XYNTHA- antihemophilic factor (recombinant)

XYNTHA temporarily replaces the missing clotting factor VIII that is needed for effective hemostasis. The activated partial thromboplastin time (aPTT) is prolonged in patients with hemophilia. Determination of aPTT is a conventional in vitro The pharmacokinetic parameters of XYNTHA in 30 PTPs 12 to 60 years old, who received a single infusion of 50 IU/kg XYNTHA are summarized in Table 3. In addition, 25 of the same subjects later received a single infusion of 50 IU/kg of XYNTHA for a 6-month follow-up pharmacokinetic study. The parameters were comparable between baseline and 6 months, indicating no time-dependent changes in the pharmacokinetics of XYNTHA. In a separate study, 8 of 30 subjects at least 12 years old with hemophilia A undergoing elective major surgery received a single 50 IU/kg infusion of XYNTHA. The pharmacokinetic parameters in these subjects are also summarized in Table 3. Table 3: Mean +/- SD XYNTHA Pharmacokinetic Parameters in Previously Treated Patients with Hemophilia A after Single 50 IU/kg Dose Parameter Initial Visit (n = 30) Month 6 (n = 25) Pre-surgery (n=8) Abbreviations: AUC infinity max 1/2 C max 1. 24 AUC infinity 13. 2 One subject was excluded from the calculation due to lack of a well-defined terminal phase. 4 CL (mL/hr/kg) 4. 25 Vss (mL/kg) 66. 1 Recovery (IU/dL per IU/kg) 2. 47 Table 4 shows the pharmacokinetic parameters of nine children; four aged 14 or 15 years of age, who are also included in the summary for the adults above, along with five children aged 3. 8 years after single 50 IU/kg doses of XYNTHA. Compared to adults, the half-life of XYNTHA is shorter in children and the clearance (based on per kg body weight) is approximately 40% higher in children. Table 4: Mean +/- SD XYNTHA Pharmacokinetic Parameters in Previously Treated Pediatric Patients with Hemophilia A after Single 50 IU/kg Dose Parameter Young Children (n = 5) Adolescents (n = 4) Abbreviations: AUC infinity max 1/2 Age (min-max, yr) 3. 8 14en dash15 C max 0. 21 AUC infinity 12. 4 CL (mL/hr/kg) 6. 16 Vss (mL/kg) 66. 6 Recovery (IU/dL per IU/kg) 1.

XYNTHA, Antihemophilic Factor (Recombinant), is indicated for use in adults and children with hemophilia A (congenital factor VIII deficiency) for: XYNTHA does not contain von Willebrand factor, and therefore is not indicated in patients with von Willebrand's disease. 1 1.

DOSAGE AND ADMINISTRATION
For intravenous use after reconstitution only. For intravenous use after reconstitution only ( 2 2. 1 Routine prophylaxis ( 2. 1 2. 2 2 The expected in vivo Dosage (International Units) = body weight (kg) × desired factor VIII rise (IU/dL or % of normal) × 0. 5 (IU/kg per IU/dL) or IU/dL (or % of normal) = Total Dose (IU)/body weight (kg) × 2 [IU/dL]/[IU/kg] On-demand treatment and Control of Bleeding Episodes A guide for dosing XYNTHA for on-demand treatment and control of bleeding episodes is provided in Table 1. Maintain the plasma factor VIII activity at or above the levels (in % of normal or in IU/dL) outlined in Table 1 for the indicated period. Table 1: Dosing for On-demand Treatment and Control of Bleeding Episodes Type of Bleeding Episode Factor VIII Level Required (IU/dL or % of normal) Frequency of Doses (hours) Duration of Therapy Minor Early hemarthrosis, minor muscle or oral bleeds. 20en dash40 12en dash24 At least 1 day, depending upon the severity of the bleeding episode. Moderate Bleeding into muscles. 30en dash60 12en dash24 3en dash4 days or until adequate local hemostasis is achieved. Major Gastrointestinal bleeding. 60en dash100 8en dash24 Until bleeding is resolved. Perioperative Management A guide for dosing XYNTHA during surgery (perioperative management) is provided in Table 2. Maintain the plasma factor VIII activity level at or above the level (in % of normal or in IU/dL) outlined in Table 2 for the indicated period. Monitor the replacement therapy by means of plasma factor VIII activity. Table 2: Dosing for Perioperative Management Type of Surgery Factor VIII Level Required (IU/dL or % of normal) Frequency of Doses (hours) Duration of Therapy (days) Minor Minor operations, including tooth extraction. For tooth extraction, a single infusion plus oral antifibrinolytic therapy within 1 hour may be sufficient. Major Major operations. 60en dash100 8en dash24 Until threat is resolved, or in the case of surgery, until adequate local hemostasis and wound healing are achieved. Routine Prophylaxis see Clinical Pharmacology (12. 3) Preparation 1. Note: registered see Dosage and Administration (2. 4) Reconstitution 1. Do not remove the adapter from the package. gently Note: 12. Note: The tubing of the infusion set included with this kit does not contain DEHP. Image Image Image Image Image Image Image Image For intravenous infusion after reconstitution only. Inspect the final XYNTHA solution visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution should be clear to slightly opalescent and colorless. If it is not, discard the solution and use a new kit. Use the tubing and the prefilled diluent syringe provided in this kit or a single sterile disposable plastic syringe. Do not administer XYNTHA in the same tubing or container with other medicinal products. Note: Image Image These instructions are for the use of only one XYNTHA Vial Kit with one XYNTHA SOLOFUSE Kit. see Dosage and Administration (2. 3) Image Image Image Image Image Image Image.
Instructions for Use
XYNTHA registered ZIN [Antihemophilic Factor (Recombinant)] XYNTHA is supplied as a lyophilized powder. Before you can infuse it (intravenous injection), you must reconstitute the powder by mixing it with the liquid diluent supplied. The liquid diluent is 0. 9% sodium chloride. Reconstitute and infuse XYNTHA using the infusion set, diluent, syringe, and adapter provided in this kit. Please follow the directions below for the proper use of this product. PREPARATION AND RECONSTITUTION OF XYNTHA Preparation 1. INFUSION OF XYNTHA Reconstitution Note: 1. Do not remove the adapter from the package. gently Look carefully at the final solution. The solution should be clear to slightly opalescent and colorless. If it is not, throw away the solution and use a new kit. Note: INFUSION OF XYNTHA Your healthcare provider will teach you how to infuse XYNTHA yourself. Once you learn how to do this, you can follow the instructions in this insert. Before XYNTHA can be infused, you must reconstitute it as instructed above in the PREPARATION AND RECONSTITUTION OF XYNTHA After reconstitution, be sure to look carefully at the XYNTHA solution. Use the infusion set included in the kit to infuse XYNTHA. Do not infuse XYNTHA in the same tubing or container with other medicines. Note: ADDITIONAL INSTRUCTIONS XYNTHA is also supplied in kits that have both the XYNTHA powder and the diluent within single-use prefilled dual-chamber syringes, called XYNTHA SOLOFUSE. If you use one XYNTHA vial and one of XYNTHA SOLOFUSE for the infusion, reconstitute the XYNTHA vial and the XYNTHA SOLOFUSE according to the specific directions for that respective product kit. Use a separate 10 milliliter or larger luer lock syringe (not included in this kit) to draw back the reconstituted contents of the XYNTHA vial and XYNTHA SOLOFUSE. Use of a XYNTHA Vial Kit with a XYNTHA SOLOFUSE Kit These instructions are for the use of only one XYNTHA vial kit and one XYNTHA SOLOFUSE Kit. For further information, please contact your healthcare provider or call the Medical Information Department at Wyeth Pharmaceuticals, 1-800-438-1985. PREPARATION AND RECONSTITUTION OF XYNTHA 2. INFUSION OF XYNTHA Note: This product''s labeling may have been updated. For the most recent prescribing information, please visit www. com License no: 3 Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Logo.

The most common adverse reactions (>=10%) with XYNTHA in adult and pediatric previously treated patients (PTPs) were headache, arthralgia, pyrexia, and cough. 6 6. 2 To report SUSPECTED ADVERSE REACTIONS, contact Wyeth Pharmaceuticals LLC. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www. gov/medwatch 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. XYNTHA was evaluated in five completed clinical studies (N=178), comprising four studies with adult and pediatric PTPs. The safety and efficacy of XYNTHA was evaluated in two completed pivotal studies. In the first study (n=94), safety and efficacy were examined in PTPs with severe to moderately severe hemophilia A (factor VIII activity in plasma [FVIII:C] <=2%) who received XYNTHA for routine prophylaxis and on-demand treatment. Ninety-four subjects received at least one dose of XYNTHA, resulting in a total of 6,775 infusions [ see Clinical Studies (14) see Clinical Studies (14) Across all studies, safety was evaluated in 72 pediatric PTPs <17 years of age (46 subjects <6 years of age (4 subjects were 0 to <2 years of age), 4 subjects 6 to <12 years of age, and 22 adolescents, 12 to <17 years of age). A total of 13,109 infusions of XYNTHA were administered with a median dose per infusion of 28 IU/kg (min-max: 6en dash108 IU/kg). Across all studies, the most common adverse reactions (>=10%) with XYNTHA in adult and pediatric PTPs were headache (24%), arthralgia (23%), pyrexia (23%), and cough (12%). Other adverse reactions reported in >=5% of subjects were: diarrhea (8%), vomiting (8%), and asthenia (6%). There is a potential for immunogenicity with therapeutic proteins. The development of factor VIII inhibitors with XYNTHA was evaluated in 167 adult and pediatric PTPs with at least 50 exposure days (EDs). Laboratory-based assessments for FVIII inhibitor (partial Nijmegen modification of the Bethesda inhibitor assay) were conducted in the clinical studies. The criterion for a positive FVIII result test result was >=0. Across all studies, 4 subjects developed factor VIII inhibitors (2. The completed clinical studies for XYNTHA examined 178 subjects (30 for surgical prophylaxis) who had previously been treated with factor VIII (PTPs). In the first safety and efficacy study, factor VIII inhibitors were detected in two of 89 subjects (2. 2%) who completed >=50 EDs. In a Bayesian statistical analysis, results from this study were used to update PTP results from a prior supporting study using XYNTHA manufactured at the initial facility (with one de novo None of the PTPs developed anti-CHO (Chinese hamster ovary) or anti-TN8. 2 antibodies. One PTP developed anti-FVIII antibodies; but, this subject did not develop an inhibitor. In the surgery study, one low titer persistent inhibitor and one transient false-positive inhibitor were reported. In this study, one surgical subject developed anti-CHO cell antibodies with no associated allergic reaction. One subject developed anti-FVIII antibodies; but, this subject did not develop an inhibitor. Across all studies, immunogenicity was evaluated in 64 pediatric PTPs <17 years of age with at least 50 EDs (43 children <6 years of age, 4 subjects 6 to <12 years of age, and 17 adolescents, 12 to <17 years of age). Of these, 2 pediatric subjects developed an inhibitor. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody, including neutralizing antibody, positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparisons of the incidence of antibodies to XYNTHA with the incidence of antibodies to other products may be misleading. 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 following postmarketing adverse reaction has been reported for XYNTHA: Inadequate therapeutic response.

XYNTHA is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including hamster proteins. Do not use in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including hamster proteins.

Pediatrics: Half-lives are shorter, volumes of distribution are larger, and recovery is lower after XYNTHA administration in children. Higher or more frequent dosing may be needed. 4 Risk Summary It is not known whether XYNTHA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Animal reproduction studies have not been conducted with XYNTHA. There is no information available on the effect of factor VIII replacement therapy on labor and delivery. XYNTHA should be used only if clinically indicated. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2en dash4% and 15en dash20%, respectively. Risk Summary There is no information regarding the presence of XYNTHA in human milk, the effect on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for XYNTHA and any potential adverse effects on the breastfed child from XYNTHA or from the underlying maternal condition. Safety and efficacy with XYNTHA were evaluated in clinical studies in 68 pediatric subjects <17 years of age (18 subjects aged 12 to <17 years, 50 subjects aged <=12 years). There were no apparent differences in the efficacy and safety in pediatric subjects as compared to adults [ see Adverse Reactions (6. 1) Clinical Studies (14). In comparison to the pharmacokinetic parameters reported in adults, children have shorter half-lives, larger volumes of distribution and lower recovery of factor VIII after XYNTHA administration. The clearance (based on per kg body weight) is approximately 40% higher in children. Higher or more frequent doses may be required to account for the observed differences in pharmacokinetic parameters [ see Clinical Pharmacology (12. 3) Clinical studies of XYNTHA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

=12 years of age and 8 subjects <12 years of age) received XYNTHA for routine prophylaxis, for comparison of annualized bleeding rate (ABR) to on-demand treatment alone as a part of 2 completed studies. XYNTHA was administered for routine prophylaxis at a dose of 25 +/- 5 IU/kg every other day (in subjects <12 years of age) or 30 +/- 5 IU/kg administered 3 times weekly (in subjects 12 years of age or older), with provisions for dose escalation based on pre-specified criteria (over a 4-week period, 2 spontaneous bleeds into a major joint and/or target joint, or 3 or more spontaneous bleeding episodes in any location). Among these 102 subjects, 7 dose escalations were prescribed for 6 subjects. In subjects >=12 years, 42 subjects (42/94 or 45%) reported no bleeding while on routine prophylaxis. The mean+/-SD total ABR during routine prophylaxis was 4. 64 with median (min-max) of 1. The mean ABR for subjects during routine prophylaxis was 88% lower than the mean ABR for subjects during on-demand treatment (Table 7). In subjects <12 years, 4 subjects (4/8 or 50%) reported no bleeding while on routine prophylaxis. The mean+/-SD total ABR during routine prophylaxis was 1. 2 with median (min-max) of 0. The mean ABR for subjects during routine prophylaxis was 97% lower than the mean ABR for subjects during on-demand treatment (Table 7). Table 7: Summary of Annualized Bleeding Rate During Routine Prophylaxis Treatment with XYNTHA Age Category (years) Number of Subjects % Reduction from OD Treated Total Routine Prophylaxis ABR Mean +/- SD Median (Min-Max) Treated Spontaneous Routine Prophylaxis ABR Mean +/- SD Median (Min-Max) Treated Traumatic Routine Prophylaxis ABR Mean +/- SD Median (Min-Max) OD = on demand; ABR = annualized bleeding rate; SD = standard deviation, Min = minimum, Max = maximum. 0 to <12 8 97% 1. 2) >=12 94 The treated total ABR mean +/- SD during prophylaxis for the 93 subjects aged >=12 years (outlier removed), was 3. 18 with median (min-max) of 1. The spontaneous treated ABR mean +/- SD was 1. 87 with median (min-max) of 0. The traumatic ABR mean +/- SD was 1. 99 with median (min-max) of 0. 3) 12 to <17 18 The treated total ABR mean +/- SD during prophylaxis for the 17 adolescents (outlier removed), was 5. 90 with median (min-max) of 2. The spontaneous ABR mean +/- SD was 1. 94 with median (min-max) of 0. The traumatic ABR mean +/- SD was 3. 77 with median (min-max) of 1. 6) >=17 76 89% 3.
REFERENCES
1. Thromb Haemost 2. N Engl J Med 3. 4. Lancet 5. N Engl J Med 6. Blood 7. Lancet 8. N Engl J Med 9. Thromb Haemost 10. Haemophilia 11. Haemophilia 12. Thromb Haemost 13. Sem Hematol. 14. Biotechnol Bioeng 15. Textbook of Hemophilia 16. 17.
FDA-Approved Patient Labeling
Patient Information XYNTHA registered ZIN [Antihemophilic Factor (Recombinant)] Please read this patient information carefully before using XYNTHA and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical problems or your treatment. What is XYNTHA? XYNTHA is an injectable medicine that is used to help control and reduce bleeding in people with hemophilia A. Hemophilia A is also called classic hemophilia. Your healthcare provider may give you XYNTHA when you have surgery. XYNTHA is not used to treat von Willebrand''s disease. What should I tell my healthcare provider before using XYNTHA? Tell your healthcare provider about all of your medical conditions, including if you: Tell your healthcare provider about all of the medicines you take, including all prescription and non-prescription medicines, such as over-the-counter medicines, supplements, or herbal remedies. How should I infuse XYNTHA? Step-by-step instructions for infusing with XYNTHA are provided at the end of this leaflet. The steps listed below are general guidelines for using XYNTHA. Always follow any specific instructions from your healthcare provider. If you are unsure of the procedures, please call your healthcare provider before using. Call your healthcare provider right away if bleeding is not controlled after using XYNTHA. Call your healthcare provider right away if you take more than the dose you should take. Talk to your healthcare provider before traveling. Plan to bring enough XYNTHA for your treatment during this time. What are the possible side effects of XYNTHA? Call your healthcare provider or go to the emergency department right away if you have any of the following symptoms because these may be signs of a serious allergic reaction: Common side effects of XYNTHA are Your body can make antibodies against XYNTHA (called "inhibitors") that may stop XYNTHA from working properly. Your healthcare provider may need to take blood tests from time to time to monitor for inhibitors. Talk to your healthcare provider about any side effect that bothers you or that does not go away. You may report side effects to FDA at 1-800-FDA-1088. How should I store XYNTHA? Store XYNTHA in the refrigerator at 36° to 46°F (2° to 8°C). Store the diluent syringe at 36° to 77°F (2° to 25°C). Do not freeze. Protect from light. XYNTHA can last at room temperature (below 77°F) for up to 3 months. If you store XYNTHA at room temperature, carefully write down the date you put XYNTHA at room temperature, so you will know when to either put it back in the refrigerator, use it immediately, or throw it away If stored at room temperature, XYNTHA can be returned one time Infuse XYNTHA within 3 hours of reconstitution. You can keep the reconstituted solution at room temperature before infusion for up to 3 hours. If you have not used it in 3 hours, throw it away. Do not use reconstituted XYNTHA if it is not clear to slightly opalescent and colorless. Dispose of all materials, whether reconstituted or not, in an appropriate medical waste container. What else should I know about XYNTHA? Medicines are sometimes prescribed for purposes other than those listed here. Talk to your healthcare provider if you have any concerns. You can ask your healthcare provider for information about XYNTHA that was written for healthcare professionals. Do not share XYNTHA with other people, even if they have the same symptoms that you have.">NONCLINICAL TOXICOLOGY
No studies have been conducted with XYNTHA to assess its mutagenic or carcinogenic potential. XYNTHA has been shown to be comparable to the predecessor product with respect to its biochemical and physicochemical properties, as well as its nonclinical in vivo Preclinical studies evaluating XYNTHA in hemophilia A dogs without inhibitors demonstrated safe and effective restoration of hemostasis. XYNTHA demonstrated a toxicological profile that was similar to the toxicological profile observed with the predecessor product. Toxicity associated with XYNTHA was primarily associated with anti-FVIII neutralizing antibody generation first detectable at 15 days of repeat dosing in high (approximately 735 IU/kg/day) level-dosed, non-human primates.
CLINICAL STUDIES
Three completed multicenter, open-label studies support the analysis of safety and efficacy of XYNTHA in on-demand treatment and control of bleeding episodes and perioperative management, and routine prophylaxis in PTPs with hemophilia A. These completed clinical studies for XYNTHA examined 174 PTP subjects, 94 from the first study, and 50 from a second study, for on-demand treatment and routine prophylaxis and 30 from a third study for surgical prophylaxis. Subjects with severe to moderately severe hemophilia A (FVIII:C <=2%) and no history of FVIII inhibitors were eligible for the trials. On-demand Treatment and Control of Bleeding Episodes On-demand treatment in adolescents and adults Ninety-four (94) subjects, 12 years of age and older received XYNTHA in a routine prophylaxis treatment regimen with on-demand treatment administered as clinically indicated. All 94 subjects were treated with at least one dose and all are included in the intent-to-treat (ITT) population. Eighty-nine (89) subjects accrued >=50 EDs. Median age for the 94 treated subjects was 24 years (mean 28 and min-max: 12en dash60 years). Of these 94 subjects, 30 evaluable subjects participated in a randomized crossover pharmacokinetics substudy. Twenty-five (25/30) of these subjects with FVIII:C <=1% completed both the first (PK1) and the second (PK2) pharmacokinetic assessments [ see Clinical Pharmacology (12. 3) 16 Fifty-three subjects (53/94) received XYNTHA on-demand treatment for a total of 187 bleeding episodes. Seven of these bleeding episodes occurred in subjects prior to switching to a prophylaxis treatment regimen. One hundred ten of 180 bleeds (110/180 or 61%) occurred <=48 hours after the last dose and 39% (70/180 bleeds) occurred >48 hours after the last dose. The majority of bleeds reported to occur <=48 hours after the last prophylaxis dose were traumatic (64/110 bleeds or 58%). Forty-two bleeds (42/70 or 60%) reported to occur >48 hours after the last prophylaxis dose were spontaneous. The on-demand treatment dosing regimen was determined by the investigator. The median dose for on-demand treatment was 31 IU/kg (min-max: 6en dash74 IU/kg) and the median exposure per subject was 3 days (min-max: 1en dash26). The majority of bleeding episodes (173/187 or 93%) resolved with 1 or 2 infusions (Table 5). One hundred thirty-two of 187 bleeding episodes (132/187 or 71%) treated with XYNTHA were rated excellent or good in their response to initial treatment, 45 (24%) were rated moderate. Five (3%) were rated no response, and 5 (3%) were not rated. Table 5: Summary of Response to Infusions to Treat New Bleeding Episode by Number of Infusions Needed for Resolution Response to 1 st Number of Infusions (%) 1 Number of Infusions (%) 2 Number of Infusions (%) 3 Number of Infusions (%) 4 Number of Infusions (%) >4 Total Number of Bleeds Excellent Excellent: 42 (95. 0) 44 Good Good: 69 (78. 0) 88 Moderate Moderate: 24 (53. 7) 45 No Response No Response: 0 (0. 0) 5 Not Assessed 4 (80. 0) 5 Includes one infusion with commercial FVIII that occurred before routine prophylaxis began. Total 139 (74. 1) 187 Of the 94 subjects described above, in the first completed open-label safety and efficacy study of XYNTHA, 18 were adolescent subjects 12 to <17 years of age with severe to moderately severe hemophilia A (FVIII:C <=2%). Ten (10) of these adolescent subjects, received XYNTHA for the on-demand treatment of 66 bleeding episodes, with the majority of the bleeding episodes (63/66 or 95%) resolving with 1 or 2 infusions. The response to infusion was rated on a pre-specified 4 point hemostatic efficacy scale. Thirty-eight (38) of 66 bleeding episodes (58%) were rated excellent or good in their response to initial treatment, 24 (36%) were rated as moderate, and 4 (6%) were not rated. The median dose per on demand infusion was 47 IU/kg (min-max: 24en dash74). On-demand treatment in children Additional data for 50 subjects are available from a second safety and efficacy study of XYNTHA in children (<=12 years of age) with severe to moderately severe hemophilia A (FVIII:C <=2%). Of the 50 subjects, 38 subjects received XYNTHA for on-demand and follow-up treatment of 562 bleeding episodes with the majority of the bleeding episodes (518/562 or 92%) resolving with 1 or 2 infusions. Of 559 bleeding episodes treated with XYNTHA with response assessments to the first infusion, 526 (94%) were rated excellent or good in their response to initial treatment and 27 (5%) were rated as moderate. The median dose per on-demand infusion was 28 IU/kg (min-max: 10en dash92). Perioperative Management In a study (n=30) for surgical prophylaxis in subjects with hemophilia A, XYNTHA was administered to 25 efficacy-evaluable PTPs undergoing major surgical procedures (11 total knee replacements, 1 hip replacement, 5 synovectomies, 1 left ulnar nerve transposition release, 1 ventral hernia repair/scar revision, 1 knee arthroscopy, 1 revision and debridement of the knee after a total knee replacement, 1 hip arthroplasty revision, 1 stapes replacement, 1 ankle arthrodesis, and 1 pseudotumor excision). 17 The results of the hemostatic efficacy ratings for these subjects are presented in Table 6. Investigator''s ratings of efficacy at the end of surgery and at the end of the initial postoperative period were excellent or good for all assessments. Intraoperative blood loss was reported as "normal" or "absent" for all subjects. Thirteen of the subjects (13/25 or 52%) had blood loss in the postoperative period. The postoperative blood loss was rated as "normal" for ten of these cases while three cases were rated "abnormal" (1 due to hemorrhage following surgical trauma to the epigastric artery, 1 due to an 800 mL blood loss after hip replacement surgery, and 1 after an elbow synovectomy where the blood loss could not be measured by the investigator). Table 6: Summary of Hemostatic Efficacy Time of Hemostatic Efficacy Assessment Excellent Excellent: Good Good: Number of subjects End of surgery 18 (72%) 7 (28%) 25 End of initial postoperative period End of initial postoperative period is date of discharge or postoperative Day 6, whichever occurs later. 23 (92%) 2 (8%) 25 Routine Prophylaxis One hundred and two (102) subjects (94 subjects >=12 years of age and 8 subjects <12 years of age) received XYNTHA for routine prophylaxis, for comparison of annualized bleeding rate (ABR) to on-demand treatment alone as a part of 2 completed studies. XYNTHA was administered for routine prophylaxis at a dose of 25 +/- 5 IU/kg every other day (in subjects <12 years of age) or 30 +/- 5 IU/kg administered 3 times weekly (in subjects 12 years of age or older), with provisions for dose escalation based on pre-specified criteria (over a 4-week period, 2 spontaneous bleeds into a major joint and/or target joint, or 3 or more spontaneous bleeding episodes in any location). Among these 102 subjects, 7 dose escalations were prescribed for 6 subjects. In subjects >=12 years, 42 subjects (42/94 or 45%) reported no bleeding while on routine prophylaxis. The mean+/-SD total ABR during routine prophylaxis was 4. 64 with median (min-max) of 1. The mean ABR for subjects during routine prophylaxis was 88% lower than the mean ABR for subjects during on-demand treatment (Table 7). In subjects <12 years, 4 subjects (4/8 or 50%) reported no bleeding while on routine prophylaxis. The mean+/-SD total ABR during routine prophylaxis was 1. 2 with median (min-max) of 0. The mean ABR for subjects during routine prophylaxis was 97% lower than the mean ABR for subjects during on-demand treatment (Table 7). Table 7: Summary of Annualized Bleeding Rate During Routine Prophylaxis Treatment with XYNTHA Age Category (years) Number of Subjects % Reduction from OD Treated Total Routine Prophylaxis ABR Mean +/- SD Median (Min-Max) Treated Spontaneous Routine Prophylaxis ABR Mean +/- SD Median (Min-Max) Treated Traumatic Routine Prophylaxis ABR Mean +/- SD Median (Min-Max) OD = on demand; ABR = annualized bleeding rate; SD = standard deviation, Min = minimum, Max = maximum. 0 to <12 8 97% 1. 2) >=12 94 The treated total ABR mean +/- SD during prophylaxis for the 93 subjects aged >=12 years (outlier removed), was 3. 18 with median (min-max) of 1. The spontaneous treated ABR mean +/- SD was 1. 87 with median (min-max) of 0. The traumatic ABR mean +/- SD was 1. 99 with median (min-max) of 0. 3) 12 to <17 18 The treated total ABR mean +/- SD during prophylaxis for the 17 adolescents (outlier removed), was 5. 90 with median (min-max) of 2. The spontaneous ABR mean +/- SD was 1. 94 with median (min-max) of 0. The traumatic ABR mean +/- SD was 3. 77 with median (min-max) of 1. 6) >=17 76 89% 3.
REFERENCES
1. Thromb Haemost 2. N Engl J Med 3. 4. Lancet 5. N Engl J Med 6. Blood 7. Lancet 8. N Engl J Med 9. Thromb Haemost 10. Haemophilia 11. Haemophilia 12. Thromb Haemost 13. Sem Hematol. 14. Biotechnol Bioeng 15. Textbook of Hemophilia 16. 17.
FDA-Approved Patient Labeling
Patient Information XYNTHA registered ZIN [Antihemophilic Factor (Recombinant)] Please read this patient information carefully before using XYNTHA and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical problems or your treatment. What is XYNTHA? XYNTHA is an injectable medicine that is used to help control and reduce bleeding in people with hemophilia A. Hemophilia A is also called classic hemophilia. Your healthcare provider may give you XYNTHA when you have surgery. XYNTHA is not used to treat von Willebrand''s disease. What should I tell my healthcare provider before using XYNTHA? Tell your healthcare provider about all of your medical conditions, including if you: Tell your healthcare provider about all of the medicines you take, including all prescription and non-prescription medicines, such as over-the-counter medicines, supplements, or herbal remedies. How should I infuse XYNTHA? Step-by-step instructions for infusing with XYNTHA are provided at the end of this leaflet. The steps listed below are general guidelines for using XYNTHA. Always follow any specific instructions from your healthcare provider. If you are unsure of the procedures, please call your healthcare provider before using. Call your healthcare provider right away if bleeding is not controlled after using XYNTHA. Call your healthcare provider right away if you take more than the dose you should take. Talk to your healthcare provider before traveling. Plan to bring enough XYNTHA for your treatment during this time. What are the possible side effects of XYNTHA? Call your healthcare provider or go to the emergency department right away if you have any of the following symptoms because these may be signs of a serious allergic reaction: Common side effects of XYNTHA are Your body can make antibodies against XYNTHA (called "inhibitors") that may stop XYNTHA from working properly. Your healthcare provider may need to take blood tests from time to time to monitor for inhibitors. Talk to your healthcare provider about any side effect that bothers you or that does not go away. You may report side effects to FDA at 1-800-FDA-1088. How should I store XYNTHA? Store XYNTHA in the refrigerator at 36° to 46°F (2° to 8°C). Store the diluent syringe at 36° to 77°F (2° to 25°C). Do not freeze. Protect from light. XYNTHA can last at room temperature (below 77°F) for up to 3 months. If you store XYNTHA at room temperature, carefully write down the date you put XYNTHA at room temperature, so you will know when to either put it back in the refrigerator, use it immediately, or throw it away If stored at room temperature, XYNTHA can be returned one time Infuse XYNTHA within 3 hours of reconstitution. You can keep the reconstituted solution at room temperature before infusion for up to 3 hours. If you have not used it in 3 hours, throw it away. Do not use reconstituted XYNTHA if it is not clear to slightly opalescent and colorless. Dispose of all materials, whether reconstituted or not, in an appropriate medical waste container. What else should I know about XYNTHA? Medicines are sometimes prescribed for purposes other than those listed here. Talk to your healthcare provider if you have any concerns. You can ask your healthcare provider for information about XYNTHA that was written for healthcare professionals. Do not share XYNTHA with other people, even if they have the same symptoms that you have.

Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC

XYNTHA- antihemophilic factor (recombinant) Product manual source documgent