Hemlibra

WARNING: THROMBOTIC MICROANGIOPATHY AND THROMBOEMBOLISM Cases of thrombotic microangiopathy and thrombotic events were reported when on average a cumulative amount of >100 U/kg/24 hours of activated prothrombin complex concentrate was administered for 24 hours or more to patients receiving HEMLIBRA prophylaxis. Monitor for the development of thrombotic microangiopathy and thrombotic events if aPCC is administered. Discontinue aPCC and suspend dosing of HEMLIBRA if symptoms occur. WARNING: THROMBOTIC MICROANGIOPATHY and THROMBOEMBOLISM See full prescribing information for complete boxed warning. Cases of thrombotic microangiopathy and thrombotic events were reported when on average a cumulative amount of >100 U/kg/24 hours of activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more to patients receiving HEMLIBRA prophylaxis. Monitor for the development of thrombotic microangiopathy and thrombotic events if aPCC is administered. Discontinue aPCC and suspend dosing of HEMLIBRA if symptoms occur.

5 WARNINGS AND PRECAUTIONS Immunogenicity: Anti-emicizumab antibodies (including neutralizing antibodies) have developed in HEMLIBRA-treated patients. In case of clinical signs of loss of efficacy, promptly assess the etiology and consider a change in treatment if neutralizing antibodies are suspected. ( 5.3 , 12.6 , 14.3 ) Laboratory Coagulation Test Interference: HEMLIBRA interferes with activated clotting time (ACT), activated partial thromboplastin time (aPTT), and coagulation laboratory tests based on aPTT, including one-stage aPTT-based single-factor assays, aPTT-based Activated Protein C Resistance (APC-R), and Bethesda assays (clotting-based) for factor VIII (FVIII) inhibitor titers. Intrinsic pathway clotting-based laboratory tests should not be used. ( 5.4 , 7.2 ) 5.1 Thrombotic Microangiopathy Associated with HEMLIBRA and aPCC Cases of thrombotic microangiopathy (TMA) were reported from clinical trials when on average a cumulative amount of >100 U/kg/24 hours of activated prothrombin 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 Clinical Pharmacology (12.6) , Clinical Studies (14.3) ] . 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)

<table ID="Table1" width="75%"><caption>Table 1 Coagulation Test Results Affected and Unaffected by HEMLIBRA</caption><col width="50%" align="left" valign="top"/><col width="50%" align="left" valign="top"/><thead><tr><th styleCode="Lrule Rrule" align="center">Results Affected by HEMLIBRA</th><th styleCode="Rrule" align="center">Results Unaffected by HEMLIBRA</th></tr></thead><tbody><tr><td styleCode="Lrule Rrule">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)</td><td styleCode="Rrule">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<footnote>For important considerations regarding FVIII chromogenic activity assays, see <content styleCode="italics"><linkHtml href="#S7.2">Drug Interactions (7.2)</linkHtml></content>.</footnote> Immuno-based assays (i.e., ELISA, turbidimetric methods) Genetic tests of coagulation factors (e.g., Factor V Leiden, Prothrombin 20210)</td></tr></tbody></table>

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Thrombotic Microangiopathy Associated with HEMLIBRA and aPCC [see Warnings and Precautions (5.1) ] Thromboembolism Associated with HEMLIBRA and aPCC [see Warnings and Precautions (5.2) ] Most common adverse reactions (incidence ≥ 10%) are injection site reactions, headache, and arthralgia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following adverse reactions are based on pooled data from two randomized trials in adult and adolescent patients (HAVEN 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. 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 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. Immune system disorders : hypersensitivity.

<table ID="Table2" width="75%"><caption>Table 2 Adverse Reactions Reported in &#x2265; 5% of Patients from Pooled Clinical Trials with HEMLIBRA</caption><col width="34%" align="left" valign="middle"/><col width="33%" align="left" valign="middle"/><col width="33%" align="center" valign="middle"/><thead><tr><th align="center" styleCode="Lrule Rrule">Body System</th><th align="center" styleCode="Rrule">Adverse Reaction</th><th styleCode="Rrule">Number of Patients n (%) (N = 391)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" rowspan="2">General Disorders and Administration Site Conditions</td><td styleCode="Rrule">Injection site reaction<footnote>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. </footnote></td><td styleCode="Rrule">85 (22%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pyrexia</td><td styleCode="Rrule" align="center">23 (6%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nervous System Disorders</td><td styleCode="Rrule">Headache</td><td styleCode="Rrule">57 (15%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Gastrointestinal Disorders</td><td styleCode="Rrule">Diarrhea</td><td styleCode="Rrule">22 (6%)</td></tr><tr><td styleCode="Lrule Rrule">Musculoskeletal and Connective Tissue Disorders</td><td styleCode="Rrule">Arthralgia</td><td styleCode="Rrule">59 (15%)</td></tr></tbody></table>

<table ID="Table3" width="75%"><caption>Table 3 Characterization of aPCC Treatment<footnote>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. </footnote> in Pooled Clinical Trials</caption><col width="25%" align="center" valign="middle"/><col width="25%" align="center" valign="middle"/><col width="25%" align="center" valign="middle"/><col width="25%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule" rowspan="2">Duration of aPCC treatment</th><th styleCode="Rrule Botrule" colspan="3">Average cumulative amount of aPCC over 24 hours (U/kg/24 hours)</th></tr><tr><th styleCode="Lrule Rrule">&lt; 50</th><th styleCode="Rrule">50 &#x2013; 100</th><th styleCode="Rrule">&gt; 100</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">&lt; 24 hours</td><td styleCode="Rrule">11</td><td styleCode="Rrule">76</td><td styleCode="Rrule">18</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">24 &#x2013; 48 hours</td><td styleCode="Rrule">0</td><td styleCode="Rrule">6</td><td styleCode="Rrule">3<footnote ID="t3fa">Thrombotic event.</footnote></td></tr><tr><td styleCode="Lrule Rrule">&gt; 48 hours</td><td styleCode="Rrule">1</td><td styleCode="Rrule">5</td><td styleCode="Rrule">10<footnoteRef IDREF="t3fa"/>^,<footnote ID="t3fb">Thrombotic microangiopathy.</footnote>^,<footnoteRef IDREF="t3fb"/>^,<footnoteRef IDREF="t3fb"/></td></tr></tbody></table>