omogenic activity assays as described below. chromogenic fviii activity tests may be manufactured with either human or bovine coagulation proteins. assays containing human coagulation factors are responsive to hemlibra but may overestimate the clinical hemostatic potential of hemlibra. in contrast, assays containing bovine coagulation factors are insensitive to hemlibra (no activity measured) and can be used to monitor endogenous or infused fviii activity, or to measure anti-fviii inhibitors. hemlibra remains active in the presence of inhibitors against fviii, so it will produce a false-negative result in clotting-based bethesda assays for functional inhibition of fviii. instead, a chromogenic bethesda assay utilizing a bovine-based fviii chromogenic test that is insensitive to hemlibra may be used. due to the long half-life of hemlibra, effects on coagulation assays may persist for up to 6 months after the last dose [see clinical pharmacology (12.3) ] .

hrombin complex concentrate (apcc) was administered for 24 hours or more to patients receiving hemlibra prophylaxis. in clinical trials, thrombotic microangiopathy was reported in 0.8% of patients (3/391) and in 8.1% of patients (3/37) who received at least one dose of apcc. patients presented with thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury, without severe deficiencies in adamts13 activity. evidence of improvement was seen within one week following discontinuation of apcc. one patient resumed hemlibra following resolution of tma. consider the benefits and risks if apcc must be used in a patient receiving hemlibra prophylaxis. due to the long half-life of hemlibra, the potential for an interaction with apcc may persist for up to 6 months after the last dose. monitor for the development of tma when administering apcc. immediately discontinue apcc and interrupt hemlibra prophylaxis if clinical symptoms and/or laboratory findings consistent with tma occur, and manage as clinically indicated. consider the benefits and risks of resuming hemlibra prophylaxis following complete resolution of tma on a case-by-case basis. 5.2 thromboembolism associated with hemlibra and apcc thrombotic events were reported from clinical trials when on average a cumulative amount of >100 u/kg/24 hours of apcc was administered for 24 hours or more to patients receiving hemlibra prophylaxis. in clinical trials, thrombotic events were reported in 0.5% of patients (2/391) and in 5.4% of patients (2/37) who received at least one dose of apcc. no thrombotic event required anticoagulation therapy. evidence of improvement or resolution was seen within one month following discontinuation of apcc. one patient resumed hemlibra following resolution of thrombotic event. consider the benefits and risks if apcc must be used in a patient receiving hemlibra prophylaxis. due to the long half-life of hemlibra, the potential for an interaction with apcc may persist for up to 6 months after the last dose. monitor for the development of thromboembolism when administering apcc. immediately discontinue apcc and interrupt hemlibra prophylaxis if clinical symptoms, imaging, or laboratory findings consistent with thromboembolism occur, and manage as clinically indicated. consider the benefits and risks of resuming hemlibra prophylaxis following complete resolution of thrombotic events on a case-by-case basis. 5.3 immunogenicity treatment with hemlibra may induce anti-drug antibodies. anti-emicizumab-kxwh antibodies were reported in 5.1% of patients (34/668) treated with hemlibra in clinical trials. most patients with anti-emicizumab-kxwh antibodies did not experience a change in hemlibra plasma concentrations or an increase in bleeding events; however, in uncommon cases (incidence < 1%), the presence of neutralizing antibodies with decreasing plasma concentration may be associated with loss of efficacy [see adverse reactions (6.1 , 6.2) ] . monitor for clinical signs of loss of efficacy (e.g., increase in breakthrough bleeding events) and if observed, promptly assess the etiology and consider a change in treatment if neutralizing anti-emicizumab-kxwh antibodies are suspected. 5.4 laboratory coagulation test interference hemlibra affects intrinsic pathway clotting-based laboratory tests, including activated clotting time (act), activated partial thromboplastin time (aptt), and all assays based on aptt, such as one-stage factor viii (fviii) activity ( table 1 ). therefore, intrinsic pathway clotting-based laboratory test results in patients treated with hemlibra should not be used to monitor hemlibra activity, determine dosing for factor replacement or anti-coagulation, or measure fviii inhibitor titers [see drug interactions (7.2) ]. laboratory tests affected and unaffected by hemlibra are shown in table 1 . table 1 coagulation test results affected and unaffected by hemlibra results affected by hemlibra results unaffected by hemlibra activated partial thromboplastin time (aptt) bethesda assays (clotting-based) for fviii inhibitor titers one-stage, aptt-based, single-factor assays aptt-based activated protein c resistance (apc-r) activated clotting time (act) bethesda assays (bovine chromogenic) for fviii inhibitor titers thrombin time (tt) one-stage, prothrombin time (pt)-based, single-factor assays chromogenic-based single-factor assays other than fviii for important considerations regarding fviii chromogenic activity assays, see drug interactions (7.2) . immuno-based assays (i.e., elisa, turbidimetric methods) genetic tests of coagulation factors (e.g., factor v leiden, prothrombin 20210)

rophylaxis. missed dose if a dose of hemlibra is missed administer as soon as possible and then resume usual dosing schedule. do not administer two doses on the same day to make up for a missed dose. 2.2 preparation and administration hemlibra is intended for use under the guidance of a healthcare provider. after proper training in subcutaneous injection technique, a patient may self-inject, or the patient's caregiver may administer hemlibra, if a healthcare provider determines that it is appropriate. self-administration is not recommended for children less than 7 years of age. the hemlibra "instructions for use" contains more detailed instructions on the preparation and administration of hemlibra [see instructions for use ] . visually inspect hemlibra for particulate matter and discoloration before administration. hemlibra for subcutaneous administration is a colorless to slightly yellow solution. do not use if particulate matter is visible or product is discolored. a syringe, a transfer needle with filter and an injection needle are needed to withdraw hemlibra solution from the vial and inject it subcutaneously. refer to the hemlibra " instructions for use " for handling instructions when combining vials. do not combine hemlibra vials of different concentrations (i.e. 30 mg/ml and 150 mg/ml) in a single injection. please see below the selection criteria for the recommended device options: administer doses of hemlibra up to 1 ml with a 1 ml syringe. a 1 ml syringe fulfilling the following criteria may be used: transparent polypropylene or polycarbonate syringe with luer-lock tip, graduation 0.01 ml, sterile, for injection only, single-use, latex-free and non-pyrogenic, commercially available in the us. administer doses of hemlibra greater than 1 ml and up to 2 ml with a 2 ml or 3 ml syringe. a 2 ml or 3 ml syringe fulfilling the following criteria may be used: transparent polypropylene or polycarbonate syringe with luer-lock tip, graduation 0.1 ml, sterile, for injection only, single-use, latex-free, and non-pyrogenic, commercially available in the us. a transfer needle with a filter fulfilling the following criteria should be used: stainless steel needle with luer-lock connection, sterile, 18 gauge, length 1 to 1½ inch, single bevel or semi-blunted tip, single-use, latex-free, containing a 5-micron filter and non-pyrogenic, commercially available in the us. an injection needle fulfilling the following criteria may be used: stainless steel with luer-lock connection, sterile, 26 gauge (acceptable range: 25 – 27 gauge), length preferably ⅜ inch or maximal length ½ inch, single-use, latex-free and non-pyrogenic, including needle safety feature, commercially available in the us. administer each injection at a different anatomic location (upper outer arms, thighs, or any quadrant of abdomen) than the previous injection. an injection should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact. administration of hemlibra in the upper outer arm should only be performed by a caregiver or healthcare provider. discard any unused hemlibra remaining in the single-dose vial.

n 1 and haven 3), one single-arm trial in adult and adolescent patients (haven 4), one single-arm trial in pediatric patients (haven 2), and one dose-finding trial, in which a total of 391 male patients with hemophilia a received at least one dose of hemlibra as routine prophylaxis. two hundred eighty-one patients (72%) were adults (18 years and older), 50 (13%) were adolescents (12 years up to less than 18 years), 55 (14%) were children (2 years up to less than 12 years), and five (1%) were infants (1 month up to less than 2 years). the median duration of exposure across the studies was 34.1 weeks (0.1 to 224.4 weeks). the most frequently reported adverse reactions observed in ≥ 10% of patients treated with hemlibra were injection site reactions, headache, and arthralgia. four patients (1%) in the clinical trials receiving hemlibra prophylaxis withdrew from treatment due to adverse reactions, which were thrombotic microangiopathy, skin necrosis and superficial thrombophlebitis, headache, and injection site reaction. one patient (1/668) withdrew from treatment after developing neutralizing anti-emicizumab-kxwh antibodies associated with loss of efficacy [see warnings and precautions (5.3) , adverse reactions (6.2) ] . adverse reactions observed in patients who received hemlibra are shown in table 2 . table 2 adverse reactions reported in ≥ 5% of patients from pooled clinical trials with hemlibra body system adverse reaction number of patients n (%) (n = 391) general disorders and administration site conditions injection site reaction includes injection site bruising, injection site discomfort, injection site erythema, injection site hematoma, injection site induration, injection site pain, injection site pruritus, injection site rash, injection site reaction, injection site swelling, injection site urticaria, and injection site warmth. 85 (22%) pyrexia 23 (6%) nervous system disorders headache 57 (15%) gastrointestinal disorders diarrhea 22 (6%) musculoskeletal and connective tissue disorders arthralgia 59 (15%) characterization of apcc treatment in pooled clinical trials there were 130 instances of apcc treatment in 37 patients, of which 13 instances (10%) consisted of on average a cumulative amount of >100 u/kg/24 hours of apcc for 24 hours or more; two of the 13 were associated with thrombotic events and three of the 13 were associated with tma ( table 3 ). no tma or thrombotic events were associated with the remaining instances of apcc treatment. table 3 characterization of apcc treatment an instance of apcc treatment is defined as all doses of apcc received by a patient, for any reason, until there was a 36-hour treatment-free break. in pooled clinical trials duration of apcc treatment average cumulative amount of apcc over 24 hours (u/kg/24 hours) < 50 50 – 100 > 100 < 24 hours 11 76 18 24 – 48 hours 0 6 3 thrombotic event. > 48 hours 1 5 10 , thrombotic microangiopathy. , , injection site reactions in total, 85 patients (22%) reported injection site reactions (isrs). all isrs observed in hemlibra clinical trials were reported as mild to moderate intensity and 93% resolved without treatment. the commonly reported isr symptoms were injection site erythema (11%), injection site pain (4%), and injection site pruritus (4%). other less common (<1%) reactions rhabdomyolysis rhabdomyolysis was reported in two adult patients with asymptomatic elevations in serum creatine kinase without associated renal or musculoskeletal symptoms. in both instances, the event occurred following an increase in physical activity. 6.2 immunogenicity as with all therapeutic proteins, there is a potential for immunogenicity. the detection of antibody formation is highly 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, concomitant medication, and underlying disease. for these reasons, comparison of the incidence of antibodies to emicizumab-kxwh in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. the immunogenicity of hemlibra was evaluated using an enzyme-linked immunosorbent assay (elisa) or an electrochemiluminescence (ecl) assay for anti-emicizumab-kxwh antibodies. in the 7 phase iii clinical trials, antibody positive samples were further evaluated for neutralizing anti-emicizumab-kxwh antibodies using a modified fviii chromogenic assay. a total of 668 patients were tested for anti-emicizumab-kxwh antibodies. in the pooled phase iii clinical trials, 5.1% of patients (34/668) tested positive for anti-emicizumab-kxwh antibodies and 2.7% of patients (18/668) developed anti-emicizumab-kxwh antibodies that were neutralizing in vitro . the anti-emicizumab antibody positive rate may be under-reported due to the limitation of the assay. of these 18 patients, the neutralizing anti-emicizumab-kxwh antibodies did not have a clinically meaningful impact on the pharmacokinetics or efficacy of hemlibra in 14 patients, while decreased emicizumab-kxwh plasma concentrations were observed in four patients (0.6%). one patient (0.2%) from haven 2, who developed neutralizing anti-emicizumab-kxwh antibodies and decreased emicizumab-kxwh plasma concentrations, experienced loss of efficacy (manifest as breakthrough bleeding) after 5 weeks of treatment and discontinued hemlibra treatment. overall, the safety profile of hemlibra was similar between those patients with anti-emicizumab-kxwh antibodies (including neutralizing antibodies) and those without [see warnings and precautions (5.3) , adverse reactions (6.1) ] . 6.3 postmarketing experience the following adverse reactions have been identified during post-approval use of hemlibra. 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. skin and subcutaneous tissue disorders : rash, urticaria, angioedema

omogenic activity assays as described below. chromogenic fviii activity tests may be manufactured with either human or bovine coagulation proteins. assays containing human coagulation factors are responsive to hemlibra but may overestimate the clinical hemostatic potential of hemlibra. in contrast, assays containing bovine coagulation factors are insensitive to hemlibra (no activity measured) and can be used to monitor endogenous or infused fviii activity, or to measure anti-fviii inhibitors. hemlibra remains active in the presence of inhibitors against fviii, so it will produce a false-negative result in clotting-based bethesda assays for functional inhibition of fviii. instead, a chromogenic bethesda assay utilizing a bovine-based fviii chromogenic test that is insensitive to hemlibra may be used. due to the long half-life of hemlibra, effects on coagulation assays may persist for up to 6 months after the last dose [see clinical pharmacology (12.3) ] .

milk, the effects on the breastfed child, or the effects on milk production. human igg is known to be present in human milk. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for hemlibra and any potential adverse effects on the breastfed child from hemlibra or from the underlying maternal condition. 8.3 females and males of reproductive potential contraception women of childbearing potential should use contraception while receiving hemlibra. 8.4 pediatric use the safety and efficacy of hemlibra have been established in pediatric patients. use of hemlibra in pediatric patients with hemophilia a is supported by two randomized trials (haven 1 and haven 3) and two single-arm trials (haven 2 and haven 4). all clinical trials included pediatric patients in the following age group: 47 adolescents (12 years up to less than 18 years). only haven 2 included pediatric patients in the following age groups: 55 children (2 years up to less than 12 years) and five infants (1 month up to less than 2 years). no differences in efficacy were observed between the different age groups [see clinical studies (14) ] . the steady-state plasma trough concentrations of emicizumab-kxwh were comparable in adult and pediatric patients older than 6 months at equivalent weight-based doses. lower concentrations of emicizumab-kxwh were predicted in pediatric patients less than 6 months old [see clinical pharmacology (12.3) ] . in general, the adverse reactions in hemlibra-treated pediatric patients were similar in type to those seen in adult patients with hemophilia a [see adverse reactions (6.1) ] . 8.5 geriatric use clinical studies of hemlibra did not include a sufficient number of patients aged 65 and over to determine whether they respond differently from younger patients. other reported clinical experience has not identified differences in responses between the elderly and younger patients.

ions in hemlibra-treated pediatric patients were similar in type to those seen in adult patients with hemophilia a [see adverse reactions (6.1) ] .

6 mg/kg once every four weeks auc ss , τ = area under the concentration time curve at steady-state over the dosing interval (τ = 1, 2, or 4 weeks); c max, ss = maximum plasma concentration at steady state; c trough, ss = trough concentration at steady state. c max, ss (µg/ml) 55.1 ± 15.9 58.3 ± 16.4 67 ± 17.7 auc ss,τ (µg/ml*day) 376 ± 109 752 ± 218 1503 ± 437 c trough, ss (µg/ml) 51.2± 15.2 46.9 ± 14.8 38.5 ± 14.2 c max / c trough ratio (µg/ml) 1.08 ± 0.03 1.26 ± 0.12 1.85 ± 0.47 absorption following subcutaneous administration, the mean (± sd) absorption half-life was 1.6 ± 1 day. the absolute bioavailability following subcutaneous administration of 1 mg/kg was between 80.4% and 93.1%. similar pharmacokinetic profiles were observed following subcutaneous administration in the abdomen, upper arm, and thigh [see dosage and administration (2.2) ] . distribution the mean apparent volume of distribution (% coefficient of variation [%cv]) was 10.4 l (26.0%). elimination the mean apparent clearance (%cv) was 0.27 l/day (28.4%) and the mean elimination apparent half-life (± sd) was 26.9 ± 9.1 days. specific populations the pharmacokinetics of emicizumab-kxwh are not influenced by age (1 year to 77 years), race (white 62.7%, asian 22.9%, and black 8%), inhibitor status (inhibitor present, 50%), mild hepatic impairment (defined as total bilirubin 1× to ≤ 1.5× the upper limit of normal (uln) and any aspartate transaminase (ast) level), moderate hepatic impairment (defined as total bilirubin 1.5× to ≤ 3× the uln and any ast level), mild renal impairment (defined as creatinine clearance (crcl) of 60 – 89 ml/min), and moderate renal impairment (defined as crcl of 30 – 59 ml/min). emicizumab-kxwh has not been studied in patients with severe hepatic or renal impairment. in pediatric patients less than 6 months old, the predicted concentrations of emicizumab-kxwh were 19% to 33% lower than the older patients, especially with the 3 mg/kg once every two weeks or 6 mg/kg once every four weeks maintenance dose. body weight : the apparent clearance and volume of distribution of emicizumab-kxwh increased with increasing body weight (9 kg to 156 kg). dosing in mg/kg provides similar emicizumab-kxwh exposure across body weight range. drug interaction studies no drug-drug interaction studies have been conducted with hemlibra.

steady state; c trough, ss = trough concentration at steady state. c max, ss (µg/ml) 55.1 ± 15.9 58.3 ± 16.4 67 ± 17.7 auc ss,τ (µg/ml*day) 376 ± 109 752 ± 218 1503 ± 437 c trough, ss (µg/ml) 51.2± 15.2 46.9 ± 14.8 38.5 ± 14.2 c max / c trough ratio (µg/ml) 1.08 ± 0.03 1.26 ± 0.12 1.85 ± 0.47 absorption following subcutaneous administration, the mean (± sd) absorption half-life was 1.6 ± 1 day. the absolute bioavailability following subcutaneous administration of 1 mg/kg was between 80.4% and 93.1%. similar pharmacokinetic profiles were observed following subcutaneous administration in the abdomen, upper arm, and thigh [see dosage and administration (2.2) ] . distribution the mean apparent volume of distribution (% coefficient of variation [%cv]) was 10.4 l (26.0%). elimination the mean apparent clearance (%cv) was 0.27 l/day (28.4%) and the mean elimination apparent half-life (± sd) was 26.9 ± 9.1 days. specific populations the pharmacokinetics of emicizumab-kxwh are not influenced by age (1 year to 77 years), race (white 62.7%, asian 22.9%, and black 8%), inhibitor status (inhibitor present, 50%), mild hepatic impairment (defined as total bilirubin 1× to ≤ 1.5× the upper limit of normal (uln) and any aspartate transaminase (ast) level), moderate hepatic impairment (defined as total bilirubin 1.5× to ≤ 3× the uln and any ast level), mild renal impairment (defined as creatinine clearance (crcl) of 60 – 89 ml/min), and moderate renal impairment (defined as crcl of 30 – 59 ml/min). emicizumab-kxwh has not been studied in patients with severe hepatic or renal impairment. in pediatric patients less than 6 months old, the predicted concentrations of emicizumab-kxwh were 19% to 33% lower than the older patients, especially with the 3 mg/kg once every two weeks or 6 mg/kg once every four weeks maintenance dose. body weight : the apparent clearance and volume of distribution of emicizumab-kxwh increased with increasing body weight (9 kg to 156 kg). dosing in mg/kg provides similar emicizumab-kxwh exposure across body weight range. drug interaction studies no drug-drug interaction studies have been conducted with hemlibra.

g/kg once every week was allowed after 24 weeks on hemlibra prophylaxis for patients who experienced two or more qualified bleeds (i.e., spontaneous and clinically significant bleeds occurring at steady state). for arm d patients, dose up-titration was allowed after the second qualifying bleed. during the study, five patients underwent up-titration of their maintenance dose; however, this study was not designed to investigate the 3 mg/kg once every week dosing regimen. eighty-nine patients previously treated with episodic (on demand) fviii were randomized in a 2:2:1 ratio to receive hemlibra prophylaxis 1.5 mg/kg once every week (arm a), 3 mg/kg once every two weeks (arm b), or no prophylaxis (arm c), with stratification by prior 24-week bleed rate (< 9 or ≥ 9). sixty-three patients previously treated with prophylactic fviii were enrolled into arm d to receive hemlibra prophylaxis (1.5 mg/kg once every week). efficacy was evaluated after a minimum of 24 weeks of follow-up based on the bleed rate for bleeds requiring treatment with coagulation factors among patients previously treated with episodic (on-demand) fviii who were randomized to hemlibra prophylaxis 1.5 mg/kg once every week (arm a) or 3 mg/kg once every two weeks (arm b) compared with those receiving no prophylaxis (arm c). the study also evaluated the randomized comparison of arms a and c and arms b and c for the efficacy of hemlibra prophylaxis in reducing the number of all bleeds, spontaneous bleeds, joint bleeds, and target joint bleeds. the efficacy of hemlibra prophylaxis compared with previous prophylactic fviii was also evaluated in patients who had participated in a non-interventional study (nis) prior to enrollment (arm d). only patients from the nis were included in this comparison, because bleed and treatment data were collected with the same level of granularity as that used in haven 3. the efficacy results of hemlibra prophylaxis (1.5 mg/kg once every week and 3 mg/kg once every two weeks) compared with no prophylaxis with respect to rate of treated bleeds, all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds are shown in table 5 . table 5 annualized bleed rate with hemlibra prophylaxis versus no prophylaxis in patients ≥ 12 years of age without factor viii inhibitors endpoint hemlibra 1.5 mg/kg once every week (n = 36) hemlibra 3 mg/kg once every two weeks (n = 35) no prophylaxis (n = 18) abr = annualized bleed rate; ci = confidence interval; iqr = interquartile range, 25th percentile to 75th percentile. treated bleeds abr (95% ci) based on negative binomial regression model. 1.5 (0.9, 2.5) 1.3 (0.8, 2.3) 38.2 (22.9, 63.8) % reduction (95% ci) p-value 96% (92.5%, 98%) < 0.0001 97% (93.4%, 98.3%) < 0.0001 - % patients with 0 bleeds (95% ci) 55.6 (38.1, 72.1) 60 (42.1, 76.1) 0 (0, 18.5) median abr (iqr) 0 (0, 2.5) 0 (0, 1.9) 40.4 (25.3, 56.7) all bleeds abr (95% ci) 2.5 (1.6, 3.9) 2.6 (1.6, 4.3) 47.6 (28.5, 79.6) % reduction (95% ci) p-value 95% (90.1%, 97%) < 0.0001 94% (89.7%, 97%) < 0.0001 - % patients with 0 bleeds (95% ci) 50 (32.9, 67.1) 40 (23.9, 57.9) 0 (0, 18.5) median abr (iqr) 0.6 (0, 3.9) 1.6 (0, 4) 46.9 (26.1, 73.9) treated spontaneous bleeds abr (95% ci) 1.0 (0.5, 1.9) 0.3 (0.1, 0.8) 15.6 (7.6, 31.9) % reduction (95% ci) p-value 94% (84.9%, 97.5%) < 0.0001 98% (94.4%, 99.4%) < 0.0001 - % patients with 0 bleeds (95% ci) 66.7 (49.0, 81.4) 88.6 (73.3, 96.8) 22.2 (6.4, 47.6) median abr (iqr) 0 (0, 1.3) 0 (0, 0) 10.8 (2.1, 26) treated joint bleeds abr (95% ci) 1.1 (0.6, 1.9) 0.9 (0.4, 1.7) 26.5 (14.7, 47.8) % reduction (95% ci) p-value 96% (91.5%, 98.1%) < 0.0001 97% (93%, 98.5%) < 0.0001 - % patients with 0 bleeds (95% ci) 58.3 (40.8, 74.5) 74.3 (56.7, 87.5) 0 (0, 18.5) median abr (iqr) 0 (0, 1.9) 0 (0, 1.3) 21.3 (14.5, 41.3) treated target joint bleeds abr (95% ci) 0.6 (0.3, 1.4) 0.7 (0.3, 1.6) 13 (5.2, 32.3) % reduction (95% ci) p-value 95% (85.7%, 98.4%) < 0.0001 95% (85.3%, 98.2%) < 0.0001 - % patients with 0 bleeds (95% ci) 69.4 (51.9, 83.7) 77.1 (59.9, 89.6) 27.8 (9.7, 53.5) median abr (iqr) 0 (0, 1.4) 0 (0, 0) 12.8 (0, 39.1) in the haven 3 intra-patient analysis, hemlibra prophylaxis resulted in a statistically significant (p < 0.0001) reduction (68%) in bleed rate for treated bleeds compared with previous fviii prophylaxis collected in the nis prior to enrollment (see table 6 ). table 6 intra-patient comparison of annualized bleed rate with hemlibra prophylaxis versus previous fviii prophylaxis endpoint hemlibra 1.5 mg/kg once every week (n = 48) previous fviii prophylaxis (n = 48) abr = annualized bleed rate; ci = confidence interval; iqr = interquartile range, 25th percentile to 75th percentile. median observation period (weeks) 33.7 30.1 treated bleeds abr (95% ci) based on negative binomial regression model. 1.5 (1, 2.3) 4.8 (3.2, 7.1) % reduction (95% ci) p-value 68% (48.6%, 80.5%) < 0.0001 % patients with 0 bleeds (95% ci) 54.2 (39.2, 68.6) 39.6 (25.8, 54.7) median abr (iqr) 0 (0, 2.1) 1.8 (0, 7.6) haven 4 (adult and adolescent patients) the haven 4 study (nct03020160) was a single-arm, multicenter, open-label, clinical trial in 41 adult and adolescent males (aged ≥ 12 years and ≥ 40 kg) with hemophilia a with or without fviii inhibitors who previously received either episodic (on demand) or prophylactic treatment with fviii or bypassing agents. patients received hemlibra prophylaxis at 3 mg/kg once weekly for the first 4 weeks followed by 6 mg/kg once every four weeks thereafter. efficacy was evaluated in a subgroup of 36 patients with hemophilia a without fviii inhibitors based on the bleed rate for bleeds requiring treatment with coagulation factors. the study also evaluated the efficacy of hemlibra prophylaxis on all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds. the efficacy results of hemlibra prophylaxis 6 mg/kg once every four weeks with respect to rate of treated bleeds, all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds are shown in table 7 . the median observation time was 25.6 weeks (range 24.1 – 29.4 weeks). table 7 annualized bleed rate with hemlibra prophylaxis 6 mg/kg once every four weeks in patients ≥ 12 years of age without factor viii inhibitors endpoint abr based on negative binomial regression model. (95% ci) n = 36 median abr (iqr) n = 36 % zero bleeds (95% ci) n = 36 abr = annualized bleed rate; ci = confidence interval; iqr = interquartile range, 25th percentile to 75th percentile. treated bleeds 2.6 (1.5, 4.7) 0 (0, 2.1) 52.8 (35.5, 69.6) all bleeds 4.8 (3.2, 7.1) 2.1 (0, 6.1) 27.8 (14.2, 45.2) treated spontaneous bleeds 0.6 (0.2, 1.6) 0 (0, 0) 83.3 (67.2, 93.6) treated joint bleeds 1.8 (0.8, 4) 0 (0, 1.9) 69.4 (51.9, 83.7) treated target joint bleeds 1.1 (0.4, 3.7) 0 (0, 0) 83.3 (67.2, 93.6) 14.2 hemophilia a with fviii inhibitors the efficacy of hemlibra for routine prophylaxis in patients with hemophilia a with fviii inhibitors was evaluated in three clinical trials [adult and adolescent studies (haven 1 and haven 4) and a pediatric study (haven 2)]. haven 1 (adult and adolescent patients) the haven 1 study (nct02622321) was a randomized, multicenter, open-label, clinical trial in 109 adult and adolescent males (aged ≥ 12 years and ≥ 40 kg) with hemophilia a with fviii inhibitors who previously received either episodic (on-demand) or prophylactic treatment with bypassing agents. patients received hemlibra prophylaxis (arms a, c, and d), 3 mg/kg once weekly for the first 4 weeks followed by 1.5 mg/kg once every week thereafter, or no prophylaxis (arm b). patients in arm b could switch to hemlibra prophylaxis after completing at least 24 weeks without prophylaxis. dose up-titration to 3 mg/kg once every week was allowed after 24 weeks on hemlibra prophylaxis for patients who experienced two or more qualified bleeds (i.e., spontaneous and clinically significant bleeds occurring at steady state). during the study, two patients underwent up-titration of their maintenance dose; however, this study was not designed to investigate the 3 mg/kg once every week dosing regimen. fifty-three patients previously treated with episodic (on-demand) bypassing agents were randomized in a 2:1 ratio to receive hemlibra prophylaxis (arm a) or no prophylaxis (arm b), with stratification by prior 24-week bleed rate (< 9 or ≥ 9). forty-nine patients previously treated with prophylactic bypassing agents were enrolled into arm c to receive hemlibra prophylaxis. seven patients previously treated with episodic (on-demand) bypassing agents who had participated in the nis prior to enrollment, but were unable to enroll into haven 1 prior to the closure of arms a and b, were enrolled into arm d to receive hemlibra prophylaxis. efficacy was evaluated after a minimum of 24 weeks of follow-up based on the bleed rate for bleeds requiring treatment with coagulation factors among patients previously treated with episodic bypassing agents who were randomized to hemlibra prophylaxis (arm a) compared with those receiving no prophylaxis (arm b). the study also evaluated the randomized comparison of arms a and b for the efficacy of hemlibra prophylaxis in reducing the number of all bleeds, spontaneous bleeds, joint bleeds, and target joint bleeds, as well as patient-reported symptoms and physical functioning. the efficacy of hemlibra prophylaxis compared with previous prophylactic bypassing agents was also evaluated in patients who had participated in the nis prior to enrollment (arm c). only patients from the nis were included in this comparison, because bleed and treatment data were collected with the same level of granularity as that used in haven 1. the efficacy results of hemlibra prophylaxis 1.5 mg/kg once every week compared with no prophylaxis with respect to rate of treated bleeds, all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds are shown in table 8 . table 8 annualized bleed rate with hemlibra prophylaxis versus no prophylaxis in patients ≥ 12 years of age with factor viii inhibitors endpoint hemlibra 1.5 mg/kg once every week (n = 35) no prophylaxis (n = 18) abr = annualized bleed rate; ci = confidence interval; iqr = interquartile range, 25th percentile to 75th percentile. treated bleeds abr (95% ci) based on negative binomial regression model. 2.9 (1.7, 5.0) 23.3 (12.3, 43.9) % reduction (95% ci) p-value 87% (72.3%, 94.3%) < 0.0001 % patients with 0 bleeds (95% ci) 62.9 (44.9, 78.5) 5.6 (0.1, 27.3) median abr (iqr) 0 (0, 3.7) 18.8 (13.0, 35.1) all bleeds abr (95% ci) 5.5 (3.6, 8.6) 28.3 (16.8, 47.8) % reduction (95% ci) p-value 80% (62.5%, 89.8%) < 0.0001 % patients with 0 bleeds (95% ci) 37.1 (21.5, 55.1) 5.6 (0.1, 27.3) median abr (iqr) 2 (0, 9.9) 30.2 (18.3, 39.4) treated spontaneous bleeds abr (95% ci) 1.3 (0.7, 2.2) 16.8 (9.9, 28.3) % reduction (95% ci) p-value 92% (84.6%, 96.3%) < 0.0001 % patients with 0 bleeds (95% ci) 68.6 (50.7, 83.1) 11.1 (1.4, 34.7) median abr (iqr) 0 (0, 3.3) 15.2 (6.6, 30.4) treated joint bleeds abr (95% ci) 0.8 (0.3, 2.2) 6.7 (2.0, 22.4) % reduction (95% ci) p-value 89% (48%, 97.5%) 0.0050 % patients with 0 bleeds (95% ci) 85.7 (69.7, 95.2) 50.0 (26.0, 74.0) median abr (iqr) 0 (0, 0) 1 (0, 14.4) treated target joint bleeds abr (95% ci) 0.1 (0.03, 0.6) 3.0 (1.0, 9.1) % reduction (95% ci) p-value 95% (77.3%, 99.1%) 0.0002 % patients with 0 bleeds (95% ci) 94.3 (80.8, 99.3) 50.0 (26.0, 74.0) median abr (iqr) 0 (0, 0) 1 (0, 6.5) descriptive analyses were conducted to assess hemlibra prophylaxis once every week using 12-week treatment intervals up to week 72. the descriptive mean abrs for treated bleeds are shown in table 9 . table 9 annualized bleed rate with hemlibra prophylaxis once every week per 12-week intervals in patients ≥ 12 years of age with factor viii inhibitors endpoint time interval (weeks) 1 – 12 (n = 109) 13 – 24 (n = 108) 25 – 36 (n = 93) 37 – 48 (n = 93) 49 – 60 (n = 57) 61 – 72 (n = 42) abr = annualized bleed rate; ci = confidence interval based on poisson distribution; n = number of patients who contributed data for analyses at each time interval. treated bleeds mean abr (95% ci) 3.9 (1.1, 10.2) 2.2 (0.3, 7.6) 0.9 (0, 5.5) 0.4 (0, 4.4) 0.5 (0, 4.7) 0.6 (0, 4.9) in the haven 1 intra-patient analysis, hemlibra prophylaxis resulted in a statistically significant (p = 0.0003) reduction (79%) in bleed rate for treated bleeds compared with previous bypassing agent prophylaxis collected in the nis prior to enrollment ( table 10 ). table 10 intra-patient comparison of annualized bleed rate with hemlibra prophylaxis versus previous bypassing agent prophylaxis endpoint hemlibra 1.5 mg/kg once every week (n = 24) previous bypassing agent prophylaxis (n = 24) abr = annualized bleed rate; ci = confidence interval; iqr = interquartile range, 25th percentile to 75th percentile. median observation period (weeks) 30.1 32.1 treated bleeds abr (95% ci) based on negative binomial regression model. 3.3 (1.3, 8.1) 15.7 (11.1, 22.3) % reduction (95% ci) p-value 79% (51.4%, 91.1%) 0.0003 % patients with 0 bleeds (95% ci) 70.8 (48.9, 87.4) 12.5 (2.7, 32.4) median abr (iqr) 0 (0, 2.2) 12 (5.7, 24.2) the haven 1 study evaluated patient-reported hemophilia-related symptoms (painful swellings and presence of joint pain) and physical functioning (pain with movement and difficulty walking far) using the physical health score of the haemophilia-specific quality of life (haem-a-qol) questionnaire for patients ≥ 18 years of age. the hemlibra prophylaxis arm (arm a) showed an improvement compared with the no prophylaxis arm (arm b) in the haem-a-qol physical health subscale score at the week 25 assessment ( table 11 ). the improvement in the physical health score was further supported by the total score as measured by the haem-a-qol at week 25. table 11 change in haem-a-qol physical health score with hemlibra prophylaxis versus no prophylaxis in patients (≥ 18 years of age) with factor viii inhibitors at week 25 haem-a-qol scores at week 25 hemlibra 1.5 mg/kg once every week (n = 25 number of patients ≥ 18 years who completed the haem-a-qol questionnaire. ) no prophylaxis (n = 14 ) physical health score (range 0 to 100) lower scores are reflective of better functioning. adjusted mean adjusted for baseline, and baseline by treatment group interaction. 32.6 54.2 difference in adjusted means (95% ci) 21.6 (7.9, 35.2) p-value 0.0029 haven 2 (pediatric patients) the haven 2 study (nct02795767) was a single-arm, multicenter, open-label, clinical trial in pediatric males (age < 12 years, or 12 – 17 years who weigh < 40 kg) with hemophilia a with fviii inhibitors. patients received hemlibra prophylaxis at 3 mg/kg once weekly for the first 4 weeks followed by 1.5 mg/kg once every week thereafter. the study evaluated the efficacy of hemlibra prophylaxis, including the efficacy of hemlibra prophylaxis compared with previous episodic (on-demand) and prophylactic bypassing agent treatment in patients who had participated in a non-interventional study (nis) prior to enrollment (intra-patient analysis). at the time of the interim analysis, efficacy was evaluated in 59 pediatric patients who were < 12 years of age and had been receiving hemlibra prophylaxis for at least 12 weeks, including 38 patients age 6 to < 12 years, 17 patients age 2 to < 6 years, and four patients age < 2 years. annualized bleed rate (abr) and percent of patients with zero bleeds were calculated for 59 patients ( table 12 ). the median observation time for these patients was 29.6 weeks (range 18.4 – 63 weeks). table 12 annualized bleed rate with hemlibra prophylaxis 1.5 mg/kg once every week in pediatric patients < 12 years of age with factor viii inhibitors (interim analysis) endpoint abr based on negative binomial regression model. (95% ci) n = 59 median abr (iqr) n = 59 % zero bleeds (95% ci) n = 59 abr = annualized bleed rate; ci = confidence interval; iqr = interquartile range, 25th percentile to 75th percentile. treated bleeds 0.3 (0.1, 0.5) 0 (0, 0) 86.4 (75, 94) all bleeds 3.8 (2.2, 6.5) 0 (0, 3.4) 55.9 (42.4, 68.8) treated spontaneous bleeds 0 (0, 0.2) 0 (0, 0) 98.3 (90.9, 100) treated joint bleeds 0.2 (0.1, 0.4) 0 (0, 0) 89.8 (79.2, 96.2) treated target joint bleeds 0.1 (0, 0.7) 0 (0, 0) 96.6 (88.3, 99.6) in the intra-patient analysis, 18 pediatric patients who had participated in the nis had an abr for treated bleeds of 19.8 (95% ci [15.3, 25.7]) on previous bypassing agent treatment (prophylactic treatment in 15 patients and on-demand treatment for 3 patients). hemlibra prophylaxis resulted in an abr for treated bleeds of 0.4 (95% ci [0.2, 0.9]) based on negative binomial regression, corresponding to a 98% reduction in bleed rate. on hemlibra prophylaxis, 14 patients (77.8%) had zero treated bleeds. the haven 2 study evaluated patient-reported hemophilia-related symptoms (painful swellings and presence of joint pain) and physical functioning (pain with movement) using the physical health score of the hemophilia-specific quality of life short form (haemo-qol-sf) questionnaire for patients ≥ 8 to < 12 years of age. hemlibra prophylaxis showed improvement from baseline in the haemo-qol-sf physical health subscale score at the week 25 assessment. haven 4 (adult and adolescent patients) the haven 4 study (nct03020160) was a single-arm, multicenter, open-label, clinical trial in 41 adult and adolescent males (aged ≥ 12 years and ≥ 40 kg) with hemophilia a with or without fviii inhibitors who previously received either episodic (on demand) or prophylactic treatment with fviii or bypassing agents. patients received hemlibra prophylaxis at 3 mg/kg once weekly for the first 4 weeks followed by 6 mg/kg once every four weeks thereafter. efficacy was evaluated in a subgroup of 5 patients with hemophilia a with fviii inhibitors based on the bleed rate for bleeds requiring treatment with coagulation factors. the median observation time was 26.1 weeks (range 24.4 – 28.6 weeks). hemlibra prophylaxis resulted in an abr (95% ci) for treated bleeds of 1.2 (0.1, 14.8) based on negative binomial regression. on hemlibra prophylaxis, 4 patients had zero treated bleeds. the efficacy results of hemlibra prophylaxis (1.5 mg/kg once every week, 3 mg/kg once every two weeks, and 6 mg/kg once every four weeks) with respect to rate of treated bleeds are shown in table 13 . table 13 annualized bleed rate (treated bleeds) with hemlibra prophylaxis in patients with or without factor viii inhibitors endpoint haven 1 haven 2 haven 3 haven 4 hemlibra 1.5 mg/kg once every week (n = 35) no prophylaxis (n = 18) hemlibra 1.5 mg/kg once every week (n = 59) hemlibra 1.5 mg/kg once every week (n = 36) hemlibra 3 mg/kg once every two weeks (n = 35) no prophylaxis (n = 18) hemlibra 6 mg/kg once every four weeks (n = 41) abr = annualized bleed rate; ci = confidence interval; iqr = interquartile range, 25th percentile to 75th percentile; haven 1 = adult and adolescent patients with factor viii inhibitors; haven 2 = pediatric patients with factor viii inhibitors; haven 3 = adult and adolescent patients without factor viii inhibitors; haven 4 = adult and adolescent patients with or without factor viii inhibitors. median efficacy period (weeks) 29.3 24 29.6 29.6 31.3 24 25.6 abr (95% ci) based on negative binomial regression model. 2.9 (1.7, 5) 23.3 (12.3, 43.9) 0.3 (0.1, 0.5) 1.5 (0.9, 2.5) 1.3 (0.8, 2.3) 38.2 (22.9, 63.8) 2.4 (1.4, 4.3) % reduction vs no prophylaxis (95% ci), p-value 87% (72.3%, 94.3%) < 0.0001 - - 96% (92.5%, 98%) < 0.0001 97% (93.4%, 98.3%) < 0.0001 - - % patients with 0 bleeds (95% ci) 62.9 (44.9, 78.5) 5.6 (0.1, 27.3) 86.4 (75, 94) 55.6 (38.1, 72.1) 60 (42.1, 76.1) 0 (0, 18.5) 56.1 (39.7, 71.5) % patients with 0 - 3 bleeds (95% ci) 85.7 (69.7, 95.2) 11.1 (1.4, 34.7) 100 (93.9, 100) 91.7 (77.5, 98.2) 94.3 (80.8, 99.3) 5.6 (0.1, 27.3) 90.2 (76.9, 97.3) median abr (iqr) 0 (0, 3.7) 18.8 (13, 35.1) 0 (0, 0) 0 (0, 2.5) 0 (0, 1.9) 40.4 (25.3, 56.7) 0 (0, 2.1)

ard hemlibra if not used immediately. discard any unused hemlibra.

er to consult their healthcare provider if apcc is required in cumulative doses exceeding 100 u/kg. advise the patient and/or caregiver to seek immediate medical attention if any signs or symptoms of thrombotic microangiopathy occur [see warnings and precautions (5.1) ] . thromboembolism associated with hemlibra and apcc inform the patient and/or caregiver of the potential risk of thromboembolism if apcc is administered while receiving hemlibra prophylaxis. instruct the patient and/or caregiver to consult their healthcare provider if apcc is required in cumulative doses exceeding 100 u/kg. advise the patient and/or caregiver to seek immediate medical attention if any signs or symptoms of thromboembolism occur [see warnings and precautions (5.2) ] . immunogenicity inform the patient and/or caregiver of the uncommon occurrence (incidence < 1%) of loss of efficacy while receiving hemlibra prophylaxis due to immunogenicity (neutralizing anti-emicizumab-kxwh antibodies). instruct the patient and/or caregiver to promptly report clinical signs of loss of efficacy (e.g., increase in breakthrough bleeding events) [see warnings and precautions (5.3) ]. laboratory coagulation test interference inform the patient and/or caregiver that hemlibra interferes with some laboratory tests that measure blood clotting and may cause a false reading. advise the patient and/or caregiver that they should notify any healthcare provider about this possibility prior to any blood tests or medical procedures [see warnings and precautions (5.4) ] . instruction on injection technique hemlibra is intended for use under the guidance of a healthcare provider. if a patient or caregiver is to administer subcutaneous hemlibra, instruct him/her in injection techniques and assess his/her ability to inject subcutaneously to ensure proper administration of subcutaneous hemlibra and the suitability for home use [see instructions for use ] . advise the patient to follow the recommendations in the fda-approved patient labeling regarding proper sharps disposal.