hypotension, lethargy, nausea, vomiting, dysphagia, paresthesia, restlessness, wheezing and dyspnea. immediately discontinue administration and initiate appropriate treatment if allergic or anaphylactic-type reactions occur. in case of severe allergic reactions, consider alternative hemostatic measures. there are literature reports of allergic reactions occurring in close temporal association with the development of factor ix inhibitors. ixinity contains trace amounts of chinese hamster ovary (cho) proteins. patients treated with this product may develop hypersensitivity to cho proteins. 5.2 neutralizing antibodies development of neutralizing antibodies (inhibitors) to ixinity may occur. if expected factor ix activity plasma levels are not attained, or if bleeding is not controlled as expected with the calculated dose, perform an assay that measures factor ix inhibitor concentration [ see warnings and precautions (5.5) ]. patients with factor ix inhibitors are at an increased risk of severe hypersensitivity reactions or anaphylaxis if re-exposed to ixinity. 5.3 nephrotic syndrome nephrotic syndrome may occur with ixinity. nephrotic syndrome has been reported following attempted immune tolerance induction in hemophilia b patients with factor ix inhibitors and a history of allergic reactions. 5.4 thromboembolism thromboembolism has occurred with ixinity use. because of the potential risk for thromboembolism with the use of factor ix products, monitor for early signs of thromboembolism and consumptive coagulopathy when administering ixinity to patients with liver disease, fibrinolysis, peri-operative status, or risk for thromboembolic events or disseminated intravascular coagulation. 5.5 monitoring laboratory tests monitor patients for factor ix activity levels with the one-stage clotting assay to confirm that adequate factor ix levels have been achieved and maintained, when clinically indicated. factor ix results can be affected by the type of aptt reagent used [ see dosage and administration (2.1) ]. monitor patients 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 ixinity. assays used to determine if factor ix inhibitor is present should be titered in bethesda units (bus).

nt of bleeding, the patient’s clinical condition, age, and pharmacokinetic parameters of factor ix, such as incremental recovery and half-life. initial dose calculate the initial dose of ixinity based on the empirical finding that one international unit (iu) of ixinity per kg body weight increases the circulating level of factor ix by 0.98 international units/dl (iu/dl) of plasma in adults and children. initial dose = body weight (kg) x desired factor ix increase (% of normal or iu/dl) × reciprocal of observed recovery (iu/kg per iu/dl) incremental recovery in previously treated patients (ptps) base calculation of the dose on the patient’s individual incremental recovery using serial factor ix activity assays, to account for the wide range of inter-individual differences in incremental recovery and the type of aptt reagent used for the assay. titrate the dose based on the patient’s clinical response and individual pharmacokinetics, in particular incremental recovery and half-life. for an incremental recovery of 0.98 iu/dl per iu/kg, calculate the dose as follows: dose (iu) = body weight (kg) x desired factor ix increase (% of normal or iu/dl) × 1.02 dl/kg examples (assuming patient’s baseline factor ix level is < 1% of normal): a dose of 4550 international units (ius) of ixinity administered to a 70 kg patient should be expected to result in a peak post-infusion factor ix increase of 4550 iu × (0.98 iu/dl per iu/kg)/(70 kg) = 64 iu/dl (approximately 60% of normal) a peak of 70% is required in a 60 kg patient. the appropriate dose would be (60 kg × 70 iu/dl)/(0.98 iu/dl per iu/kg) = 4286 iu monitor factor ix activity to ensure that the desired factor ix activity level has been achieved [ see warnings and precautions (5.5) ]. titrate doses using factor ix activity and pharmacokinetic parameters such as half-life and incremental recovery, as well as by taking the clinical situation into consideration, to adjust the dose and frequency of repeated infusions as appropriate. factor ix activity measurements in the clinical laboratory may be affected by the type of activated partial thromboplastin time (aptt) reagent or laboratory standard used [ see warnings and precautions (5.5) ]. on-demand treatment and control of bleeding episodes and perioperative management of bleeding guides for dosing ixinity in the on-demand treatment and control of bleeding episodes ( table 1 ) and perioperative management ( table 2 ) are provided in the tables below. individual patients may vary in their response to factor ix and may demonstrate different levels of in vivo recovery and different half-lives. for surgical procedures, initiate treatment with ixinity early enough pre-operatively to achieve and maintain the desired factor ix level before starting the procedure. routine prophylaxis the dose for previously treated patients (ptps) is 40 to 70 iu/kg twice weekly. adjust the dose based on the individual patient’s age, bleeding pattern, and physical activity. table 1 dosing for on-demand treatment and control of bleeding episodes adapted from srivastava et al. 2013 (1) . type of bleeding episode desired peak factor ix level (% of normal or iu/dl) dosing interval (hours) duration of therapy (days) minor early bleeds: uncomplicated hemarthroses and superficial muscle (except iliopsoas) with no neurovascular compromise, other soft tissue 30-60 24 1-3, until healing is achieved moderate hemarthrosis of longer duration, recurrent hemarthrosis, mucous membranes, deep lacerations, hematuria 40-60 24 2-7, until healing is achieved major or life threatening iliopsoas, deep muscle with neurovascular injury, substantial blood loss, cns, pharyngeal, retropharyngeal, retroperitoneal 60-100 12-24 2-14, until healing is achieved table 2 dosing for perioperative management adapted from srivastava et al. 2013 (1) . type of surgery desired peak factor ix level (% of normal or iu/dl) dosing interval (hours) duration of therapy (days) minor (including uncomplicated dental extractions) pre-op 50-80 post-op 30-80 24 1-5, depending on type of procedure major pre-op 60-80 post-op 40-60 30-50 20-40 8-24 1-3 4-6 7-14 2.2 preparation and reconstitution the procedures below are provided as general recommendations for the preparation and reconstitution of ixinity. before starting reconstitution and administration you will need the following items that are included in each kit of ixinity: one (or more) vial(s) of ixinity 250, 500, 1000, 1500, 2000, or 3000 iu powder one (or more) 10 ml syringe(s), pre-filled with 5 ml of sterile water for injection (pre-filled syringe) with plunger rod attached one sterile vial adapter with filter in addition, you will need the following items that are not included in the kit: one sterile luer-lok™ syringe (administration syringe); additional or larger syringes may be required if pooling multiple vials sterile alcohol swabs sterile infusion set sterile gauze pad sterile bandage always work on a clean surface and wash your hands before performing the following procedures: use aseptic technique during reconstitution procedure. allow ixinity and the pre-filled syringe to reach room temperature before use. remove cap from the vial (see figure a ). peel back the cover of the vial adapter package (leave the vial adapter in the package). figure a place the administration syringe, if using, and vial adapter on a clean flat work surface. twist off the cap of the pre-filled syringe and place it on the clean flat surface (see figure b ). figure b wipe the top of the ixinity vial with an alcohol swab (or similar germicidal solution) and allow it to dry. place on a clean, flat surface. firmly hold the package containing the vial adapter on a clean, flat surface. connect the pre-filled syringe to the vial adapter by pushing the syringe tip down onto the luer-lok in the center of the vial adapter, and screw until the syringe is secured (see figure c ). figure c carefully lift up the combined syringe-and-vial-adapter and remove it from the plastic package (see figure d ). figure d with one hand, continue to hold the combined syringe-and-vial-adapter. with the other hand, hold the ixinity vial tightly on a clean, flat surface. in a continuous motion, place the vial adapter over the ixinity vial; firmly push the filter spike of the vial adapter through the center of ixinity vial’s rubber circle until the clear plastic cap snaps onto the ixinity vial (see figure e ). push the plunger down to complete the transfer of all liquid from the syringe to the ixinity vial. figure e with the syringe and the vial still attached, gently swirl, in a circular motion, the ixinity vial until the product is fully dissolved/reconstituted (see figure f ). figure f remove the pre-filled syringe (now empty) from the vial adapter by turning it counterclockwise until it is completely detached (see figure g ). figure g remove the administration syringe from its packaging. leave the vial adapter attached to the vial and attach the administration syringe to the vial adapter by turning clockwise until it is securely attached (see figure h ). figure h keeping the administration syringe plunger pressed, turn the ixinity vial upside down. draw the solution from the vial through the filter spike in the vial adapter by pulling the plunger back slowly until all solution is transferred into the administration syringe (see figure i ). figure i keep the administration syringe plunger facing downwards and prevent it from moving. with one hand hold the vial-and-vial-adapter, and with the other hand firmly grasp the barrel of the administration syringe and unscrew the syringe from the vial adapter (see figure j ). figure j if only dosing with a single vial, proceed to administer ixinity via intravenous infusion; otherwise proceed to pooling instructions. pooling instructions 1. if two or more vials are required to achieve the required dose, remove the pre-filled syringe from the vial adapter on the reconstituted second vial by turning it counterclockwise until it is completely detached. 2. leave the vial adapter attached to the vial and attach the administration syringe containing the reconstituted ixinity from the first vial by turning it clockwise until it is securely in place. 3. turn the ixinity vial upside down and slowly pull on the plunger rod to draw the solution into the administration syringe (see figure i ). 4. continue with remaining vials, if required. once pooling is complete, proceed to administer ixinity via intravenous infusion. after reconstitution of the lyophilized powder, all dosage strengths should yield a clear, colorless solution without visible particles. discard if visible particulate matter or discoloration is observed. infuse reconstituted solution immediately or within 3 hours of storage at room temperature after reconstitution. do not refrigerate after reconstitution. do not touch the syringe tip or the inside of the cap. place the syringe containing the ixinity solution on the clean surface, making sure that the tip does not touch anything. figure a figure b figure c figure d figure e figure f figure g figure h figure i figure j 2.3 administration for intravenous use after reconstitution only. inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. do not mix ixinity with other medicinal products for infusion. attach the administration syringe containing the reconstituted ixinity solution to a sterile infusion set. adapt the infusion rate to the comfort level of each patient, not exceeding 10 ml per minute. record the name and batch number of the product in the patient record. dispose of any unused product or waste material in accordance with local requirements.

as probably or possibly related to study drug are provided in the table below. table 3 summary of adverse reactions meddra standard system organ class adverse reaction number of events number of subjects (n = 77) (%) congenital, familial and genetic disorders hemophilia (i.e. lack of efficacy) 1 1 (1.3%) general disorders and administration site conditions asthenia 1 1 (1.3%) injection site discomfort 1 1 (1.3%) infections and infestations influenza 1 1 (1.3%) nervous system disorders headache 5 2 (2.6%) dysgeusia 1 1 (1.3%) lethargy 1 1 (1.3%) psychiatric disorders apathy 1 1 (1.3%) depression 1 1 (1.3%) skin and subcutaneous tissue disorders rash pruritic 1 1 (1.3%) 6.2 immunogenicity all subjects participating in the clinical trial were monitored for inhibitory and non-inhibitory antibodies to factor ix and antibodies for cho proteins at the following time points; pre-infusion, after the first 5 exposure days, and then every 3 months thereafter. no subjects in ixinity clinical trials developed inhibitors to factor ix, including 55 subjects with more than 50 exposure days and 45 of those subjects with more than 100 exposure days. non-inhibitory factor ix binding antibodies were detected in 30% (23/77) of subjects, including 5 subjects positive at baseline. in three of the subjects, the non-inhibitory factor ix antibodies were persistent, while in the remainder the antibodies were sporadic and non-persistent. no clinical adverse findings related to non-inhibitory factor ix antibody formation were identified. detection of non-inhibitory antibodies against factor ix has been reported following administration of other factor ix products. the clinical significance of this finding is unknown. in ixinity clinical trials, 29% (20/68) of subjects tested positive for antibodies against cho cell proteins. no clinical adverse findings were associated with these antibodies. reports have been published of sporadic detection of antibodies against cho cell proteins in subjects treated with other recombinant coagulation factor products produced in cho cells, as well as in non-hemophilic subjects (2). the clinical significance of this is unknown. the manufacturing process for ixinity was modified to include an additional step to ensure increased clearance of cho proteins to address the anti-cho protein response seen in clinical trials. the anti-cho protein response status of the clinical trial subjects who transitioned to the modified product (n = 17) remained negative (n = 10), stable/nonspecific assay binding (n = 5), or declined (n = 2) after the transition to modified ixinity for at least 3 months. the detection of antibody formation is dependent on the sensitivity and specificity of the assay. additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection and concomitant medications. for these reasons, comparisons of the incidence of antibodies to ixinity with the incidence of antibodies to other products may be misleading. 6.3 postmarketing experience the following adverse reactions have been identified during post approval use of ixinity. 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. immune system disorders: anaphylaxis vascular disorders: deep vein thrombosis the following class adverse reactions have been seen with another recombinant factor ix: inadequate factor ix recovery, inhibitor development, angioedema, hypotension, and thrombosis.

aged 65 and over. it is not known whether elderly patients respond differently than younger patients. individualize dose selection for elderly patients [ see dosage and administration (2.1) ].

harmacokinetic studies are summarized below in table 4 . table 4 pharmacokinetic parameters for ixinity (n = 32) parameters mean (± sd) (range) auc 0–∞ (iu/dl/hr) 1573 (± 451) (862-2643) incremental recovery (iu/dl per iu/kg) 0.98 (± 0.21) (0.67-1.50) terminal half-life (hours) 24 (± 7) (13-43) c max (iu/dl) 73 (± 17) (51-113) mean residence time (hours) 32 (± 6) (19-47) vd ss (ml/kg) 175 (± 57) (102-314) clearance [ml/(kg·hr)] 5.1 (± 1.3) (2.8-7.7) pharmacokinetic parameters were re-assessed in a subset of 14 subjects after routine treatment with ixinity for a median of 5.8 months (range 3.1 to 18.6 months) as summarized in table 5 below. table 5 pharmacokinetic parameters for ixinity following repeat-dosing (n = 14) parameters initial mean (± sd) repeat-dosing pk mean (± sd) auc 0–∞ (iu/dl/hr) 1438 (± 409) 1530 (± 435) incremental recovery (iu/dl per iu/kg) 0.96 (± 0.22) 0.95 (± 0.18) terminal half-life (hours) 24 (± 7) 24 (± 6) c max (iu/dl) 73 (± 16) 73 (± 15) mean residence time (hours) 30 (± 6) 31 (± 5) vd ss (ml/kg) 193 (± 62) 185 (± 70) clearance [ml/(kg·hr)] 5.6 ± (1.3) 5.3 (± 1.5) repeat dosing did not impact the pharmacokinetics of ixinity. the pk data were divided into two subgroups of subjects with a bmi ≤ 30 (n = 26) or bmi > 30 (n = 6). the auc (0-∞) and c max values of ixinity were 40% and 34% higher, respectively, in subjects with bmi > 30.

18.6 months) as summarized in table 5 below. table 5 pharmacokinetic parameters for ixinity following repeat-dosing (n = 14) parameters initial mean (± sd) repeat-dosing pk mean (± sd) auc 0–∞ (iu/dl/hr) 1438 (± 409) 1530 (± 435) incremental recovery (iu/dl per iu/kg) 0.96 (± 0.22) 0.95 (± 0.18) terminal half-life (hours) 24 (± 7) 24 (± 6) c max (iu/dl) 73 (± 16) 73 (± 15) mean residence time (hours) 30 (± 6) 31 (± 5) vd ss (ml/kg) 193 (± 62) 185 (± 70) clearance [ml/(kg·hr)] 5.6 ± (1.3) 5.3 (± 1.5) repeat dosing did not impact the pharmacokinetics of ixinity. the pk data were divided into two subgroups of subjects with a bmi ≤ 30 (n = 26) or bmi > 30 (n = 6). the auc (0-∞) and c max values of ixinity were 40% and 34% higher, respectively, in subjects with bmi > 30.

th a history of a detectable factor ix inhibitor (≥ 0.6 bu), a history of hypersensitivity reactions following exposure to factor ix-containing products, a known allergic reaction to hamster proteins, evidence of severe liver impairment, evidence of impaired renal function, cd4 count < 400 cells/mm 3 , or any coagulation defect other than hemophilia b. in addition, there was a prospective, open-label, uncontrolled, multicenter substudy where 17 subjects (16 male, 1 female carrier) underwent surgeries (19 major procedures in males) receiving ixinity for perioperative management; some of the surgery subjects also participated in the treatment trial. of the 68 ptps in the treatment group, subjects were primarily prescribed a routine prophylaxis (n = 58) or an on-demand regimen (n = 9); one subject was not assigned a regimen. subjects were allowed to switch regimens during the course of the study. as a result, 61 subjects were treated at some point with routine prophylaxis treatment and 12 were treated at some point with an on-demand regimen. subjects in the routine prophylaxis therapy group received mean intravenous doses of 55 ± 12.8 iu/kg of ixinity twice weekly. subjects in the on-demand therapy group received mean doses of 60 ± 18.2 iu/kg (median 59.3, interquartile range 49.9, 71.8) for bleeding episodes. the mean number of exposure days (ed) was 138.2 (median 127.5), including 45 subjects with ≥ 100 ed and 55 subjects with ≥ 50 ed. median duration on study for the on-demand group was 14.1 months (range 2.3-36.9). prophylaxis and reduction of bleeding episodes in the prophylaxis arm, the mean annualized bleed rate (abr) was 3.55 ( table 6 ). table 6 efficacy of prophylaxis with ixinity (n=61) total abr mean ± sd 3.55 ± 7.19 median (iqr) 1.52 (0 – 3.47) spontaneous abr mean ± sd 1.07± 3.06 median (iqr) 0.00 (0 – 1.22) subjects with zero bleeding episodes % (n) 31.1% (19) control of bleeding episodes a total of 508 bleeding episodes were treated with ixinity, of which 286 bleeds were recorded for subjects treated with the routine prophylaxis treatment regimen and 222 with the on-demand regimen. bleeding resolved in 360 episodes (70.9%) after a single infusion of ixinity and in 66 (13.0%) episodes after two infusions. for 24 bleeding episodes (4.7%), five or more infusions were required; these 24 bleeding episodes were predominantly related to trauma, target joints, or muscle bleeds. hemostatic efficacy to resolve a bleed was rated by subjects as excellent or good in 84% of treated bleeding episodes. excellent was defined as a dramatic response with abrupt pain relief and clear reduction in joint or hemorrhage site size, and good was defined as pain relief or reduction in hemorrhage size that may have required an additional infusion for resolution. perioperative management the efficacy analysis of ixinity in perioperative management included 19 major surgeries performed in 16 male ptps between 12 and 56 years of age (female carrier not included in efficacy analysis). efficacy of ixinity for support of major surgery was based on the surgeon’s assessment of efficacy including: a) at the time of surgery as estimation of blood loss as ‘less than expected’, ‘expected’, or ‘more than expected’; and b) at 12 and 24 hours post-surgical assessments of hemostasis as ‘adequate’, ‘better than adequate’, or ‘poorly controlled’. transfusion requirements to support surgery were also monitored. there were no transfusions required during the procedures. ixinity was administered during major surgical procedures as bolus (n = 13) or continuous infusion (n = 6). ixinity was rated as adequate or better in controlling hemostasis post-surgery as assessed by the surgeon when used in various procedures, including, knee arthroplasty (n = 8), elbow arthroplasty (n = 2), knee amputation (n = 1), percutaneous achilles tendon lengthening (n = 1), open inguinal hernia repair (n = 1), tibiotalar fusion (n = 1), arthroscopic synovectomy (n = 2), and debridement (ankle, knee) (n = 3). in all instances, blood loss at surgery was ‘expected’ or ‘less than expected’ as assessed by the surgeon.

d solution immediately or within 3 hours of storage at room temperature after reconstitution. do not refrigerate after reconstitution.

you. what should i tell my healthcare provider before using ixinity? you should tell your healthcare provider if you: have or have had any medical problems take any medicines, including prescription and non-prescription medicines, such as over-the-counter medicines, supplements, or herbal remedies have any allergies, including allergies to hamsters are breastfeeding. it is not known if ixinity passes into your milk and if it can harm your baby are pregnant or planning to become pregnant. it is not known if ixinity may harm your baby have been told that you have inhibitors to factor ix (because ixinity may not work for you) how should i infuse ixinity? ixinity is given directly into the bloodstream. ixinity should be administered as ordered by your healthcare provider. you should be trained on how to do infusions by your healthcare provider or hemophilia treatment center. many people with hemophilia b learn to infuse their ixinity by themselves or with the help of a family member. see the step-by-step guide ( instructions for use ) provided at the end of this leaflet. your healthcare provider will tell you how much ixinity to use based on your weight, the severity of you hemophilia b, and where you are bleeding. you may have to have blood tests done after getting ixinity to be sure that your blood level of factor ix is high enough to stop the bleeding. call you healthcare provider right away if your bleeding does not stop after taking ixinity. what are the possible side effects of ixinity? allergic reactions may occur with ixinity. call your healthcare provider or get emergency treatment right away if you get any of the following symptoms: rash, hives, itching, tightness of the throat, chest pain or tightness, difficulty breathing, lightheadedness, dizziness, nausea, or fainting. tell your healthcare provider about any side effect that bothers you or does not go away. the most common side effect of ixinity in clinical trials was headache. these are not all the side effects possible with ixinity. you can ask your healthcare provider for information that is written for healthcare professionals. call your healthcare provider for medical advice about side effects. you may report side effects to the fda at 1-800-fda-1088. what are the ixinity dosage strengths? ixinity comes in vials containing six different dosage strengths: 250, 500, 1000, 1500, 2000 and 3000 international units (iu). the actual strength will be printed on the label of the vial and on the box. the six different strengths in the vials are color coded as follows: color code nominal strength yellow 250 iu blue 500 iu green 1000 iu orange 1500 iu red 2000 iu brown 3000 iu always check the actual dosage strength printed on the label to make sure you are using the strength prescribed by your healthcare provider. how should i store ixinity? 250 iu strength only; store at 2 to 8°c (36 to 46°f). do not freeze. 500, 1000, 1500, 2000, and 3000 iu strengths; store at 2 to 25°c (36 to 77°f). do not freeze. do not use ixinity after the expiration date printed on the label. throw away any unused ixinity and diluents after it reaches this date. reconstituted product (after mixing dry product with sterile water for injection) must be used within 3 hours and cannot be stored or refrigerated. discard any ixinity left in the vial at the end of your infusion. what else should i know about ixinity? your body may form inhibitors to factor ix. an inhibitor is part of the body’s immune system. if you form inhibitors, it may stop ixinity from working properly. consult with your healthcare provider to make sure you are carefully monitored with blood tests to check for the development of inhibitors to factor ix. consult your doctor promptly if bleeding is not controlled with ixinity as expected. medicines are sometimes prescribed for purposes other than those listed here. do not use ixinity for a condition for which it is not prescribed. do not share ixinity with other people, even if they have the same symptoms as you. resources available to patients for information on patient assistance programs that may be available to you, please call our ixinity patient care center at 1-855-ixinity (1-855-494-6489). manufactured by: medexus pharma, inc. chicago, il 60606 u.s. license no. 2220 part number: 640070