Emicizumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yashasvi Aryaputra[2];
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Black Box Warning
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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 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.
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Overview
Emicizumab is a Acetylcholine release inhibitor, Adrenergic receptor agonist that is FDA approved for the (type of indication of drug) of a list of indications, separated by commas.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include a list of adverse reactions, separated by commas..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Condition 1
- Dosing Information
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Condition 2
- Dosing Information
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Off-Label Use and Dosage (Adult)
Guideline-Supported Use
Condition 1
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
Condition 2
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
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Non–Guideline-Supported Use
Condition 1
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Condition 2
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Condition 3
- Dosing Information
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Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Condition 1
- Dosing Information
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Condition 2
- Dosing Information
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Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
Condition 1
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
Condition 2
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
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Non–Guideline-Supported Use
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Condition 2
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Condition 3
- Dosing Information
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Contraindications
- None
Warnings
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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 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.
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Conidition 1
(Description)
Conidition 2
(Description)
Conidition 3
(Description)
Adverse Reactions
Clinical Trials Experience
Central Nervous System
- (list/description of adverse reactions)
Cardiovascular
- (list/description of adverse reactions)
Respiratory
- (list/description of adverse reactions)
Gastrointestinal
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Hypersensitive Reactions
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Miscellaneous
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Condition 2
Central Nervous System
- (list/description of adverse reactions)
Cardiovascular
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Respiratory
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Gastrointestinal
- (list/description of adverse reactions)
Hypersensitive Reactions
- (list/description of adverse reactions)
Miscellaneous
- (list/description of adverse reactions)
Postmarketing Experience
(Description)
Drug Interactions
- Hypercoagulability with Concomitant Use of aPCC, rFVIIa, or FVIII
- Drug-Laboratory Test Interactions
Hypercoagulability with Concomitant Use of aPCC, rFVIIa, or FVIII
- Clinical experience suggests that a drug interaction exists with HEMLIBRA and aPCC.
- There is a possibility for hypercoagulability with rFVIIa or FVIII with HEMLIBRA based on preclinical experiments.
Drug-Laboratory Test Interactions
- HEMLIBRA restores the tenase cofactor activity of missing activated factor VIII (FVIIIa). Coagulation laboratory tests based on intrinsic clotting (i.e., aPTT) measure the total clotting time including time needed for activation of FVIII to FVIIIa by thrombin. Such intrinsic pathway-based tests will yield overly shortened clotting times with HEMLIBRA, which does not require activation by thrombin. The overly shortened intrinsic clotting time will then disturb all single-factor assays based on aPTT, such as the one-stage FVIII activity assay; however, single-factor assays utilizing chromogenic or immuno-based methods are unaffected by HEMLIBRA and may be used to monitor coagulation parameters during treatment, with specific considerations for FVIII chromogenic activity assays as described below.
- Chromogenic FVIII activity tests may be manufactured with either human or bovine coagulation proteins. Assays containing human coagulation factors are responsive to HEMLIBRA but may overestimate the clinical hemostatic potential of HEMLIBRA. In contrast, assays containing bovine coagulation factors are insensitive to HEMLIBRA (no activity measured) and can be used to monitor endogenous or infused FVIII activity, or to measure anti-FVIII inhibitors.
- HEMLIBRA remains active in the presence of inhibitors against FVIII, so it will produce a false-negative result in clotting-based Bethesda assays for functional inhibition of FVIII. Instead, a chromogenic Bethesda assay utilizing a bovine-based FVIII chromogenic test that is insensitive to HEMLIBRA may be used.
- Due to the long half-life of HEMLIBRA, effects on coagulation assays may persist for up to 6 months after the last dose.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): Risk Summary
- There are no available data on HEMLIBRA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Animal reproduction studies have not been conducted with emicizumab-kxwh. It is not known whether HEMLIBRA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. HEMLIBRA should be used during pregnancy only if the potential benefit for the mother outweighs the risk to the fetus.
- All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2 – 4% and 15 – 20%, respectively.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Emicizumab in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Emicizumab during labor and delivery.
Nursing Mothers
Risk Summary
- There is no information regarding the presence of emicizumab-kxwh in human milk, the effects on the breastfed child, or the effects on milk production. Human IgG is known to be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for HEMLIBRA and any potential adverse effects on the breastfed child from HEMLIBRA or from the underlying maternal condition.
Pediatric Use
- The safety and efficacy of HEMLIBRA have been established in pediatric patients. Use of HEMLIBRA in pediatric patients with hemophilia A with FVIII inhibitors is supported by a randomized trial (HAVEN 1) and a single-arm trial (HAVEN 2). HAVEN 1 included pediatric patients in the following age group: 38 adolescents (12 years to less than 18 years). HAVEN 2 included pediatric patients in the following age groups: 55 children (2 years up to less than 12 years) and two infants (1 month up to less than 2 years). No differences in efficacy were observed between the different age groups.
- In general, the adverse reactions in HEMLIBRA-treated pediatric patients were similar in type to those seen in adult patients with hemophilia A with FVIII inhibitors.
- The steady-state plasma trough concentrations of emicizumab-kxwh were comparable in adult and pediatric patients at equivalent weight-based doses.
Geriatic Use
- Clinical studies of HEMLIBRA did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.
Gender
There is no FDA guidance on the use of Emicizumab with respect to specific gender populations.
Race
There is no FDA guidance on the use of Emicizumab with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Emicizumab in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Emicizumab in patients with hepatic impairment.
Females of Reproductive Potential and Males
Contraception
- Women of childbearing potential should use contraception while receiving HEMLIBRA.
Immunocompromised Patients
There is no FDA guidance one the use of Emicizumab in patients who are immunocompromised.
Administration and Monitoring
Administration
(Oral/Intravenous/etc)
Monitoring
Condition 1
(Description regarding monitoring, from Warnings section)
Condition 2
(Description regarding monitoring, from Warnings section)
Condition 3
(Description regarding monitoring, from Warnings section)
IV Compatibility
There is limited information regarding the compatibility of Emicizumab and IV administrations.
Overdosage
There is limited information regarding Emicizumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
Emicizumab?
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| Therapeutic monoclonal antibody | |
| Source | zu |
| Target | Activated factor IX, factor X |
| Identifiers | |
| CAS number | |
| ATC code | B02 |
| PubChem | ? |
| Chemical data | |
| Formula | ? |
| Mol. mass | ? |
| Synonyms | ACE910 |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Metabolism | ? |
| Half life | ? |
| Excretion | ? |
| Therapeutic considerations | |
| Pregnancy cat. |
? |
| Legal status |
Template:Unicode Prescription only |
| Routes | Subcutaneous injection |
Mechanism of Action
- HEMLIBRA bridges activated factor IX and factor X to restore the function of missing activated factor VIII that is needed for effective hemostasis.
Structure
There is limited information regarding Emicizumab Structure in the drug label.
Pharmacodynamics
There is limited information regarding Emicizumab Pharmacodynamics in the drug label.
Pharmacokinetics
- Emicizumab-kxwh exhibited dose-proportional pharmacokinetics over a dose range of 0.3 mg/kg (0.1 times approved recommended starting dosage) to 3 mg/kg once weekly following subcutaneous administration. Following multiple subcutaneous administrations of 3 mg/kg once weekly for the first 4 weeks in hemophilia A patients, mean (± SD) trough plasma concentrations of emicizumab-kxwh increased to achieve 54.6 ± 14.3 μg/mL at Week 5. Trough plasma concentrations above 50 μg/mL were sustained thereafter with the recommended weekly dosage of 1.5 mg/kg; the mean (± SD) trough plasma concentrations of emicizumab-kxwh at steady-state was 52.8 ± 13.5 µg/mL.
Absorption
- Following subcutaneous administration, the mean (± SD) absorption half-life was 1.7 ± 1 day.
- The absolute bioavailability following subcutaneous administration of 1 mg/kg was between 80.4% and 93.1%. Similar pharmacokinetic profiles were observed following subcutaneous administration in the abdomen, upper arm, and thigh.
Distribution
- The mean apparent volume of distribution was 11.4 L (95% confidence interval (CI) [10.6, 12.1]).
Elimination
- The mean apparent clearance (95% CI) was 0.24 L/day (0.22, 0.26) and the mean elimination apparent half-life (± SD) was 27.8 ± 8.1 days.
Specific Populations
- The pharmacokinetics of emicizumab-kxwh are not influenced by age (3 years to 75 years), race (White 54%, Asian 30.5% and Black 8.5%), inhibitor status (inhibitor present, 92%), mild hepatic impairment (defined as total bilirubin 1× to ≤ 1.5× the upper limit of normal (ULN) and any aspartate transaminase (AST) level) and moderate hepatic impairment (defined as total bilirubin 1.5× to ≤ 3× the ULN and any AST level).
- Body weight: The apparent clearance and volume of distribution of emicizumab-kxwh increased with increasing body weight (14.2 kg to 131 kg). Dosing in mg/kg provides similar emicizumab-kxwh exposure across body weight range.
Drug Interaction Studies
- No drug-drug interaction studies have been conducted with HEMLIBRA.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Studies in animals investigating the carcinogenic effects of emicizumab-kxwh have not been conducted. In vitro and in vivo testing of emicizumab-kxwh for genotoxicity was not conducted.
- Animal fertility studies have not been conducted; however, emicizumab-kxwh did not cause any toxicological changes in the reproductive organs of male or female cynomolgus monkeys at doses of up to 30 mg/kg/week in subcutaneous general toxicity studies of up to 26-week duration and at doses of up to 100 mg/kg/week in a 4-week intravenous general toxicity study.
Clinical Studies
- The efficacy of HEMLIBRA for routine prophylaxis in patients with hemophilia A with FVIII inhibitors was evaluated in two clinical trials [an adult and adolescent study (HAVEN 1) and a pediatric study (HAVEN 2)].
HAVEN 1
- The HAVEN 1 study (NCT02622321) was a randomized, multicenter, open-label, clinical trial in 109 adult and adolescent males (aged 12 to 75 years and > 40 kg) with hemophilia A with FVIII inhibitors who previously received either episodic (on-demand) or prophylactic treatment with bypassing agents. Patients received weekly HEMLIBRA prophylaxis (Arms A, C, and D), 3 mg/kg once weekly for the first 4 weeks followed by 1.5 mg/kg once weekly thereafter, or no prophylaxis (Arm B). Dose up-titration to 3 mg/kg once weekly was allowed after 24 weeks on HEMLIBRA prophylaxis in case of suboptimal efficacy (i.e., ≥ 2 spontaneous and clinically significant bleeds). During the study, two patients underwent up-titration of their maintenance dose to 3 mg/kg once weekly.
- Fifty-three patients previously treated with episodic (on-demand) bypassing agents were randomized in a 2:1 ratio to receive HEMLIBRA prophylaxis (Arm A) or no prophylaxis (Arm B), with stratification by prior 24-week bleed rate (< 9 or ≥ 9). Patients randomized to Arm B could switch to HEMLIBRA prophylaxis after completing at least 24 weeks without prophylaxis.
- Forty-nine patients previously treated with prophylactic bypassing agents were enrolled into Arm C to receive HEMLIBRA prophylaxis. Seven patients previously treated with episodic (on-demand) bypassing agents who had participated in a non-interventional study (NIS) prior to enrollment, but were unable to enroll into HAVEN 1 prior to the closure of Arms A and B, were enrolled into Arm D to receive HEMLIBRA prophylaxis.
- Efficacy was evaluated based on the annualized bleeding rate (ABR) requiring treatment with coagulation factors (minimum of 24 weeks or date of discontinuation) among patients previously treated with episodic bypassing agents who were randomized to HEMLIBRA prophylaxis (Arm A) compared with those receiving no prophylaxis (Arm B). The trial also evaluated the randomized comparison of Arms A and B for the efficacy of weekly HEMLIBRA prophylaxis in reducing the number of all bleeds, spontaneous bleeds, joint bleeds, and target joint bleeds, as well as patient-reported symptoms and physical functioning.
- The study also evaluated the efficacy of weekly HEMLIBRA prophylaxis compared with previous episodic (on-demand) and prophylactic bypassing agents in patients who had participated in the NIS prior to enrollment (Arms A and C, respectively). Only patients from the NIS were included in this comparison, because bleed and treatment data were collected with the same level of granularity in both periods.
- The efficacy results of HEMLIBRA prophylaxis compared with no prophylaxis in bleed rate for treated bleeds, all bleeds, treated spontaneous bleeds, treated joint bleeds and treated target joint bleeds are shown in TABLE 4.
- In the intra-patient analysis, HEMLIBRA prophylaxis resulted in a statistically significant (p = 0.0003) reduction (79%) in bleed rate for treated bleeds compared with previous bypassing agent prophylaxis collected in the NIS prior to enrollment (TABLE 5).
- The study evaluated patient-reported hemophilia-related symptoms (painful swellings and presence of joint pain) and physical functioning (pain with movement and difficulty walking far) using the Physical Health Score of the Haemophilia-specific Quality of Life (Haem-A-QoL) questionnaire for patients aged ≥ 18 years. The weekly HEMLIBRA prophylaxis arm (Arm A) showed an improvement compared with the no prophylaxis arm (Arm B) in the Haem-A-QoL Physical Health Subscale score at the Week 25 assessment (TABLE 6). The improvement in the Physical Health Score was further supported by the Total Score as measured by the Haem-A-QoL at Week 25.
HAVEN 2
- The HAVEN 2 study (NCT02795767) was a single-arm, multicenter, open-label, clinical study in pediatric males (age < 12 years, or 12 – 17 years who weigh < 40 kg) with hemophilia A with FVIII inhibitors. Patients received HEMLIBRA prophylaxis at 3 mg/kg once weekly for the first 4 weeks followed by 1.5 mg/kg once weekly thereafter.
- The study evaluated the efficacy of weekly HEMLIBRA prophylaxis, including the efficacy of weekly HEMLIBRA prophylaxis compared with previous episodic (on-demand) and prophylactic bypassing agent treatment in patients who had participated in a non-interventional study (NIS) prior to enrollment (intra-patient analysis).
- At the time of the interim analysis, efficacy was evaluated in 23 pediatric patients who were < 12 years old and had been receiving weekly HEMLIBRA prophylaxis for at least 12 weeks, including 19 patients age 6 to < 12 years and 4 patients age 2 to < 6 years.
- Annualized bleed rate (ABR) and percent of patients with zero bleeds were calculated for 23 patients (TABLE 7). The median observation time for these patients was 38.1 weeks (12.7 – 41.6 weeks).
- In the intra-patient analysis, 13 pediatric patients who had participated in the NIS had an ABR of 17.2 (95% CI [12.4, 23.8]) on previous bypassing agent treatment (prophylactic treatment in 12 patients and on-demand treatment for one patient). Weekly HEMLIBRA prophylaxis resulted in an ABR for treated bleeds of 0.2 (95% CI [0.1, 0.8]) based on negative binomial regression, corresponding to a 99% reduction in bleed rate. On HEMLIBRA prophylaxis, 11 patients (84.6%) had zero treated bleeds.
How Supplied
- HEMLIBRA (emicizumab-kxwh) injection is available as a sterile, preservative-free, colorless to slightly yellow solution in single-dose vials in the following dosage strengths:
Storage
- Store HEMLIBRA vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake.
- Store HEMLIBRA vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake.
- Prior to administration, if needed, unopened vials of HEMLIBRA may be stored out of and then returned to refrigeration. The temperature and total combined time out of refrigeration should not exceed 30°C (86°F) and 7 days (at a temperature below 30°C [86°F]), respectively.
- Once removed from the vial, discard HEMLIBRA if not used immediately.
- Discard any unused HEMLIBRA.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
Use of Bypassing Agents
- Inform the patient and/or caregiver that HEMLIBRA increases coagulation potential. Advise the patient and/or caregiver to discontinue prophylactic use of bypassing agents the day before starting HEMLIBRA prophylaxis. Discuss the use of bypassing agents with the patient and/or caregiver prior to starting HEMLIBRA prophylaxis.
Thrombotic Microangiopathy Associated with HEMLIBRA and aPCC
- Inform the patient and/or caregiver of the potential risk of thrombotic microangiopathy if aPCC is administered while receiving HEMLIBRA prophylaxis. Instruct the patient and/or caregiver to consult their healthcare provider if aPCC is required in cumulative doses exceeding 100 U/kg. Advise the patient and/or caregiver to seek immediate medical attention if any signs or symptoms of thrombotic microangiopathy occur.
Thromboembolism Associated with HEMLIBRA and aPCC
- Inform the patient and/or caregiver of the potential risk of thromboembolism if aPCC is administered while receiving HEMLIBRA prophylaxis. Instruct the patient and/or caregiver to consult their healthcare provider if aPCC is required in cumulative doses exceeding 100 U/kg. Advise the patient and/or caregiver to seek immediate medical attention if any signs or symptoms of thromboembolism occur.
Laboratory Coagulation Test Interference
- Inform the patient and/or caregiver that HEMLIBRA interferes with some laboratory tests that measure blood clotting and may cause a false reading. Advise the patient and/or caregiver that they should notify any healthcare provider about this possibility prior to any blood tests or medical procedures.
Instruction on Injection Technique
- HEMLIBRA is intended for use under the guidance of a healthcare provider. If a patient or caregiver is to administer subcutaneous HEMLIBRA, instruct him/her in injection techniques and assess his/her ability to inject subcutaneously to ensure proper administration of subcutaneous HEMLIBRA and the suitability for home use.
- Advise the patient to follow the recommendations in the FDA-approved patient labeling regarding proper sharps disposal.
Precautions with Alcohol
Alcohol-Emicizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
- Hemlibra
Look-Alike Drug Names
There is limited information regarding Emicizumab Look-Alike Drug Names in the drug label.
Drug Shortage Status
Drug Shortage
Price
References
The contents of this FDA label are provided by the National Library of Medicine.