with inherited blood coagulation defects. In: A.L. Bloom, D.P. Thomas (Eds.): Hemostasis and Thrombosis. Edinburgh: Churchill Livingstone, 1987, pp. 465-493. 9. T. Abe, M. Kazama: An International Survey on the Appropriate Dosage of Hemophilias and Related Congenital Coagulopathies. In: Proceedings of the 3rd International Symposium on Haemostasis and Thrombosis, 1982, pp. 273-304. 10. I. M. Nilsson, Å. Ahlberg, G. Björlin: Clinical Experience with a Swedish Factor IX Concentrate. Acta Med. Scand., 190, 1971, pp. 257-266. 11. J. N. George, R. T. Breckenridge: The Use of Factor VIII and Factor IX Concentrates During Surgery. JAMA, 214, 1970, 9, pp. 1673-1676. Baxter Healthcare Corporation Westlake Village, CA 91362 USA. Revised: / July 2012

PATIENT INFORMATION Advise patients to report to their physician any decrease in effectiveness of Factor IX treatment, as this can indicate development of inhibitors. Hypersensitivity, including anaphylaxis, has been reported for factor IX complex concentrate products. Inform patients of the early symptoms and signs of hypersensitivity reaction, including hives, rash, swelling, chest tightness, shortness of breath, wheezing, faintness, decrease in blood pressure, and rapid heartbeat. Advise patients to discontinue use of the product and contact their physician and/or seek immediate emergency care if these symptoms occur.

PATIENT INFORMATION 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 and seek emergency care immediately for serious symptoms. Inform patients of all signs and symptoms of parvovirus B19 infection, which is especially serious in 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.

OVERDOSE No information provided. CONTRAINDICATIONS None known.

SIDE EFFECTS Adverse reactions with Profilnine may include headache, fever, chills, flushing, nausea, vomiting, tingling, lethargy, urticaria, and manifestations of allergic reactions. The following adverse reactions have been identified during post-approval use of Profilnine: hypersensitivity reactions including shortness of breath, diaphoresis, and hypotension, as well as thrombosis including pulmonary embolism and deep vein thrombosis, disseminated intravascular coagulation, and inhibitor development. 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. To report SUSPECTED ADVERSE REACTIONS, contact Grifols at 1-888-GRIFOLS (1-888-474- 3657) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS No information provided.

WARNINGS Transmissible Infectious Agents Because Profilnine is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. Inhibitors Patients can develop neutralizing antibodies (inhibitors) after treatment with Profilnine. Monitor patients for inhibitors, which should be quantified in Bethesda Units (BU) using appropriate laboratory testing. Hypersensitivity Hypersensitivity, including anaphylaxis, has been reported. Inform patients of the early symptoms and signs of hypersensitivity reaction, including hives, generalized urticaria, angioedema, chest tightness, dyspnea, wheezing, faintness, hypotension, tachycardia, and anaphylaxis. Thrombosis The use of factor IX complex concentrates has been associated with the development of thromboembolic complications. Patients at increased risk for thrombosis include those undergoing surgery, post surgery, with known liver disease, and with signs of fibrinolysis, thrombosis, or disseminated intravascular coagulation (DIC)5. When administering Profilnine to these high-risk patients, monitor for early signs of consumptive coagulopathy with appropriate laboratory testing. Only administer Profilnine to patients when the benefits outweigh the risks. PRECAUTIONS Vasomotor reactions may result from overly rapid administration. Do not exceed the recommended infusion rate of 10 mL/min. Pregnancy Category C Animal reproduction studies have not been conducted with Profilnine. It is also not known whether Profilnine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Only give Profilnine to a pregnant woman if clearly indicated. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Natural Rubber Latex Sensitivity Certain components used in the packaging of this product contain natural rubber latex. In patients with sensitivity to natural rubber latex, use Profilnine only if needed.

WARNINGS Thrombosis Thromboembolic events (deep vein thrombosis, pulmonary embolism, thrombotic stroke) as well as disseminated intravascular coagulation (DIC) have been reported with BEBULIN. The risk of thromboembolic complications including DIC and hyperfibrinolysis is higher in patients with congenital or acquired coagulation disorders, with repeated dosing or high doses of BEBULIN. Because of the risk of thromboembolic complications, closely monitor patients when administering BEBULIN: Monitor patients closely for signs and symptoms of intravascular coagulation or thrombosis. Monitor Factor IX level in patients predisposed to thromboembolic complications including patients with a history of coronary artery disease, patients with liver disease, pre- or postoperative patients, and neonates. Stop the infusion immediately and initiate appropriate diagnostic and therapeutic measures at the first signs or symptoms of thrombosis or embolism. Anaphylaxis And Hypersensitivity Reactions Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been reported with BEBULIN. Manifestations of hypersensitivity or allergic reactions include anaphylactic shock, hypotension, hypertension, chest tightness, dizziness, paresthesia, lethargy, restlessness, vomiting, urticaria, erythema, pyrexia, chills, and rash. In the event of an anaphylactic/anaphylactoid reaction, stop the infusion immediately and administer appropriate emergency treatment. 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 receiving factor IX products including BEBULIN.4 The safety and efficacy of using factor IX products including Bebulin for immune tolerance induction have not been established. Transmission Of Infectious Agents Because BEBULIN is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and theoretically, the classic Creutzfeldt-Jakob disease agent. This also applies to unknown or emerging viruses and other pathogens. No cases of transmission of viral diseases or vCJD have been associated with BEBULIN. ALL infections thought by a physician to possibly 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.). PRECAUTIONS Interference With Heparin Sensitivity Laboratory Testing BEBULIN contains heparin. Take heparin content into account when performing clotting tests sensitive to heparin. 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. Pediatric Use The safety and efficacy of the use of BEBULIN in pediatric patients have not been established. REFERENCES 4. I. Warrier: Management of haemophilia B patients with inhibitors and anaphylaxis. Haemophilia, 4 (4), pp.574-576.