Cases of thrombotic microangiopathy and thrombotic events were reported when on average a cumulative amount of >100 units/kg/24 hours of activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more to patients receiving emicizumab prophylaxis. Monitor for the development of thrombotic microangiopathy and thrombotic events if aPCC is administered. Discontinue aPCC and suspend dosing of emicizumab if symptoms occur.
Hemophilia A, prophylaxis: SUBQ:
Initial: 3 mg/kg once weekly for 4 weeks
Maintenance: 1.5 mg/kg once weekly or 3 mg/kg once every 2 weeks or 6 mg/kg once every 4 weeks
Note: Prophylactic use of bypassing agents should be discontinued the day before starting therapy. Prophylactic use of FVIII may be continued during the first week of therapy.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling.
CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer's labeling.
Severe impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
(For additional information see "Emicizumab: Pediatric drug information")
Hemophilia A, prophylaxis: Note: Prophylactic use of bypassing agents should be discontinued the day before starting therapy. Prophylactic use of FVIII may be continued during the first week of therapy.
Infants, Children, and Adolescents:
Initial loading dose: SubQ: 3 mg/kg once weekly for first 4 weeks (4 doses)
Maintenance therapy: Note: Multiple regimens available, and selection should be based on health care provider preferences and increased patient adherence. SubQ: 1.5 mg/kg once weekly or 3 mg/kg once every 2 weeks or 6 mg/kg once every 4 weeks
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling; the pharmacokinetics of emicizumab were not shown to be altered in patients with mild (CrCl 60 to 89 mL/minute) and moderate (CrCl 30 to 59 mL/minute) renal impairment.
There are no dosage adjustments provided in the manufacturer's labeling; the pharmacokinetics of emicizumab were not shown to be altered in patients with mild (total bilirubin 1 to 1.5 times ULN) and moderate (total bilirubin 1.5 to 3 times ULN) hepatic impairment.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Subcutaneous [preservative free]:
Hemlibra: Emicizumab-kxwh 30 mg/1 mL (1 mL); Emicizumab-kxwh 150 mg/1 mL (1 mL); Emicizumab-kxwh 60 mg/0.4 mL (0.4 mL); Emicizumab-kxwh 105 mg/0.7 mL (0.7 mL)
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Subcutaneous:
Hemlibra: 30 mg/mL (1 mL); 60 mg/0.4 mL (0.4 mL); 105 mg/0.7 mL (0.7 mL); 150 mg/mL (1 mL)
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Hemlibra: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761083s011lbl.pdf#page=21
SUBQ: For SUBQ administration. Do not shake. Use an 18-gauge transfer needle containing a 5-micron filter to withdraw dose and a 26-gauge injection needle (acceptable range: 25 to 27 gauge) with a 3/8- to ½-inch needle to administer dose. Administer immediately after removal from vial. Administer doses up to 1 mL with a 1 mL syringe and doses >1 mL and up to 2 mL with a 2 or 3 mL syringe. Rotate injection sites (upper outer arms, thighs, or any quadrant of abdomen). Do not inject into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact. Patient may self-inject, or the patient's caregiver may administer; however, only a health care provider should administer in the upper outer arm. Self-administration is not recommended for children <7 years of age.
Refer to product information for preparation and additional administration techniques. Do not use different vials of different concentrations when combining vials to administer prescribed dose.
SubQ: For SubQ administration. Do not shake. Administer immediately after removal of dose from vial. Use an 18-gauge transfer needle containing a 5-micron filter to withdraw dose and a 26-gauge injection needle (acceptable range: 25 to 27 gauge) with a 3/8- to 1/2-inch needle to administer dose. Administer doses up to 1 mL with a 1 mL syringe and doses >1 mL and up to 2 mL with a 2 or 3 mL syringe. Rotate injection sites (upper outer arms, thighs, or any quadrant of abdomen). Do not inject into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.
Note: Patient may self-inject or the patient's caregiver may administer after training; however, only a health care provider or caregiver should administer in the upper outer arm. Self-administration is not recommended for patients <7 years of age.
Refer to product information for preparation and additional administration techniques. Do not use different vials of different concentrations when combining vials to administer prescribed dose.
Hemophilia A, prophylaxis: Routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A (congenital factor VIII deficiency) with or without factor VIII inhibitors
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in pediatric patients and adults.
>10%:
Local: Erythema at injection site (11%), injection site reaction (22%, including bruising at injection site, discomfort at injection site, hematoma at injection site, induration at injection site, injection site pruritus, rash at injection site, swelling at injection site, urticaria at injection site, warm sensation at injection site)
Nervous system: Headache (15%)
Neuromuscular & skeletal: Arthralgia (15%)
1% to 10%:
Dermatologic: Injection site pruritus (4%)
Gastrointestinal: Diarrhea (6%)
Immunologic: Antibody development (5%; neutralizing: 3%)
Local: Pain at injection site (4%)
Miscellaneous: Fever (6%)
<1%: Rhabdomyolysis
Frequency not defined:
Cardiovascular: Superficial thrombophlebitis
Dermatologic: Skin necrosis
Hematologic & oncologic: Thrombotic microangiopathy
There are no contraindications listed in the US manufacturer's labeling.
Canadian labeling: Hypersensitivity to emicizumab or any component of the formulation.
Concerns related to adverse effects:
• Antibody formation: Antibody formation may occur but is rarely associated with a decrease in emicizumab plasma concentrations or a decrease in efficacy. If clinical signs of loss of efficacy (eg, increase in breakthrough bleeding events) occur, consider a change in therapy if neutralizing anti-emicizumab antibodies are suspected.
• Thrombotic microangiopathy and thromboembolism: Patients presented with thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury, without severe deficiencies in ADAMTS13 activity; improvement of thrombotic microangiopathy and thromboembolism was seen within 1 week and 1 month, respectively, following discontinuation of activated prothrombin complex concentrate (aPCC). The potential for an interaction with aPCC may persist for up to 6 months after the last dose of emicizumab due to the long half-life of emicizumab. If these complications occur, discontinue aPCC immediately and interrupt emicizumab; consider benefits vs risks of resuming emicizumab following complete resolution of thrombotic microangiopathy and thrombotic events.
None known.
Anti-inhibitor Coagulant Complex (Human): Emicizumab may enhance the thrombogenic effect of Anti-inhibitor Coagulant Complex (Human). Risk C: Monitor therapy
Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Patients who could become pregnant should use effective contraception during therapy.
Animal reproduction studies have not been conducted.
Emicizumab is a humanized monoclonal antibody (IgG4). Potential placental transfer of human IgG is dependent upon the IgG subclass and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009).
Therapies other than emicizumab are currently recommended for the management of hemophilia A in pregnant patients (WFH [Srivastava 2020]).
It is not known if emicizumab is present in breast milk. However, emicizumab is a humanized monoclonal immunoglobulin; endogenous IgG is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
Monitor for thrombotic microangiopathy and thrombotic events if aPCC is administered with emicizumab.
Monitor factor activity using single factor assays utilizing chromogenic or immuno-based methods. Chromogenic FVIII activity tests may be manufactured with either human or bovine coagulation proteins; human coagulation factors assays may overestimate the clinical hemostatic potential of emicizumab; however, bovine coagulation factors assays are insensitive to emicizumab (no activity measured) and can be used to monitor endogenous or infused FVIII activity, or to measure anti-FVIII inhibitors. Emicizumab will produce a false negative result in clotting-based Bethesda assays for functional inhibition of FVIII; a chromogenic Bethesda assay utilizing a bovine-based FVIII chromogenic test that is insensitive to emicizumab may be used. Due to the long half-life of emicizumab, effects on coagulation assays may persist ≤6 months after the last dose.
For patients with suspected neutralizing antibody formation to emicizumab, measure emicizumab levels using a modified one-stage assay including an additional predilution step of test plasma and assay calibration with emicizumab calibrators (WFH 2020).
Classification of hemophilia; normal is defined as 100% factor VIII (WFH [Srivastava 2020])
Severe: Factor level <1% of normal
Moderate: Factor level 1% to 5% of normal
Mild: Factor level >5% to <40% of normal
Emicizumab, a humanized monoclonal modified immunoglobulin G4 (IgG4) antibody with a bispecific factor IXa- and factor X-directed antibody, bridges activated factor IX and factor X to restore the function of missing activated factor VIII that is needed for effective hemostasis. Emicizumab has no structural relationship or sequence homology to FVIII and, therefore, does not induce or enhance the development of direct inhibitors to FVIII.
Note: Pharmacokinetic parameters were not influenced by age and similar in pediatric and adult patients (1 to 77 years of age).
Distribution: Vd: 10.4 L
Bioavailability: SubQ: 80.4% to 93.1%
Half-life elimination: 26.9 ± 9.1 days
Body weight: Clearance and volume of distribution increase with increasing body weight (9 kg to 156 kg). Dosing in mg/kg provides similar emicizumab exposure across body weight range.
Solution (Hemlibra Subcutaneous)
30 mg/mL (per mL): $3,789.60
60 mg/0.4 mL (per 0.4 mL): $7,579.20
105 mg/0.7 mL (per 0.7 mL): $13,263.61
150 mg/mL (per mL): $18,948.01
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