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  • CLASSES

    Other Hemostatics

    BOXED WARNING

    Thromboembolism

    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. 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]

    DEA CLASS

    Rx

    DESCRIPTION

    Bispecific factor IXa and factor X directed humanized monoclonal antibody
    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
    Associated with thrombotic microangiopathy and thrombotic events when used with more than 100 units/kg/24 hours of activated prothrombin complex concentrate (aPCC)

    COMMON BRAND NAMES

    Hemlibra

    HOW SUPPLIED

    Hemlibra Subcutaneous Inj Sol: 0.4mL, 0.7mL, 1mL, 30mg, 60mg, 105mg, 150mg

    DOSAGE & INDICATIONS

    For routine bleeding 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.
    Subcutaneous dosage
    Adults

    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]

    Infants, Children, and Adolescents

    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]

    Neonates

    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]

    MAXIMUM DOSAGE

    Adults

    3 mg/kg/week subcutaneously; maintenance doses up to 6 mg/kg/DOSE may be given every 4 weeks.

    Geriatric

    3 mg/kg/week subcutaneously; maintenance doses up to 6 mg/kg/DOSE may be given every 4 weeks.

    Adolescents

    3 mg/kg/week subcutaneously; maintenance doses up to 6 mg/kg/DOSE may be given every 4 weeks.

    Children

    3 mg/kg/week subcutaneously; maintenance doses up to 6 mg/kg/DOSE may be given every 4 weeks.

    Infants

    3 mg/kg/week subcutaneously; maintenance doses up to 6 mg/kg/DOSE may be given every 4 weeks.

    Neonates

    3 mg/kg/week subcutaneously; maintenance doses up to 6 mg/kg/DOSE may be given every 4 weeks.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Emicizumab is a colorless to slightly yellow solution. Do not use if particulate matter is visible or product is discolored.
    Administer a missed dose as soon as possible and then resume the usual dosing schedule. Do not administer 2 doses on the same day to make up for a missed dose.[62628]

    Subcutaneous Administration

    After proper training in subcutaneous injection technique, a patient may self-inject, or the patient's caregiver may administer emicizumab if a healthcare provider determines that it is appropriate. Self-administration is not recommended for children younger than 7 years.
    Do not combine emicizumab vials of different concentrations in a single injection.
    Allow the vial(s) to warm to room temperature for 15 minutes before preparing the injection. Do not warm the vial by any other way.
    Do not shake.
    Administer emicizumab with a sterile, for injection only, single-use, latex-free, nonpyrogenic, transparent polypropylene or polycarbonate syringe with Luer-Lock tip. Administer doses up to 1 mL in a 1 mL syringe with 0.01 mL graduation. Administer doses more than 1 mL and up to 2 mL in a 2 or 3 mL syringe with 0.1 mL graduation. Doses more than 2 mL will need to be administered in multiple injections.
    Use a sterile, 18 gauge, 1 to 1.5 inch, single bevel or semi-blunted tip, single-use, latex-free, nonpyrogenic, stainless steel transfer needle with Luer-Lock connection. Push and twist the transfer needle clockwise on to the syringe until it is fully attached.
    Slowly pull back on the plunger and draw air into the syringe that is the same amount as the prescribed dose.
    Hold the syringe by the barrel with the transfer needle pointing up. Pull the transfer needle cap straight off and set aside.
    With the vial on a flat surface, insert the transfer needle and syringe straight down into the center of the vial stopper.
    Keep the needle in the vial and turn the vial upside down.
    Push on the plunger to inject the air from the syringe above the medicine. Keep finger pressed down on the syringe plunger. Do not inject air into the medicine.
    Slide the tip of the needle down so that it is within the medicine. Slowly pull back the plunger to fill the syringe with more than the amount needed for the prescribed dose.
    Keep the needle in the vial and check the syringe for larger air bubbles. Remove any larger air bubbles by gently tapping the syringe barrel until the air bubbles rise to the top of the syringe. Move the tip of the needle above the medicine and slowly push the plunger up to expel the air bubbles out of the syringe.
    If the amount of emicizumab in the syringe is now at or below the prescribed dose, move the tip of the needle to within the medicine, and slowly pull back the plunger until the syringe has more than the amount of emicizumab needed for the prescribed dose.
    Remove the syringe and transfer needle from the vial. Using 1 hand, slide the transfer needle into the cap and scoop upwards to cover the needle. Once the needle is covered, push the transfer needle cap towards the syringe to fully attach it with 1 hand.
    Remove the transfer needle from the syringe by twisting counter-clockwise and gently pulling.
    If more than 1 vial is needed to get the total prescribed dose, remove the syringe and transfer needle from the first vial. Remove the transfer needle from the syringe, attach a new transfer needle, and access a new vial as described above.
    Use a sterile, 26 gauge (acceptable range: 25 to 27 gauge), three-eighths inch (preferable) to one-half inch (maximal) length, single-use, latex-free, nonpyrogenic, stainless steel injection needle with Luer-Lock connection. Push and twist the injection needle clockwise onto the syringe until it is fully attached.
    Move the safety shield away from the needle and towards the syringe barrel. Pull the injection needle cap away from the syringe.
    Slowly push the plunger to the prescribed dose.
    Inject the dose subcutaneously immediately after withdrawing into the syringe.
    Administer each injection at a different location (i.e., upper outer arms, thighs, or abdomen) than the previous injection. Do not inject into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact. Administration into the upper outer arm should only be performed by a caregiver or healthcare provider.
    Pinch the injection site and fully insert the needle at a 45- or 90-degree angle. Do not hold or push on the plunger while inserting the needle.
    Hold the position of the syringe and let go of the pinched injection site.
    Inject the dose by gently pushing the plunger all the way down.
    Remove the needle and syringe from the injection site at the same angle as was inserted.
    Move the safety shield forward 90 degrees, away from the syringe barrel. Hold the syringe with 1 hand and press the safety shield down against a flat surface until you hear a click.
    Do not rub the injection site after injection.
    Storage: Discard any unused emicizumab remaining in the single-dose vial. Unopened vials may be stored out of the refrigerator and then returned to the refrigerator. Do not store out of the refrigerator at a temperature of more than 30 degrees C (86 degrees F) or for more than 7 days.[62628]

    STORAGE

    Hemlibra:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store and dispense in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Thromboembolism

    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. 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

    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.

    Pregnancy

    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.

    Breast-feeding

    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.

    Contraception requirements, reproductive risk

    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.

    ADVERSE REACTIONS

    Severe

    thrombotic microangiopathy / Delayed / 0.8-8.1
    rhabdomyolysis / Delayed / 0-1.0
    hemolytic anemia / Delayed / Incidence not known
    thromboembolism / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known

    Moderate

    erythema / Early / 11.0-11.0
    thrombocytopenia / Delayed / Incidence not known
    hematoma / Early / Incidence not known
    antibody formation / Delayed / Incidence not known

    Mild

    injection site reaction / Rapid / 22.0-22.0
    headache / Early / 15.0-15.0
    arthralgia / Delayed / 15.0-15.0
    fever / Early / 6.0-6.0
    diarrhea / Early / 6.0-6.0
    pruritus / Rapid / 4.0-4.0
    urticaria / Rapid / Incidence not known
    rash / Early / Incidence not known

    DRUG INTERACTIONS

    Antihemophilic Factor, AHF, Factor VIII: (Moderate) There is a possibility for hypercoagulability with concomitant use of emicizumab and antihemophilic factor, AHF, factor VIII based on preclinical experiments.
    Antihemophilic Factor, Fc Fusion Protein, Recombinant: (Moderate) There is a possibility for hypercoagulability with concomitant use of emicizumab and antihemophilic factor VIII (recombinant) based on preclinical experiments.
    Antihemophilic Factor, Porcine Sequence, Recombinant: (Moderate) There is a possibility for hypercoagulability with concomitant use of emicizumab and antihemophilic factor VIII (recombinant) based on preclinical experiments.
    Anti-inhibitor Coagulant Complex: (Moderate) Consider the benefits and risks if anti-inhibitor coagulant complex (human), also known as activated prothrombin complex concentrate (aPCC), must be used in a patient receiving emicizumab. Monitor for the development of thrombotic microangiopathy (TMA) and thrombosis when administering aPCC. Discontinue aPCC and interrupt emicizumab administration if clinical symptoms or laboratory findings consistent with TMA or thrombosis occur, and manage as clinically indicated. Consider benefits and risks of resuming emicizumab after resolution of TMA or thrombosis on a case-by-case basis. TMA and thrombotic events have been reported when, on average, a cumulative amount of more than 100 units/kg/24 hours of aPCC was administered for 24 hours or more to patients receiving emicizumab.
    Factor VIIa, Recombinant: (Moderate) There is a possibility for hypercoagulability with concomitant use of emicizumab and factor VIIa (recombinant) based on preclinical experiments.

    PREGNANCY AND LACTATION

    Pregnancy

    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.

    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.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    Emicizumab 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]

    Subcutaneous Route

    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]