Introduction

Humanized bispecific monoclonal antibody that binds to factor IX/IXa and factor X/Xa.

Uses for Emicizumab-kxwh (Systemic)

Hemophilia A

Routine prophylaxis to prevent or reduce frequency of bleeding episodes in adults and pediatric patients (neonates and older) with hemophilia A (congenital factor VIII deficiency; classic hemophilia) with or without factor VIII inhibitors. Designated an orphan drug by FDA for this use.

Not indicated for treatment of acute bleeding episodes and breakthrough bleeding. For breakthrough bleeding in patients without inhibitors, clotting factor VIII concentrates should be used. For patients with inhibitors who are experiencing acute bleeds, treatment with recombinant activated factor VIIa (rFVIIa) is recommended. Use of activated prothrombin complex concentrate (aPCC) generally should be avoided.

The World Federation of Hemophilia and Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation publishes guidelines on the management of hemophilia. MASAC guidelines provide recommendations on use and management of emicizumab in addition to acute bleed management in patients receiving the drug.

Prophylactic therapy with clotting factor concentrates or other non-factor replacement product (e.g., emicizumab) is considered the current standard of care for patients with severe hemophilia A (factor VIII activity <1%). Prophylaxis also may be considered in patients with mild or moderate hemophilia A depending on their risk of bleeding.

Based on the current evidence, MASAC states that patients with inhibitors who experience spontaneous or traumatic bleeding episodes, whether treated with episodic or prophylactic bypassing agent, will likely derive significant benefit from emicizumab prophylaxis; such therapy should be considered first-line. Patients receiving prophylaxis with bypassing agents who have few bleeding episodes could consider switching to emicizumab prophylaxis based on overall cost effectiveness, reduced administration burden, and overall superior hemostatic efficacy.

Individualize specific treatment strategy based on patient's age at the time of prophylaxis initiation, bleeding phenotype, joint status, individual pharmacokinetics, lifestyle, and preference for choice of therapy.

Emicizumab-kxwh (Systemic) Dosage and Administration

General

Pretreatment Screening

• Assess the ability of the patient and/or caregiver to administer emicizumab. Patient self-administration is not recommended for children <7 years of age.

Patient Monitoring

• If a patient on emicizumab receives activated prothrombin complex concentrate (aPCC), monitor for thrombotic microangiopathy and thrombotic events.

• Note that emicizumab interferes with many clotting-based laboratory tests. Specific test types are recommended for monitoring coagulation status in patients receiving emicizumab.

Dispensing and Administration Precautions

• Do not combine different concentrations of emicizumab into a single injection.

Other General Considerations

• Emicizumab is intended for use under the guidance and supervision of a clinician, but may be self-administered if the clinician determines that the patient and/or their caregiver is competent to prepare and safely administer the drug after appropriate training and with medical follow-up as necessary.

• Discontinue bypassing agents used for prophylaxis on the day prior to starting emicizumab.

• Prophylactic use of factor VIII may be continued through the first week of emicizumab.

Administration

Sub-Q Injection

Administer by sub-Q injection into the abdomen, anterior thigh, or outer upper arm; may be self-administered after appropriate training.

Available in single-dose, preservative-free vials containing 30 mg/mL, 60 mg/0.4 mL, 105 mg/0.7 mL, or 150 mg/mL of solution. Multiple vials may be required to achieve the prescribed dose; do not combine vials containing different concentrations to make a single dose.

Materials necessary for appropriate preparation and sub-Q administration of emicizumab include a syringe (1-mL syringe for dose volumes up to 1 mL; 2- or 3-mL syringe for dose volumes greater than 1 mL and up to 2 mL); an 18-gauge transfer needle with 5-micron filter; and a 25-, 26-, or 27-gauge injection needle. These materials are not packaged with emicizumab and must be prescribed separately.

Administer dose volumes up to 1 mL using a 1-mL syringe; administer dose volumes greater than 1 mL up to 2 mL with a 2- or 3-mL syringe; dose volumes greater than 2 mL require more than 1 injection.

Use different site with each injection or separate injections by at least 1 inch if the same administration site used.

Do not inject into areas of the skin that are tender, bruised, red, hard, or not intact; avoid scars, moles, and area within 2 inches around navel.

Prior to administration, warm vials at room temperature away from direct sunlight for 15 minutes; do not use other methods to warm the drug.

Emicizumab solution should appear colorless to slightly yellow; do not use if it is cloudy, discolored, or contains particles.

Dosage

Pediatric Patients

Hemophilia A

Sub-Q

Loading dose regimen of 3 mg/kg once weekly for the first 4 weeks followed by maintenance dosage regimen.

Maintenance dosage regimen options (select appropriate regimen based on clinician preference and consideration of regimens that may increase patient adherence):

• 1.5 mg/kg once weekly

• 3 mg/kg once every 2 weeks

• 6 mg/kg once every 4 weeks

Administer missed doses as soon as possible, then resume usual schedule; do not administer 2 doses on same day.

Adults

Hemophilia A

Sub-Q

Loading dose regimen of 3 mg/kg once weekly for the first 4 weeks followed by maintenance dosage regimen.

Maintenance dosage regimen options (select appropriate regimen based on clinician preference and consideration of regimens that may increase patient adherence):

• 1.5 mg/kg once weekly

• 3 mg/kg once every 2 weeks

• 6 mg/kg once every 4 weeks

Administer missed doses as soon as possible, then resume usual schedule; do not administer 2 doses on same day.

Special Populations

Hepatic Impairment

Manufacturer makes no specific dosage recommendations.

Renal Impairment

Manufacturer makes no specific dosage recommendations.

Geriatric Use

Manufacturer makes no specific dosage recommendations.

Contraindications

• None.

Warnings/Precautions

Warnings

Thrombotic Microangiopathy Associated with Emicizumab-kxwh and aPCC

Cases of thrombotic microangiopathy reported in patients receiving emicizumab and aPCC more frequently than in patients receiving emicizumab alone in clinical trials. (See Boxed Warning.)

Clinical presentation included thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury. Improvement noted within 1 week after discontinuing aPCC with supportive therapy alone or in conjunction with plasmapheresis.

Consider risks and benefits before using aPCC in patients receiving emicizumab. MASAC states that administration of aPCCs should be discontinued at least 24 hours prior to initiation of emicizumab. Monitor for thrombotic microangiopathy and thrombotic events if used together. Potential for interaction between aPCC and emicizumab may persist up to 6 months after last emicizumab dose; consider risks of using aPCC during this time period.

Discontinue aPCC and withhold emicizumab if symptoms or laboratory findings consistent with thrombotic microangiopathy occur; manage as clinically indicated. Consider risks and benefits of resuming emicizumab therapy on a patient-specific basis following complete resolution.

Thromboembolism Associated with Emicizumab-kxwh and aPCC

Cases of thromboembolism reported in patients receiving emicizumab and aPCC more frequently than in patients receiving emicizumab alone. (See Boxed Warning.) No events required anticoagulation therapy.

Improvement or resolution noted within one month after discontinuing aPCC.

Potential for interaction between aPCC and emicizumab may persist up to 6 months after last emicizumab dose.

Consider risks and benefits before using aPCC in patient receiving emicizumab. MASAC states that administration of aPCCs should be discontinued at least 24 hours prior to initiation of emicizumab. Monitor for thromboembolism if used together. Potential for interaction between aPCC and emicizumab may persist up to 6 months after last emicizumab dose; consider risks of using aPCC during this time period.

Discontinue aPCC and withhold emicizumab if symptoms, imaging, or laboratory findings consistent with thromboembolism occur; manage as clinically indicated. Consider risks and benefits of resuming emicizumab therapy on a patient-specific basis following complete resolution.

Other Warnings/Precautions

Laboratory Coagulation Test Interference

Emicizumab interferes with coagulation tests that are based on the intrinsic clotting pathway. Do not use laboratory tests based on the intrinsic clotting pathway to monitor emicizumab, determine dosing for factor replacement or anticoagulation, or measure factor VIII inhibitor titers in patients receiving emicizumab.

Affected tests include aPTT, clotting-based Bethesda assays for factor VIII inhibitor titers, one-stage aPTT-based single-factor assays, aPTT-based activated protein C resistance (APC-R), and activated clotting time (ACT).

Unaffected tests include bovine chromogenic Bethesda assays for factor VIII inhibitor titers, thrombin time (TT), one-stage prothrombin time-based single-factor assays, chromogenic-based single-factor assays other than factor VIII immune-based assays (i.e., ELISA, turbidimetric methods), genetic tests of coagulation factors (e.g., factor V Leiden, prothrombin 20210).

Immunogenicity

Anti-emicizumab-kxwh antibodies (including neutralizing antibodies) reported in patients receiving the drug. If signs of loss of efficacy develop, promptly assess etiology and consider a change in treatment if neutralizing antibodies are suspected.

Specific Populations

Pregnancy

No available data; use only if potential benefit to the mother outweighs potential risk to the fetus.

Lactation

Not known whether emicizumab is distributed into milk, affects nursing infants, or affects milk production. Human IgG is present in human milk. Consider developmental and health benefits of breastfeeding along with the mother's clinical need for emicizumab and any potential adverse effects on the breastfed child or from the underlying maternal condition.

Females and Males of Reproductive Potential

Use of contraception during emicizumab therapy recommended for women of childbearing potential.

Pediatric Use

Clinical efficacy and safety established in clinical trials for pediatric patients as young as 1 month of age.

No differences in efficacy noted between pediatric patients in younger and older age groups. Adverse effect profile generally similar between adults and pediatric patients.

Trough concentrations comparable between adults and pediatric patients older than 6 months of age; lower concentrations anticipated in patients younger than 6 months of age.

Geriatric Use

Insufficient clinical trial experience to detect a difference in response for patients 65 years of age and older compared with younger patients.

Hepatic Impairment

Mild (total bilirubin 1 time but not >1.5 times the ULN with any AST level) or moderate (total bilirubin 1.5 times but not >3 times the ULN with any AST level) hepatic impairment: No clinically important effect.

Severe hepatic impairment: Not studied.

Renal Impairment

Mild or moderate renal impairment (Cl_cr 30–89 mL/minute): No clinically important effect.

Severe renal impairment: Not studied.

Common Adverse Effects

Injection site reactions, headache, arthralgia.

General

Pretreatment Screening

• Assess the ability of the patient and/or caregiver to administer emicizumab. Patient self-administration is not recommended for children <7 years of age.

Patient Monitoring

• If a patient on emicizumab receives activated prothrombin complex concentrate (aPCC), monitor for thrombotic microangiopathy and thrombotic events.

• Note that emicizumab interferes with many clotting-based laboratory tests. Specific test types are recommended for monitoring coagulation status in patients receiving emicizumab.

Dispensing and Administration Precautions

• Do not combine different concentrations of emicizumab into a single injection.

Other General Considerations

• Emicizumab is intended for use under the guidance and supervision of a clinician, but may be self-administered if the clinician determines that the patient and/or their caregiver is competent to prepare and safely administer the drug after appropriate training and with medical follow-up as necessary.

• Discontinue bypassing agents used for prophylaxis on the day prior to starting emicizumab.

• Prophylactic use of factor VIII may be continued through the first week of emicizumab.

Administration

Sub-Q Injection

Administer by sub-Q injection into the abdomen, anterior thigh, or outer upper arm; may be self-administered after appropriate training.

Available in single-dose, preservative-free vials containing 30 mg/mL, 60 mg/0.4 mL, 105 mg/0.7 mL, or 150 mg/mL of solution. Multiple vials may be required to achieve the prescribed dose; do not combine vials containing different concentrations to make a single dose.

Materials necessary for appropriate preparation and sub-Q administration of emicizumab include a syringe (1-mL syringe for dose volumes up to 1 mL; 2- or 3-mL syringe for dose volumes greater than 1 mL and up to 2 mL); an 18-gauge transfer needle with 5-micron filter; and a 25-, 26-, or 27-gauge injection needle. These materials are not packaged with emicizumab and must be prescribed separately.

Administer dose volumes up to 1 mL using a 1-mL syringe; administer dose volumes greater than 1 mL up to 2 mL with a 2- or 3-mL syringe; dose volumes greater than 2 mL require more than 1 injection.

Use different site with each injection or separate injections by at least 1 inch if the same administration site used.

Do not inject into areas of the skin that are tender, bruised, red, hard, or not intact; avoid scars, moles, and area within 2 inches around navel.

Prior to administration, warm vials at room temperature away from direct sunlight for 15 minutes; do not use other methods to warm the drug.

Emicizumab solution should appear colorless to slightly yellow; do not use if it is cloudy, discolored, or contains particles.

Dosage

Pediatric Patients

Hemophilia A

Sub-Q

Loading dose regimen of 3 mg/kg once weekly for the first 4 weeks followed by maintenance dosage regimen.

Maintenance dosage regimen options (select appropriate regimen based on clinician preference and consideration of regimens that may increase patient adherence):

• 1.5 mg/kg once weekly

• 3 mg/kg once every 2 weeks

• 6 mg/kg once every 4 weeks

Administer missed doses as soon as possible, then resume usual schedule; do not administer 2 doses on same day.

Adults

Hemophilia A

Sub-Q

Loading dose regimen of 3 mg/kg once weekly for the first 4 weeks followed by maintenance dosage regimen.

Maintenance dosage regimen options (select appropriate regimen based on clinician preference and consideration of regimens that may increase patient adherence):

• 1.5 mg/kg once weekly

• 3 mg/kg once every 2 weeks

• 6 mg/kg once every 4 weeks

Administer missed doses as soon as possible, then resume usual schedule; do not administer 2 doses on same day.

Special Populations

Hepatic Impairment

Manufacturer makes no specific dosage recommendations.

Renal Impairment

Manufacturer makes no specific dosage recommendations.

Geriatric Use

Manufacturer makes no specific dosage recommendations.

No drug-drug interaction studies conducted.

Drugs Affecting Coagulation

Interaction with aPCC may produce hypercoagulable state with risk of thrombotic microangiopathy or thromboembolism. Interaction may persist for up to 6 months following last dose of emicizumab.

Consider risks and benefits of aPCC before using in patients receiving emicizumab. Monitor for thrombotic microangiopathy and thrombotic events if aPCC is used. Discontinue aPCC and withhold emicizumab if symptoms, imaging, or laboratory findings consistent with either event occur.

Coagulation Tests and Factor Assays Based on Intrinsic Clotting

Interaction with coagulation tests based on the intrinsic clotting pathway. Interaction may persist for up to 6 months following last dose of emicizumab.

Emicizumab does not affect coagulation tests based on other pathways (e.g., single-factor assays that use chromogenic or immune-based methods, assays based on bovine coagulation proteins).

Emicizumab will produce a false-negative result on clotting-based Bethesda assays for functional inhibition of factor VIII.

Specific Drugs and Laboratory Tests