İHALE DÜNYASI
İHALE DÜNYASI
BeneFIX RTS , Coagulation Factor IX (Recombinant), is a purified protein produced by recombinant DNA. It has a primary amino acid sequence that is identical to the Ala 148 allelic form of plasma-derived factor IX, and has structural and functional characteristics similar to those of endogenous factor IX. BeneFIX RTS is produced by a genetically engineered Chinese hamster ovary (CHO) cell line that is extensively characterized. No human or animal proteins are added during the purification and formulation processes of BeneFIX RTS . BeneFIX RTS is not derived from human blood and contains no preservatives, and the manufacture of BeneFIX RTS includes no added animal or human components. The stored cell banks are free of human blood or plasma products. The CHO cell line secretes recombinant factor IX into a defined cell culture medium that does not contain any proteins derived from animal or human sources, and the recombinant factor IX is purified by a chromatography purification process that does not require a monoclonal antibody step. The process also includes a membrane nanofiltration step that has the ability to retain molecules with apparent molecular weights >70,000 Da (such as large proteins and viral particles). BeneFIX RTS is a single component by SDS-polyacrylamide gel electrophoresis evaluation. The potency (in International Units, IU) is determined using an in vitro one-stage clotting assay against the World Health Organization (WHO) International Standard for Factor IX concentrate. One International Unit is the amount of factor IX activity present in 1 mL of pooled, normal human plasma. The specific activity of BeneFIX RTS is greater than or equal to 200 IU per milligram of protein. BeneFIX RTS is formulated as a sterile, nonpyrogenic, lyophilized powder preparation. BeneFIX RTS is intended for intravenous (IV) injection. It is available in single-use vials containing the labeled amount of factor IX activity, expressed in IU. Each vial contains nominally 250, 500, 1000 or 2000 IU of Coagulation Factor IX (Recombinant). After reconstitution of the lyophilized drug product, the concentrations of excipients are 0.234% sodium chloride, 8 mM L-histidine, 0.8% sucrose, 208 mM glycine, 0.004% polysorbate 80. All dosage strengths yield a clear, colorless solution upon reconstitution.
BeneFIX RTS is an antihemophilic factor (recombinant) indicated for: Control and prevention of bleeding episodes in adult and pediatric patients with hemophilia B. ( 1.1 ) Peri-operative management in adult and pediatric patients with hemophilia B. ( 1.2 ) 1.1 Control and Prevention of Bleeding Episodes in Hemophilia B BeneFIX (R)RTS , Coagulation Factor IX (Recombinant), is indicated for the control and prevention of bleeding episodes in adult and pediatric patients with hemophilia B (congenital factor IX deficiency or Christmas disease). 1.2 Peri-operative Management in Patients with Hemophilia B BeneFIX RTS , Coagulation Factor IX (Recombinant), is indicated for peri-operative management in adult and pediatric patients with hemophilia B. BeneFIX RTS , Coagulation Factor IX (Recombinant), is NOT indicated for: treatment of other factor deficiencies (e.g., factors II, VII, VIII, and X), treatment of hemophilia A patients with inhibitors to factor VIII, reversal of coumarin-induced anticoagulation, treatment of bleeding due to low levels of liver-dependent coagulation factors.
For Intravenous Use only The initial estimated dose may be determined using the following formula: ( 2 ) Required units = body weight (kg) x desired factor IX increase (IU/dL or % of normal) x reciprocal of observed recovery (IU/kg per IU/dL) Average Recovery: Adult and Pediatric (<15 years) Patients In clinical studies with adult and pediatric (<15 years) patients, one IU of BeneFIX RTS per kilogram of body weight increased the circulating activity of factor IX as follows: Adults: 0.8 ± 0.2 IU/dL [range 0.4 to 1.2 IU/dL]. ( 2.3 ) Pediatric: 0.7 ± 0.3 IU/dL [range 0.2 to 2.1 IU/dL]. ( 2.3 ) Dosing of BeneFIX RTS may differ from that of plasma-derived factor IX products. Dosage and duration of treatment with BeneFIX RTS depends on the severity of the factor IX deficiency, the location and extent of bleeding, and the patient's clinical condition, age and recovery of factor IX. ( 2.1 ) 2.1 General Considerations for Administration For Intravenous Use after Reconstitution Treatment with BeneFIX RTS , Coagulation Factor IX (Recombinant), should be initiated under the supervision of a physician experienced in the treatment of hemophilia B. Each vial of BeneFIX RTS has the rFIX potency in the International Units (IU) stated on the vial. Dosage and duration of treatment for all factor IX products depend on the severity of the factor IX deficiency, the location and extent of bleeding, and the patient's clinical condition, age and recovery of factor IX. To ensure that the desired factor IX activity level has been achieved, precise monitoring using the factor IX activity assay is advised. Doses should be titrated using the factor IX activity, pharmacokinetic parameters, such as half-life and recovery, as well as taking the clinical situation into consideration in order to adjust the dose as appropriate. Dosing of BeneFIX RTS may differ from that of plasma-derived factor IX products [ see Clinical Pharmacology ( 12 ) ]. Subjects at the low end of the observed factor IX recovery may require upward dosage adjustment of BeneFIX RTS to as much as two times (2X) the initial empirically calculated dose in order to achieve the intended rise in circulating factor IX activity. The safety and efficacy of BeneFIX RTS administration by continuous infusion have not been established [ see Warnings and Precautions ( 5 ) ]. 2.2 Method of Calculating Initial Estimated Dose The method of calculating the factor IX dose is shown in Table 1 . Table 1 number of factor IX IU required (IU) = body weight (kg) x desired factor IX increase (% or IU/dL) x reciprocal of observed recovery (IU/kg per IU/dL) Average Recovery Adult Patients in Clinical Trial In adult PTPs, on average, one International Unit (IU) of BeneFIX per kilogram of body weight increased the circulating activity of factor IX by 0.8 ± 0.2 IU/dL (range 0.4 to 1.2 IU/dL). The method of dose estimation is illustrated in Table 2 . If you use 0.8 IU/dL average increase of factor IX per IU/kg body weight administered, then: Table 2 number of factor IX IU required (IU) = body weight (kg) x desired factor IX increase (% or IU/dL) x 1.3 (IU/kg per IU/dL) Average Recovery Pediatric Patients (<15 years) in Clinical Trial In pediatric patients, on average, one international unit of BeneFIX per kilogram of body weight increased the circulating activity of factor IX by 0.7 ± 0.3 IU/dL (range 0.2 to 2.1 IU/dL; median of 0.6 IU/dL per IU/kg). The method of dose estimation is illustrated in Table 3 . If you use 0.7 IU/dL average increase of factor IX per IU/kg body weight administered, then: Table 3 number of factor IX IU required (IU) = body weight (kg) x desired factor IX increase (% or IU/dL) x 1.4 (IU/kg per IU/dL) Doses administered should be titrated to the patient's clinical response. Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses to BeneFIX RTS . Although the dose can be estimated by the calculations above, it is highly recommended that, whenever possible, appropriate laboratory tests, including serial factor IX activity assays, be performed. 2.3 Dosing Guide for Control and Prevention of Bleeding Episodes and Peri-operative Management Table 4 Type of Hemorrhage Circulating Factor IX Activity Required [% or (IU/dL)] Dosing Interval [hours] Duration of Therapy [days] Adapted from: Roberts and Eberst 1 Minor Uncomplicated hemarthroses, superficial muscle, or soft tissue 20-30 12-24 1-2 Moderate Intramuscle or soft tissue with dissection, mucous membranes, dental extractions, or hematuria 25-50 12-24 Treat until bleeding stops and healing begins, about 2 to 7 days Major Pharynx, retropharynx, retroperitoneum, CNS, surgery 50-100 12-24 7-10 2.4 Instructions for Use BeneFIX RTS is administered by intravenous (IV) infusion after reconstitution of the lyophilized powder with the supplied pre-filled diluent (0.234% sodium chloride solution) syringe. Patients should follow the specific reconstitution and administration procedures provided by their physicians. For instructions, patients should follow the recommendations in the FDA-Approved Patient Labeling [ see Patient Counseling Information ( 17.3 ) ]. Reconstitution, product administration, and handling of the administration set must be done with caution. Discard all equipment, including any reconstituted BeneFIX RTS product, in an appropriate container. Place needles used for venipuncture in a sharps container after single use. Percutaneous puncture with a needle contaminated with blood from an infected patient can transmit infectious viruses including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs. 2.5 Preparation and Reconstitution The procedures below are provided as general guidelines for the reconstitution and administration of BeneFIX RTS . Preparation Always wash your hands before performing the following procedures. Aseptic technique (meaning clean and germ-free) should be used during the reconstitution procedure. Use all components in the reconstitution and administration of this product as soon as possible after opening their sterile containers to minimize unnecessary exposure to the atmosphere. Note: If you use more than one vial of BeneFIX RTS per infusion, each vial should be reconstituted according to the following instructions. The diluent syringe should be removed leaving the vial adapter in place, and a separate large luer lock syringe may be used to draw back the reconstituted contents of each vial. Do not detach the diluent syringes or the large luer lock syringe until you are ready to attach the large luer lock syringe to the next vial adapter. Reconstitution If refrigerated allow the vial of lyophilized BeneFIX RTS and the pre-filled diluent syringe to reach room temperature. Remove the plastic flip-top cap from the BeneFIX RTS vial to expose the central portions of the rubber stopper. Wipe the top of the vial with the alcohol swab provided, or use another antiseptic solution, and allow to dry. After cleaning, do not touch the rubber stopper with your hand or allow it to touch any surface. Peel back the cover from the clear plastic vial adapter package. Do not remove the adapter from the package. Place the vial on a flat surface. While holding the adapter in the package, place the vial adapter over the vial and press down firmly on the package until the adapter spike penetrates the vial stopper. Grasp the plunger rod as shown in the diagram. Avoid contact with the shaft of the plunger rod. Attach the threaded end of the plunger rod to the diluent syringe plunger by pushing and turning firmly. Break off the tamper-resistant plastic-tip cap from the diluent syringe by snapping the perforation of the cap. Do not touch the inside of the cap or the syringe tip. The diluent syringe may need to be recapped (if not administering reconstituted BeneFIX RTS immediately), so place the cap on its top on a clean surface in a spot where it would be least likely to become environmentally contaminated. Lift the package away from the adapter and discard the package. Place the vial on a flat surface. Connect the diluent syringe to the vial adapter by inserting the tip into the adapter opening while firmly pushing and turning the syringe clockwise until secured. Slowly depress the plunger rod to inject all the diluent into the BeneFIX RTS vial. Without removing the syringe, gently swirl the contents of the vial until the powder is dissolved. Note: The final solution should be inspected visually for particulate matter before administration. The solution should appear clear and colorless. If it is not, the solution should be discarded and a new kit should be used. Invert the vial and slowly draw the solution into the syringe. Detach the syringe from the vial adapter by gently pulling and turning the syringe counter-clockwise. Discard the vial with the adapter attached. Note: If the solution is not to be used immediately, the syringe cap should be carefully replaced. Do not touch the syringe tip or the inside of the cap. BeneFIX RTS , when reconstituted, contains polysorbate-80, which is known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC). This should be considered during the preparation and administration of BeneFIX RTS , including storage time elapsed in a PVC container following reconstitution. It is important that the recommendations for dosage and administration be followed closely [ see Dosage and Administration ( 2 ) ]. Note: The tubing of the infusion set included with this kit does not contain DEHP. figure figure figure figure figure figure figure figure 2.6 Administration (Intravenous Injection) For Intravenous Use only after Reconstitution BeneFIX RTS is administered by intravenous (IV) infusion after reconstitution with the pre-filled diluent (0.234% sodium chloride solution) syringe. BeneFIX RTS should be inspected for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted solution may be stored at room temperature prior to administration, but BeneFIX RTS should be administered within 3 hours. BeneFIX RTS should be administered using the tubing provided in this kit, and the pre-filled diluent syringe provided, or a single sterile disposable plastic syringe. In addition, the solution should be withdrawn from the vial using the vial adapter. A dose of BeneFIX RTS may be administered over a period of several minutes. The rate of administration, however, should be adapted to the comfort level of each individual patient. Attach the syringe to the luer end of the infusion set tubing provided. Apply a tourniquet and prepare the injections site by wiping the skin well with an alcohol swab provided in the kit. Perform venipuncture. Insert the needle on the infusion set tubing into the vein, and remove the tourniquet. The reconstituted BeneFIX RTS product should be injected intravenously over several minutes. The rate of administration should be determined by the patient's comfort level. Reconstituted BeneFIX RTS should not be administered in the same tubing or container with other medicinal products. Agglutination of red blood cells in the tubing/syringe has been reported with the administration of BeneFIX RTS . No adverse events have been reported in association with this observation. To minimize the possibility of agglutination, it is important to limit the amount of blood entering the tubing. Blood should not enter the syringe. If red blood cell agglutination is observed in the tubing or syringe, discard all material (tubing, syringe and BeneFIX RTS solution) and resume administration with a new package. Following completion of BeneFIX RTS treatment, remove the infusion set and discard. Dispose of all unused solution, empty vial(s), and used needles and syringes in an appropriate container for throwing away waste that might hurt others if not handled properly. The safety and efficacy of administration by continuous infusion have not been established [ see Warnings and Precautions ( 5 ) ]. figure figure
BeneFIX RTS is contraindicated in patients who have manifested life-threatening, immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including hamster protein. BeneFIX RTS is contraindicated in patients who have manifested life-threatening, immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including hamster protein. ( 4 )
The most serious adverse reactions are systemic hypersensitivity reactions, including bronchospastic reactions and/or hypotension and anaphylaxis and the development of high-titer inhibitors necessitating alternative treatments to factor IX replacement therapy. The most common adverse reactions observed in clinical trials (frequency > 5% of PTPs or PUPs) were headaches, dizziness, nausea, injections site reaction, injection site pain and skin-related hypersensitivity reactions (e.g., rash, hives). The most common adverse reactions (incidence >5%) from clinical trials were nausea, injection site reaction, injection site pain, headache, dizziness and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Wyeth Pharmaceuticals Inc. at 1-800-934-5556 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. During uncontrolled open-label clinical studies with BeneFIX, Coagulation Factor IX (Recombinant), conducted in previously treated patients (PTPs), 113 adverse reactions with known or unknown relation to BeneFIX therapy were reported among 38.5% (25 of 65) of subjects (with some subjects reporting more than one event) who received a total of 7,573 infusions. These adverse reactions are summarized in Table 5 . Table 5: Adverse Reactions Reported for PTPs* Body System Adverse Reaction Number of patients (%) *Adverse reactions reported within 72 hours of an infusion of BeneFIX. 1 Low-titer transient inhibitor formation. 2 The renal infarct developed in a hepatitis C antibody-positive patient 12 days after a dose of BeneFIX for a bleeding episode. The relationship of the infarct to the prior administration of BeneFIX is uncertain. Blood and lymphatic system disorders Factor IX inhibition 1 1 (1.5%) Eye disorders Blurred vision 1 (1.5%) Gastrointestinal disorders Nausea 4 (6.2%) Vomiting 1 (1.5%) General disorders and administration site conditions Injection site reaction 5 (7.7%) Injection site pain 4 (6.2%) Fever 2 (3.1%) Infections and infestations Cellulitis at IV site 1 (1.5%) Phlebitis at IV site 1 (1.5%) Nervous system disorders Headache 7 (10.8%) Dizziness 5 (7.7%) Taste perversion (altered taste) 3 (4.6%) Shaking 1 (1.5%) Drowsiness 1 (1.5%) Renal and urinary disorders Renal infarct 2 1 (1.5%) Respiratory, thoracic and mediastinal disorders Dry cough 1 (1.5%) Hypoxia 1 (1.5%) Chest tightness 1 (1.5%) Skin and subcutaneous disorders Rash 4 (6.2%) Hives 2 (3.1%) Vascular disorders Flushing 2 (3.1%) In the 63 previously untreated patients (PUPs), who received a total of 5,538 infusions, 10 adverse reactions were reported among 9.5% of the patients (6 out of 63) having known or unknown relationship to BeneFIX. These events are summarized in Table 6 . Table 6: Adverse Reactions Reported for PUPs* Body System Adverse Reaction Number of Patients (%) *Adverse reactions reported within 72 hours of an infusion of BeneFIX. 1 Two subjects developed high-titer inhibitor formation during treatment with BeneFIX. Blood and lymphatic system disorders Factor IX inhibition 1 2 (3.2%) General disorders and administration site conditions Injection site reaction 1 (1.6%) Chills 1 (1.6%) Respiratory, thoracic and mediastinal disorders Dyspnea (respiratory distress) 2 (3.2%) Skin and subcutaneous disorders Hives 3 (4.8%) Rash 1 (1.6%) For adverse reactions thought to be related to the administration of BeneFIX, the rate of infusion should be decreased or the infusion stopped. Immunogenicity In clinical studies with 65 PTPs (defined as having more than 50 exposure days), a low-titer inhibitor was observed in one patient. The inhibitor was transient, the patient continued on study and had normal factor IX recovery pharmacokinetics at study completion (approximately 15 months after inhibitor detection). In clinical studies with pediatric PUPs, inhibitor development was observed in 2 out of 63 patients (3.2%), both were high-titer (> 5 BU) inhibitors detected after 7 and 15 exposure days, respectively. Both patients were withdrawn from the study. 6.2 Post-marketing Experience The following post-marketing adverse reactions have been reported for BeneFIX RTS : inadequate factor IX recovery, inadequate therapeutic response, inhibitor development [ see Clinical Pharmacology ( 12 ) ], anaphylaxis [ see Warnings and Precautions ( 5.2 ) ], angioedema, dyspnea, hypotension, and thrombosis. 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. The safety and efficacy of BeneFIX RTS administration by continuous infusion have not been established [ see Warnings and Precautions ( 5.3 ) ]. There have been post-marketing reports of thrombotic events, including life-threatening SVC syndrome in critically ill neonates, while receiving continuous-infusion BeneFIX RTS through a central venous catheter. Cases of peripheral thrombophlebitis and DVT have also been reported. In some, BeneFIX RTS was administered via continuous infusion, which is not an approved method of administration [ see Dosage and Administration ( 2 ) ].
Anaphylaxis and severe hypersensitivity reactions are possible. Should symptoms occur, treatment with the product should be discontinued, and emergency treatment should be sought. ( 5.2 ) BeneFIX RTS has been associated with the development of thromboembolic complications, including patients receiving continuous infusion through a central venous catheter. ( 5.3 ) Development of activity-neutralizing antibodies has been detected in patients receiving factor IX-containing products. If expected plasma factor IX activity levels are not attained, or if patient presents with allergic reaction, or if bleeding is not controlled with an expected dose, an assay that measures factor IX inhibitor concentration should be performed. ( 5.5 ) Patients may develop hypersensitivity to hamster (CHO) protein as BeneFIX RTS contains trace amounts. ( 5.2 ) 5.1 General The clinical response to BeneFIX RTS may vary. If bleeding is not controlled with the recommended dose, the plasma level of factor IX should be determined, and a sufficient dose of BeneFIX should be administered to achieve a satisfactory clinical response. If the patient's plasma factor IX level fails to increase as expected or if bleeding is not controlled after the expected dose, the presence of an inhibitor (neutralizing antibodies) should be suspected, and appropriate testing performed [ see Warnings and Precautions ( 5.6 ) ]. 5.2 Anaphylaxis and Severe Hypersensitivity Reactions Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with BeneFIX RTS and have manifested as pruritus, rash, urticaria, hives, facial swelling, dizziness, hypotension, nausea, chest discomfort, cough, dyspnea, wheezing, flushing, discomfort (generalized) and fatigue. Frequently, these events have occurred in close temporal association with the development of factor IX inhibitors. Advise patients to discontinue use of the product and contact their physician and/or seek immediate emergency care. BeneFIX RTS contains trace amounts of hamster (CHO) proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins. 5.3 Thromboembolic Complications The safety and efficacy of BeneFIX RTS administration by continuous infusion have not been established [ see Dosage and Administration ( 2 ) ]. There have been post-marketing reports of thrombotic events in patients receiving continuous-infusion BeneFIX RTS through a central venous catheter, including life-threatening superior vena cava (SVC) syndrome in critically ill neonates [ see Adverse Reactions ( 6 ) ]. 5.4 Nephrotic Syndrome Nephrotic syndrome has been reported following immune tolerance induction with factor IX products in hemophilia B patients with factor IX inhibitors and a history of allergic reactions to factor IX. The safety and efficacy of using BeneFIX RTS for immune tolerance induction have not been established. 5.5 Neutralizing Antibodies (Immunogenicity) Patients using BeneFIX RTS should be monitored for the development of factor IX inhibitors by appropriate clinical observations and laboratory tests. Inhibitors have been reported following administration of BeneFIX RTS [ see Clinical Pharmacology ( 12 ) ]. If expected plasma factor IX activity levels are not attained, or if bleeding is not controlled with an expected dose, an assay that measures factor IX inhibitor concentration should be performed. Patients with factor IX inhibitors may be at an increased risk of anaphylaxis upon subsequent challenge with factor IX. 2 Patients experiencing allergic reactions should be evaluated for the presence of an inhibitor. Patients should be observed closely for signs and symptoms of acute hypersensitivity reactions, particularly during the early phases of initial exposure to product. Because of the potential for allergic reactions with factor IX concentrates, the initial (approximately 10 - 20) administrations of factor IX should be performed under medical supervision where proper medical care for allergic reactions could be provided. 5.6 Monitoring Laboratory Tests Patients should be monitored for factor IX activity levels by the one-stage clotting assay to confirm that adequate factor IX levels have been achieved and maintained, when clinically indicated [ see Dosage and Administration ( 2 ) ]. Patients should be monitored for the development of inhibitors if expected factor IX activity plasma levels are not attained, or if bleeding is not controlled with the recommended dose of BeneFIX RTS . Assays used to determine if factor IX inhibitor is present should be titered in Bethesda Units (BUs).
None known. None known. ( 7 )