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Emicizumab
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General dosing information:
3 mg/kg/dose subcutaneously once weekly for the first 4 weeks, followed by a maintenance dose of 1.5 mg/kg/dose once every week, 3 mg/kg/dose once every 2 weeks, or 6 mg/kg/dose once every 4 weeks. Base maintenance dose selection on healthcare provider preference and patient adherence.[62628]
3 mg/kg/dose subcutaneously once weekly for the first 4 weeks, followed by a maintenance dose of 1.5 mg/kg/dose once every week, 3 mg/kg/dose once every 2 weeks, or 6 mg/kg/dose once every 4 weeks. Base maintenance dose selection on healthcare provider preference and patient adherence.[62628]
3 mg/kg/dose subcutaneously once weekly for the first 4 weeks, followed by a maintenance dose of 1.5 mg/kg/dose once every week, 3 mg/kg/dose once every 2 weeks, or 6 mg/kg/dose once every 4 weeks. Base maintenance dose selection on healthcare provider preference and patient adherence.[62628]
3 mg/kg/week subcutaneously; maintenance doses up to 6 mg/kg/DOSE may be given every 4 weeks.
3 mg/kg/week subcutaneously; maintenance doses up to 6 mg/kg/DOSE may be given every 4 weeks.
3 mg/kg/week subcutaneously; maintenance doses up to 6 mg/kg/DOSE may be given every 4 weeks.
3 mg/kg/week subcutaneously; maintenance doses up to 6 mg/kg/DOSE may be given every 4 weeks.
3 mg/kg/week subcutaneously; maintenance doses up to 6 mg/kg/DOSE may be given every 4 weeks.
3 mg/kg/week subcutaneously; maintenance doses up to 6 mg/kg/DOSE may be given every 4 weeks.
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
† Off-label indication
Emicizumab is a humanized monoclonal modified immunoglobulin G4 (IgG4) antibody with a bispecific antibody structure binding factor IXa and factor X used for routine prophylaxis of bleeding episodes in adult and pediatric patients with hemophilia A (congenital factor VIII deficiency) with or without factor VIII inhibitors. Emicizumab bridges factor IX and factor X to restore the function of missing factor VIII that is needed for effective hemostasis. In adults and adolescents with factor VIII inhibitors, emicizumab was associated with an 87% lower bleeding rate compared to those who did not receive treatment during clinical trials. In those without factor FVIII inhibitors, emicizumab prophylaxis resulted in a 96% to 97% reduction in bleeding rate. Interim data from a pediatric study of children younger than 11 years of age demonstrated a no bleed rate of 86.4% for patients treated with emicizumab over a median observation period of 29.6 weeks. Thrombotic microangiopathy and thrombotic events have been reported when, on average, a cumulative amount of more than 100 units/kg/24 hours of activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more to patients receiving emicizumab. The benefits and risks of coadministering aPCC with emicizumab must be carefully weighed.[62628] [62631]
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Thrombotic microangiopathy (TMA), thrombosis, and thromboembolism have been reported when, on average, a cumulative amount of more than 100 units/kg/24 hours of activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more to subjects receiving emicizumab. In clinical trials, TMA was reported in 0.8% (3/391) of subjects and in 8.1% (3/37) of subjects who received at least 1 dose of aPCC during emicizumab therapy. Subjects presented with thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury. Thrombotic events were reported in 0.5% (2/391) of subjects and in 5.4% (2/37) of subjects who received at least 1 dose of aPCC during emicizumab therapy. No thrombotic events required anticoagulation therapy. Evidence of improvement or resolution was seen within 1 week or 1 month of discontinuation of aPCC for TMA and thrombotic events, respectively. A single subject resumed emicizumab after resolution of TMA, and 1 subject resumed emicizumab after resolution of the thrombotic event. Consider the benefits and risks if aPCC must be used in a person receiving emicizumab. Monitor for the development of TMA and thrombotic events when administering aPCC. Discontinue aPCC and interrupt emicizumab therapy if clinical symptoms, imaging, or laboratory findings consistent with TMA or thromboembolism occur, and manage as clinically indicated. Consider benefits and risks of resuming emicizumab after resolution of TMA or thrombotic events on a case-by-case basis.[62628]
Injection site reaction was reported in 22% of subjects during clinical trials. Injection site reactions included bruising, discomfort, erythema, hematoma, induration, pain, pruritus, rash, urticaria, swelling, and warmth. All reactions were reported as mild to moderate in intensity and 93% resolved without treatment. The most commonly reported injection site reaction symptoms were erythema (11%), pruritus (4%), and pain (4%). Hypersensitivity reactions including rash, urticaria, and angioedema have been reported with postmarketing use.[62628]
Headache and fever were reported in 15% and 6% of subjects, respectively, receiving emicizumab during clinical trials.[62628]
Diarrhea was reported in 6% of subjects receiving emicizumab during clinical trials.[62628]
Arthralgia was reported in 15% of subjects receiving emicizumab during clinical trials.[62628]
Rhabdomyolysis was reported in 2 adults with asymptomatic elevations in serum creatinine kinase without associated renal or musculoskeletal symptoms. In both cases, the event occurred after an increase in physical activity.[62628]
Antibody formation was reported in 5.1% (34/668) of emicizumab-treated subjects during clinical trials; 2.7% (18/668) of subjects developed anti-emicizumab antibodies that were neutralizing in vitro. The presence of neutralizing antibodies may result in decreased emicizumab concentrations and a loss of drug efficacy. During clinical trials, decreased emicizumab concentrations were observed in 0.6% (4/668) of subjects. A single patient (1/668; 0.1%) developed neutralizing antibodies and had decreased emicizumab plasma concentrations with loss of efficacy after 5 weeks of treatment, and discontinued emicizumab treatment. Monitor for signs of loss of efficacy (e.g., increase in breakthrough bleeding). If observed, promptly assess the etiology and consider a change in treatment if neutralizing antibodies are suspected.[62628]
Thrombotic microangiopathy (TMA) and thromboembolism have been reported when, on average, a cumulative amount of more than 100 units/kg/24 hours of activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more to patients receiving emicizumab. Consider the benefits and risks if aPCC must be used in a patient receiving emicizumab. The potential for an interaction with aPCC may persist for up to 6 months after the last emicizumab dose, because of its long half-life. Monitor for the development of TMA and thromboembolism when administering aPCC. Discontinue aPCC and interrupt emicizumab administration if clinical symptoms or laboratory findings consistent with TMA or thromboembolism occur, and manage as clinically indicated. Evidence of improvement or resolution was seen within 1 week or 1 month of discontinuation of aPCC for TMA and thrombotic events, respectively. Consider benefits and risks of resuming emicizumab after resolution of TMA or thromboembolism on a case-by-case basis.[62628]
Laboratory test interference may occur in patients treated with emicizumab. Do not use intrinsic pathway clotting-based laboratory test results in patients treated with emicizumab to monitor emicizumab activity, determine dosing for factor replacement or anticoagulation, or measure factor VIII inhibitor titers. Emicizumab 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 activity. Coagulation laboratory tests based on the intrinsic clotting (i.e., aPTT) measure total clotting time including time needed for activation of FVIII to FVIIIa by thrombin. Intrinsic pathway-based tests will yield overly shortened clotting times with emicizumab, which does not require activation by thrombin. The overly shortened intrinsic clotting time will then disturb all single-factor assays based on aPTT. Effects on coagulation assays may persist for up to 6 months after the last dose of emicizumab. Single-factor assays using chromogenic or immuno-based methods are not affected by emicizumab and may be used to monitor coagulation parameters during emicizumab treatment.[62628]
There are no data regarding the use of emicizumab in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Animal reproduction studies have not been conducted. It is not known if emicizumab can cause fetal harm or can affect reproductive capacity. Use emicizumab during pregnancy only if the potential benefit for the mother outweighs the risk to the fetus.[62628]
There are no data regarding the presence of emicizumab in human milk, the effects on the breast-fed child, or the effects on milk production. Human IgG is present in human milk, and emicizumab is a humanized monoclonal modified immunoglobulin (IgG4) antibody. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for emicizumab and any potential adverse effects on the breast-fed child from emicizumab or the underlying maternal condition.[62628]
It is not known if the use of emicizumab during pregnancy is associated with reproductive risk or fetal harm. Discuss contraception requirements with the patient. Women of childbearing potential should use contraception while receiving emicizumab.[62628]
Emicizumab is a humanized monoclonal modified immunoglobulin G4 (IgG4) antibody with a bispecific antibody structure binding factor IXa and factor X. Emicizumab bridges factor IXa and factor X to restore the function of missing activated factor VIII, which is needed for effective hemostasis. Emicizumab has no structural relationship or sequence homology to factor VIII, and therefore, does not induce or enhance the development of direct inhibitors to factor VIII.[62628]
Revision Date: 03/01/2024, 11:17:35 PMEmicizumab is administered subcutaneously. After multiple subcutaneous administrations of a loading dose of 3 mg/kg once weekly for the first 4 weeks in hemophilia A patients, the mean (+/- SD) trough plasma concentrations of emicizumab increased to 52.6 +/- 13.6 mcg/mL at week 5. Sustained mean trough concentrations were 51.2 +/- 15.2 mcg/mL for patients receiving maintenance doses of 1.5 mg/kg once weekly, 46.9 +/- 14.8 mcg/mL for those receiving 3 mg/kg once every 2 weeks, and 38.5 +/- 14.2 mcg/mL for those receiving 6 mg/kg every 4 weeks. The mean apparent volume of distribution (% CV) for emicizumab was 10.4 L (26%). The mean apparent clearance of emicizumab was 0.27 L/day (28.4%), and the mean elimination apparent half-life (+/- SD) was 26.9 +/- 9.1 days.[62628]
The absolute bioavailability of emicizumab after subcutaneous administration of 1 mg/kg was between 80.4% and 93.1%. Similar pharmacokinetic properties were observed after subcutaneous administration in the abdomen, upper arm, and thigh. The mean (+/- SD) absorption half-life for emicizumab was 1.6 +/- 1 day. Cmax and AUC at steady state were 55.1 +/- 15.9 mcg/mL and 376 +/- 109 mcg/mL x day for patients recieving a maintenaince dose of 1.5 mg/kg once every week, 58.3 +/- 16.4 mcg/mL and 752 +/- 218 mcg/mL x day for those recieving 3 mg/kg once every 2 weeks, and 67 +/- 17.7 mcg/mL and 1,503 +/- 437 mcg/mL x day for those receiving 6 mg/kg once every 4 weeks.[62628]
The pharmacokinetics of emicizumab are not influenced by mild hepatic impairment (total bilirubin 1 to 1.5 times or less the upper limit of normal (ULN) and any aspartate transaminase (AST) concentration) or moderate hepatic impairment (total bilirubin 1.5 to 3 times or less the ULN and any AST concentration). Emicizumab has not been studied in patients with severe hepatic impairment.[62628]
The pharmacokinetics of emicizumab are not influenced by mild (CrCl of 60 to 89 mL/minute) or moderate (CrCl of 30 to 59 mL/minute) renal impairment. Emicizumab has not been studied in patients with severe renal impairment[62628]
The pharmacokinetics of emicizumab are not influenced by age in those 1 year and older. In patients younger than 6 months, the predicted concentrations of emicizumab were 19% to 33% lower than older patients, especially with a maintenance dose of 3 mg/kg once every 2 weeks or 6 mg/kg once every 4 weeks. Apparent clearance and Vd increase with increasing body weight (9 to 156 kg); however, weight-based dosing provides similar exposures.[62628]
The pharmacokinetics of emicizumab are not influenced by age (1 to 77 years).[62628]
The pharmacokinetics of emicizumab are not influenced by race.[62628]
Apparent clearance and Vd of emicizumab increased with increasing weight (9 to 156 kg). Dosing in mg/kg provides similar emicizumab exposure across body weight range.[62628]
There are no data regarding the use of emicizumab in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Animal reproduction studies have not been conducted. It is not known if emicizumab can cause fetal harm or can affect reproductive capacity. Use emicizumab during pregnancy only if the potential benefit for the mother outweighs the risk to the fetus.[62628]
There are no data regarding the presence of emicizumab in human milk, the effects on the breast-fed child, or the effects on milk production. Human IgG is present in human milk, and emicizumab is a humanized monoclonal modified immunoglobulin (IgG4) antibody. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for emicizumab and any potential adverse effects on the breast-fed child from emicizumab or the underlying maternal condition.[62628]
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