Marstacimab-hncq
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parth Vikram Singh, MBBS[2]
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Overview
Marstacimab-hncq is a tissue factor pathway inhibitor (TFPI) antagonist that is FDA approved for the prophylaxis of prevent or reduce the frequency of bleeding episodes in adult and pediatric patients 12 years of age and older with:
- hemophilia A (congenital factor VIII deficiency) without factor VIII inhibitors, or
- hemophilia B (congenital factor IX deficiency) without factor IX inhibitors.. Common adverse reactions include injection site reaction, headache andpruritus..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
HYMPAVZI is a tissue factor pathway inhibitor (TFPI) antagonist indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients 12 years of age and older with:
hemophilia A (congenital factor VIII deficiency) without factor VIII inhibitors, or
hemophilia B (congenital factor IX deficiency) without factor IX inhibitors.
====The recommended dosage of HYMPAVZI is:====
- Loading dose: 300 mg (two 150 mg injections) by subcutaneous injection
- Maintenance dose: One week after the loading dose, initiate maintenance dosing of 150 mg every week by subcutaneous injection on the same day each week, at any time of day.
- Dose adjustment to 300 mg subcutaneous injection weekly can be considered.
- Factor VIII and factor IX products can be administered for the treatment of breakthrough bleeds in patients receiving HYMPAVZI. Do not use additional doses of HYMPAVZI to treat breakthrough bleeds.
- Temporarily discontinue HYMPAVZI before major surgery.
- Injection: 150 mg/mL in a single-dose prefilled syringe.
- Injection: 150 mg/mL in a single-dose prefilled pen.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Marstacimab-hncq in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Marstacimab-hncq in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
HYMPAVZI is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in pediatric patients 12 years of age and older with:
• hemophilia A (congenital factor VIII deficiency) without factor VIII inhibitors, or • hemophilia B (congenital factor IX deficiency) without factor IX inhibitors.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Marstacimab-hncq in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Marstacimab-hncq in pediatric patients.
Contraindications
None.
Warnings
- Thromboembolic Events: Thromboembolic events may occur. Interrupt HYMPAVZI prophylaxis if symptoms occur.
- Hypersensitivity: Hypersensitivity reactions may occur. In the event of a severe allergic reaction, discontinue HYMPAVZI.
- Embryofetal Toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception.
Adverse Reactions
Clinical Trials Experience
- Thromboembolic Events.
- Hypersensitivity.
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety of HYMPAVZI was evaluated in adolescent and adult patients with severe hemophilia A or B without inhibitors (coagulation factor activity <1%) enrolled in the BASIS study.
- Patients (N = 116) received HYMPAVZI prophylaxis 300 mg loading dose followed by 150 mg every week starting at Day 8 administered subcutaneously. Among patients receiving HYMPAVZI, 97% were exposed for 6 months or longer and 75% were exposed for at least 1 year.
A serious adverse reaction of peripheral swelling occurred in one patient. Table 1 summarizes the adverse reactions reported in ≥3% of patients who received HYMPAVZI prophylaxis.
During BASIS trial 12-month active treatment phase.
Postmarketing Experience
There is limited information regarding Marstacimab-hncq Postmarketing Experience in the drug label.
Drug Interactions
Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT)
No clinically significant differences in standard measures of coagulation including activated partial thromboplastin time (aPTT) and prothrombin time (PT) were observed following marstacimab‑hncq therapy.
Use in Specific Populations
Pregnancy
Risk Summary
- Based on its mechanism of action, HYMPAVZI may cause fetal harm when administered to a pregnant woman. There are no available data on HYMPAVZI use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Female animal reproduction studies have not been conducted with HYMPAVZI. Although there are no data on marstacimab‑hncq, monoclonal antibodies can be actively transported across the placenta, and marstacimab‑hncq may cause fetal harm.
- The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Marstacimab-hncq in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Marstacimab-hncq during labor and delivery.
Nursing Mothers
Risk Summary
- There are no data on the presence of marstacimab‑hncq in either human or animal milk, the effects on the breastfed child, or the effects on milk production.
- Endogenous maternal IgG and monoclonal antibodies are known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to marstacimab‑hncq are unknown.
- The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for HYMPAVZI and any potential adverse effects on the breastfed infant from HYMPAVZI or from the underlying maternal condition.
Pediatric Use
- The safety and effectiveness of HYMPAVZI to prevent or reduce the frequency of bleeding episodes in hemophilia A or B without inhibitors have been established in pediatric patients aged 12 years and older. Use of HYMPAVZI for this indication is supported by evidence from an open‑label, multi‑center phase 3 study in 19 adolescents and 97 adults with hemophilia without inhibitors.
- The safety and effectiveness of HYMPAVZI have not been established in pediatric patients younger than 12 years old.
Geriatic Use
- One patient 65 years of age and older was enrolled in the clinical studies for hemophilia A or B without inhibitors. Clinical studies of HYMPAVZI did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.
Gender
There is no FDA guidance on the use of Marstacimab-hncq with respect to specific gender populations.
Race
There is no FDA guidance on the use of Marstacimab-hncq with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Marstacimab-hncq in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Marstacimab-hncq in patients with hepatic impairment.
Females of Reproductive Potential and Males
HYMPAVZI may cause fetal harm when administered to a pregnant woman.
Pregnancy Testing
- Verify the pregnancy status of females of reproductive potential prior to initiating HYMPAVZI treatment.
Contraception
- Females
Advise female patients of reproductive potential to use effective contraception during treatment with HYMPAVZI and for 2 months after the last dose.
Immunocompromised Patients
There is no FDA guidance one the use of Marstacimab-hncq in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Marstacimab-hncq Administration in the drug label.
Monitoring
There is limited information regarding Marstacimab-hncq Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Marstacimab-hncq and IV administrations.
Overdosage
There is limited information regarding Marstacimab-hncq overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Marstacimab-hncq Pharmacology in the drug label.
Mechanism of Action
Mechanism of Action
- Marstacimab‑hncq is a human monoclonal IgG1 antibody directed against the Kunitz domain 2 (K2) of TFPI to neutralize TFPI activity and enhance coagulation. TFPI is the primary inhibitor of the extrinsic coagulation cascade and negatively regulates thrombin generation within the extrinsic pathway of coagulation by inactivating the protease functions of FXa/FVIIa/TF complex. TFPI binds to and inhibits the factor Xa active site via its second Kunitz inhibitor domain (K2).
Structure
Marstacimab‑hncq is a tissue factor pathway inhibitor ( TFPI ) antagonist, human monoclonal immunoglobulin G Type 1 ( IgG1 ) antibody. Marstacimab‑hncq is produced by Chinese hamster ovary ( CHO ) cells by recombinant DNA technology and has a molecular mass of approximately 146 kDa.
HYMPAVZI ( marstacimab‑hncq ) injection is supplied as a sterile, preservative-free solution for subcutaneous administration. The drug product is supplied as either a single-dose 150 mg/mL prefilled syringe or as a single‑dose 150 mg/mL prefilled pen. The solution of marstacimab‑hncq is clear and colorless to light yellow with a pH of 5.8.
Each 150 mg/mL prefilled syringe or prefilled pen delivers 1 mL of HYMPAVZI. Each 1 mL of HYMPAVZI contains 150 mg of marstacimab‑hncq, and the inactive ingredients edetate disodium ( 0.05 mg ) , histidine ( 1.12 mg ) , L-histidine monohydrochloride ( 2.67 mg ) , polysorbate 80
( 0.2 mg ) , and sucrose ( 85 mg ) , in Water for Injection, USP.
Pharmacodynamics
Marstacimab‑hncq causes an increase in total TFPI (comprised of free TFPI and TFPI bound to marstacimab) and downstream biomarkers of thrombin generation such as prothrombin fragments 1+2, peak thrombin, and D‑Dimer in patients with hemophilia. These changes were observed and persisted over a 7-day period following a single subcutaneous dose and were reversible after treatment discontinuation.
Pharmacokinetics
- Estimated mean marstacimab hncq Cmin,ss, Cmax,ss, and Cavg,ss for adults and adolescents weighing at least 35 kg following marstacimab hncq 150 mg subcutaneous once-weekly administration are shown in Table 2. Marstacimab hncq area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) increase in a greater than dose-proportional manner over the dose range of 100 mg to 450 mg (0.67 to 3 times the approved recommended dosage).
- Mean steady-state accumulation ratio for marstacimab hncq is approximately 4 to 5. Marstacimab hncq steady state concentrations are achieved by approximately 60 days (8th or 9th subcutaneous dose) when administered once weekly.
Absorption
- Bioavailability of mab hncq following subcutaneous administration is approximately 71%. Median Tmax ranges from 23 to 59 hours following multiple subcutaneous administrations of marstacimab hncq to patients with hemophilia. No clinically significant differences were seen in marstacimab hncq bioavailability when administered subcutaneously in the arm, thigh or abdomen.
Distribution
- Marstacimab hncq steady-state apparent volume of distribution is 8.6 L in patients with hemophilia.
Elimination
- Marstacimab-hncq is cleared via linear and non-linear mechanisms. Marstacimab hncq exhibited non linear pharmacokinetics due to target-mediated drug disposition (TMDD) which occurs when it forms marstacimab hncq/TFPI complex. Once the target becomes saturated, linear pathway (i.e., catabolism) dominates.
- Based on population pharmacokinetic analysis, 90% of marstacimab is expected to be eliminated by the end of approximately 1 month after the last dose (median time for 50% of drug to be eliminated is approximately 7 to 10 days).
Metabolism
- Marstacimab hncq is expected to be metabolized into small peptides and amino acids by catabolic pathways in the same manner as endogenous IgG.
pecific Populations
- No clinically significant differences in pharmacokinetics of marstacimab hncq were observed based on race, hemophilia type (A and B), mild renal impairment (eGFR of 60 to 89 mL/min/1.73 m2), and mild hepatic impairment (total bilirubin >1× to ≤1.5× ULN). The effects of geriatric age (>65 years), moderate to severe renal (eGFR <59 mL/min/1.73 m2) and moderate to severe hepatic (Child Pugh class B and C) impairment on marstacimab hncq pharmacokinetics are unknown.
Body Weight
- Body weight was a significant covariate impacting the pharmacokinetics of marstacimab hncq. Marstacimab hncq exposures over the body weight range of 35 to 120 kg show a trend for increase in exposure with decrease in body weight. However, dose adjustment based on body weight is not required.
Pediatric Patients
- Marstacimab hncq clearance (CL) was 29% lower in adolescents (12 to <18 years of age) compared to adults (18 years and older). No clinically significant difference in adolescent marstacimab hncq CL (L/hr/kg) compared to adults was observed after adjusting for body weight.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- No studies have been conducted to assess marstacimab‑hncq for the potential for carcinogenicity or mutagenicity. Marstacimab‑hncq did not affect fertility when administered as a repeat dose to male rats at doses up to 1000 mg/kg/dose and an exposure margin of 212-times the exposure at a clinical dose of 300 mg subcutaneous weekly. No effects were observed in male or female reproductive organs in the repeat‑dose toxicity studies of up to 6 months in duration in rats and 3 months in duration in cynomolgus monkeys at doses of 1000 mg/kg/dose and 500 mg/kg/dose and exposure margins at least 201- and 219-times, respectively, the AUC exposure at a clinical dose of 300 mg subcutaneous weekly.
Clinical Studies
Recommended Dosage
- For subcutaneous use only.====
The recommended dosage of HYMPAVZI for adult and pediatric patients 12 years of age and older is as follows:
Loading Dose
300 mg (two 150 mg subcutaneous injections) If more than one injection is required to deliver a complete dose, administer each injection at a different injection site.
Maintenance Dose
One week after the loading dose, initiate maintenance dosing of 150 mg every week by subcutaneous injection on the same day each week, at any time of day.
Dose Adjustment During Treatment
Consider a dose adjustment to 300 mg subcutaneous injection weekly in patients weighing greater than or equal to 50 kg when control of bleeding events is judged to be inadequate by the healthcare provider. Safety and efficacy of HYMPAVZI at doses above 300 mg weekly have not been established. If more than one injection is required to deliver a complete dose, administer each injection at a different injection site.
Missed Doses
For patients on a maintenance dose of 150 mg: If a dose is missed, administer as soon as possible before the day of the next scheduled dose, and then resume usual 150 mg subcutaneous weekly dosing schedule (same schedule as prior to the missed dose or new schedule based on date of administration of missed dose). If more than 13 days have passed since the last dose was administered, administer a loading dose of 300 mg by subcutaneous injection followed by a resumption of 150 mg by subcutaneous injection once weekly thereafter. For patients on a maintenance dose of 300 mg: If one or more doses are missed, administer a dose as soon as possible, and then resume 300 mg subcutaneous weekly dosing schedule (same schedule as prior to the missed dose or new schedule based on date of administration of missed dose).
Preparation and Administration
- HYMPAVZI is intended for use under the guidance of a healthcare provider. After proper training in subcutaneous injection technique, a patient may self-inject or the patient’s caregiver may administer HYMPAVZI, if a healthcare provider determines that it is appropriate.
- Refer to the Instructions for Use for complete preparation and administration instructions.
- Prior to subcutaneous administration, HYMPAVZI may be removed from the refrigerator and allowed to warm at room temperature in the carton for 15 to 30 minutes protected from direct sunlight. Do not warm by using a heat source such as hot water or a microwave. After removal of HYMPAVZI from the refrigerator, use within 7 days or discard.
- Administer HYMPAVZI by subcutaneous injection, once weekly, at any time of the day in the abdomen or thigh. Other injection sites are acceptable if required. Administration of HYMPAVZI in the upper arm (prefilled syringe only) or buttocks (prefilled pen only) should be performed by a caregiver or healthcare professional only. HYMPAVZI should not be administered into bony areas or areas where the skin is bruised, red, tender or hard, or areas where there are scars or stretch marks. HYMPAVZI should not be injected into a vein. Rotate the injection site with each new injection.
- During treatment with HYMPAVZI, other medicinal products for subcutaneous administration should, preferably, be injected at different anatomical sites.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. HYMPAVZI is a clear and colorless to light yellow solution. Do not use if the solution is cloudy, dark yellow, or contains flakes or particles.
Changing to HYMPAVZI
- Changing from prophylactic factor replacement therapy to HYMPAVZI: Prior to initiation of HYMPAVZI, discontinue treatment with clotting factor concentrates (factor VIII or factor IX concentrates). HYMPAVZI can be initiated at any time after discontinuing clotting factor concentrates.
No data are available in patients changing from non-factor-based hemophilia medicinal products to HYMPAVZI.
= Guidance on Use with Breakthrough Bleed Treatments
Factor VIII and factor IX products can be administered for the treatment of breakthrough bleeds in patients receiving HYMPAVZI. Do not use additional doses of HYMPAVZI to treat breakthrough bleeds. Healthcare providers should discuss with all patients and/or caregivers the dose and schedule of clotting factor concentrates to use, if required, while receiving HYMPAVZI prophylaxis, including using the lowest possible effective dose of clotting factor concentrate.pleas refer to the Full Prescribing Information for the clotting factor concentrate being used.
Temporary Interruption for Surgery and Other Interventions
- Management in the Perioperative Setting
HYMPAVZI has not been evaluated in the setting of major surgery. Patients have had minor surgical procedures without discontinuing HYMPAVZI prophylaxis in clinical studies. For major surgery, discontinue HYMPAVZI and initiate management per local standard of care with clotting factor concentrate and measures to manage the risk of venous thrombosis which can be elevated in the perioperative period. Consult the product information for the clotting factor concentrate for dosage guidelines in patients with hemophilia undergoing major surgery. Resumption of HYMPAVZI therapy should consider the overall clinical status of the patient, including the presence of post-surgical thromboembolic risk factors, use of other hemostatic products and other concomitant medications.
- Management in Patients with Acute Severe Illness
There is limited experience with the use of HYMPAVZI in patients with acute severe illness. Reasons to consider temporary dose interruption of HYMPAVZI include occurrence of acute severe illness (e.g., serious infection, sepsis, trauma) in which there may be increased activation of coagulation and which the healthcare provider considers could increase the risks associated with HYMPAVZI administration. Treatment of acute severe illness should be managed per local standard of care, and continued treatment with HYMPAVZI in this situation should be weighed against the potential risks involved. Resume HYMPAVZI therapy once patient has clinically recovere.
Pregnancy Testing
Verify that females of reproductive potential are not pregnant prior to initiating HYMPAVZI HYMPAVZI (marstacimab hncq) is a clear and colorless to light yellow solution available as: Prefilled Syringe
- Injection: 150 mg/mL in a single-dose prefilled syringe
Prefilled Pen
- Injection: 150 mg/mL in a single-dose prefilled pen
How Supplied
HYMPAVZI (marstacimab hncq) injection is a sterile, preservative-free, clear and colorless to light yellow solution available as a 150 mg/mL single-dose prefilled syringe or pen for subcutaneous administration.
Prefilled Syringe
- Each carton (NDC 0069-1510-01) contains one single-dose prefilled syringe (Type I glass) with a plunger stopper (chlorobutyl elastomer) and a stainless steel 27 gauge, ½ inch staked needle with a rigid needle shield (thermoplastic elastomer).
Prefilled Pen
- Each carton (NDC 0069-2151-01) contains one single-dose prefilled pen with needle guard. The syringe inside the pen is made from Type I glass with a plunger stopper (chlorobutyl elastomer) and a stainless steel 27 gauge, ½ inch staked needle with a rigid needle shield (thermoplastic elastomer).
- HYMPAVZI is not made with natural rubber latex.
Storage
• Store refrigerated at 36°F to 46°F (2°C to 8°C) in the original carton to protect from light. • If needed, HYMPAVZI may be stored one time at room temperature [up to 86°F (30°C)] in its original carton to protect from light for up to 7 days. Once stored at room temperature, do not return to the refrigerator and discard after 7 days. • Do not freeze. • Do not shake.
Images
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Patient Counseling Information
- Advise the patient and/or caregivers to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
- Ensure that patients and caregivers who will administer HYMPAVZI receive appropriate training and instruction on the proper storage, use and handling of HYMPAVZI from a healthcare professional.
Thromboembolic Events
- Inform patients and/or caregivers that HYMPAVZI increases coagulation potential. Discuss the appropriate dosing of concomitant agents such as FVIII or FIX with the patient prior to starting on HYMPAVZI prophylaxis.
- Advise the patient to seek immediate medical attention if any signs or symptoms of thromboembolism occur.
Hypersensitivity
- Inform patients and/or caregivers that hypersensitivity reactions such as rash and pruritus are possible. Advise patients to discontinue HYMPAVZI and seek immediate emergency treatment if a severe hypersensitivity reaction occurs.
Pregnancy
- Advise female patients of reproductive potential to use effective contraception during treatment with HYMPAVZI and for 2 months after the last dose. Advise patients to report known pregnancies.
Precautions with Alcohol
Alcohol-Marstacimab-hncq interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
HYMPAVZI
Look-Alike Drug Names
There is limited information regarding Marstacimab-hncq Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.