HYMPAVZI

1 INDICATIONS AND USAGE HYMPAVZI is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and pediatric patients 6 years of age and older with: • hemophilia A (congenital factor VIII deficiency) with or without factor VIII inhibitors, or • hemophilia B (congenital factor IX deficiency) with or without factor IX inhibitors. HYMPAVZI is a tissue factor pathway inhibitor (TFPI) antagonist indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and pediatric patients 6 years of age and older with: • hemophilia A (congenital factor VIII deficiency) with or without factor VIII inhibitors, or • hemophilia B (congenital factor IX deficiency) with or without factor IX inhibitors. ( 1 )

2 DOSAGE AND ADMINISTRATION • See Full Prescribing Information for important dosing and administration instructions. ( 2.1 , 2.2 , 2.3 , 2.4 , 2.5 , 2.6 , 2.7 , 2.8 ) • Recommended Dosage in Adults and Pediatric Patients 12 Years of Age and Older: o Loading dose: 300 mg (two 150 mg injections) by subcutaneous injection. ( 2.1 ) o 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. ( 2.1 ) o Dose adjustment to 300 mg subcutaneous injection weekly can be considered. ( 2.1 ) • Recommended Dosage in Pediatric Patients 6 to less than 12 Years of Age: o Loading dose: 150 mg (one 150 mg injection or two 75 mg injections) by subcutaneous injection. ( 2.2 ) o Maintenance dose: One week after the loading dose, initiate maintenance dosing of 75 mg every week by subcutaneous injection on the same day each week, at any time of day. ( 2.2 ) o Dose adjustment to 150 mg subcutaneous injection (one 150 mg injection or two 75 mg injections) weekly can be considered. ( 2.2 ) • Factor VIII and factor IX products or bypassing agents (e.g., rFVIIa or aPCC) can be administered for the treatment of breakthrough bleeds in patients receiving HYMPAVZI. Do not use additional doses of HYMPAVZI to treat breakthrough bleeds. ( 2.5 ) • Temporarily pause HYMPAVZI at least 7 days before major surgery. ( 2.6 ) 2.1 Recommended Dosage in Adults and Pediatric Patients 12 Years of Age and Older For subcutaneous use only. The recommended dosage of HYMPAVZI for adults 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 In patients weighing greater than or equal to 50 kg, consider a dose adjustment to 300 mg subcutaneous injection weekly 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). 2.2 Recommended Dosage in Pediatric Patients 6 to less than 12 Years of Age For subcutaneous use only. The recommended dosage of HYMPAVZI for pediatric patients 6 to less than 12 years of age is as follows: Loading Dose 150 mg (one 150 mg subcutaneous injection or two 75 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 75 mg every week by subcutaneous injection on the same day each week, at any time of day. Dose Adjustment During Treatment In patients weighing greater than or equal to 25 kg, consider a dose adjustment to 150 mg subcutaneous injection (one 150 mg subcutaneous injection or two 75 mg subcutaneous injections) weekly when control of bleeding events is judged to be inadequate by the healthcare provider. Safety and efficacy of HYMPAVZI at doses above 150 mg weekly have not been established in children 6 to less than 12 years of age. 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 75 mg: If a dose is missed, administer as soon as possible before the day of the next scheduled dose, and then resume usual 75 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 150 mg by subcutaneous injection followed by a resumption of 75 mg by subcutaneous injection once weekly thereafter. For patients on a maintenance dose of 150 mg: If one or more doses are missed, administer a dose as soon as possible, and then resume 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). 2.3 Preparation and Administration • HYMPAVZI is intended for use under the guidance of a healthcare provider. After proper instruction in subcutaneous injection technique, a patient 12 years and older 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 [up to 86°F (30°C)] 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 [see How Supplied/Storage and Handling (16) ] . • Administer HYMPAVZI by subcutaneous injection, once weekly, at any time of the day in the abdomen or front of thigh. Other injection sites are acceptable if required. Administration of HYMPAVZI in the back of 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. 2.4 Changing to HYMPAVZI Changing from prophylactic factor replacement therapy or bypassing agents to HYMPAVZI: Prior to initiation of HYMPAVZI, discontinue treatment with clotting factor concentrates (factor VIII or factor IX concentrates) or bypassing agents (e.g., recombinant FVIIa [rFVIIa] or activated prothrombin complex concentrate [aPCC]). HYMPAVZI can be initiated at any time after discontinuing clotting factor concentrates or bypassing agents. No data are available in patients changing from other non-factor-based hemophilia medicinal products to HYMPAVZI. 2.5 Guidance on Use with Breakthrough Bleed Treatments Factor VIII and factor IX products or bypassing agents (e.g., rFVIIa or aPCC) 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 the clotting factor concentrates or bypassing agents to use, if required, while receiving HYMPAVZI prophylaxis . When treating breakthrough bleeds with factor VIII or factor IX products or with bypassing agents , the lowest effective dose according to the product prescribing information is recommended [see Warnings and Precautions (5.1) ] . Please refer to the Full Prescribing Information for the clotting factor concentrate or bypassing agent being used. For rFVIIa, a maximum dose of 90 mcg/kg body weight per dose and a maximum dosing frequency of every 2 hours is recommended. For aPCC, a maximum dose of 100 units/kg body weight within 24 hours is recommended. 2.6 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, pause HYMPAVZI at least 7 days prior and initiate management per local standard of care with clotting factor concentrate or bypassing agent 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 or bypassing agent 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 [see Dosage and Administration (2.1) ] . 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 recovered [see Dosage and Administration (2.1) ] . 2.7 Pregnancy Testing Verify that females of reproductive potential are not pregnant prior to initiating HYMPAVZI [see Warnings and Precautions (5.3) , Use in Specific Populations (8.1 , 8.3) ]. 2.8 Immune Tolerance Induction The safety and efficacy of HYMPAVZI in patients receiving ongoing Immune Tolerance Induction (ITI), a desensitization strategy for the eradication of inhibitors, have not been established, and no data are available. Careful assessment of the potential benefits and risks should be performed if continuation or initiation of HYMPAVZI during ITI is considered.

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS • Thromboembolic Events: Thromboembolic events may occur. Interrupt HYMPAVZI prophylaxis if symptoms occur. ( 5.1 ) • Hypersensitivity: Hypersensitivity reactions may occur. In the event of a severe allergic reaction, discontinue HYMPAVZI. ( 5.2 ) • Embryofetal Toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.3 , 8.1 , 8.3 ) • Increased Laboratory Values of Fibrin D-dimer and Prothrombin Fragment 1.2: HYMPAVZI can cause sporadic or transient increases in fibrin D-dimer and prothrombin fragment 1.2 above physiological values. ( 5.4 ) 5.1 Thromboembolic Events HYMPAVZI is a tissue factor pathway inhibitor (TFPI) antagonist, and may increase the risk of thromboembolic complications. Venous and arterial thromboembolic events were reported in 0.8% of patients (2/259) treated with HYMPAVZI in the open-label extension study [see Adverse Reactions (6.1) ] . Patients with independent risk factors for thromboembolic events may be at increased risk of thromboembolic events with use of HYMPAVZI. HYMPAVZI has not been studied in patients with a history of previous thromboembolic events [see Clinical Studies (14.1) ] . Consider the benefit and risk of using HYMPAVZI in patients with known risk factors for thromboembolism. Interrupt HYMPAVZI prophylaxis if diagnostic findings consistent with thromboembolism occur and manage as clinically indicated. If factor VIII or factor IX products or bypassing agents are indicated in a patient receiving HYMPAVZI prophylaxis, the minimum effective dose according to the product label is recommended [see Dosage and Administration (2.5) ] . 5.2 Hypersensitivity HYMPAVZI may cause hypersensitivity reactions (including but not limited to urticaria and pruritus). If HYMPAVZI-treated patients develop a severe hypersensitivity reaction, advise patients to discontinue HYMPAVZI and seek immediate emergency treatment. 5.3 Embryofetal Toxicity Based on its mechanism of action, HYMPAVZI may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with HYMPAVZI and for 2 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ] . 5.4 Increased Laboratory Values of Fibrin D-dimer and Prothrombin Fragment 1.2 Consistent with its mechanism of action and hemostatic effect, HYMPAVZI causes an increase in fibrin D‑dimer and prothrombin fragment 1.2 [see Clinical Pharmacology (12.1 , 12.2) ] . Sporadic or transient increases in levels of these biomarkers above physiological values were reported with no associated safety concerns [see Clinical Pharmacology (12.2) ] . Increased levels of fibrin D-dimer were seen in 10 (8.1%) pediatric patients age 6 to less than 18 years and 6 (4.4%) adults. Increased levels of prothrombin fragment 1.2 were seen in 13 (10.5%) pediatric patients age 6 to less than 18 years and 6 (4.4%) adults. For patients taking HYMPAVZI, these coagulation biomarkers may not be reliable predictive markers for clinical decision-making with suspicion of thrombosis such as deep vein thrombosis (DVT) and pulmonary embolism (PE).

7 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.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Thromboembolic Events [see Warnings and Precautions (5.1) ] • Hypersensitivity [see Warnings and Precautions (5.2) ] Adverse reactions reported in ≥2% of HYMPAVZI-treated patients were injection site reaction, headache, pyrexia, arthralgia, diarrhea, pruritus, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 adults and pediatric patients 6 years of age and older with severe hemophilia A (FVIII <1%) or moderately severe to severe hemophilia B (FIX ≤2%) with and without inhibitors enrolled in the BASIS and BASIS KIDS studies. A total of 259 patients received the recommended HYMPAVZI prophylaxis loading dose followed by a weekly maintenance dose starting at Day 8 administered subcutaneously [see Clinical Studies (14.1 , 14.2 , 14.3 )] . One-hundred-thirty-five (52%) were adults (18 years of age and older), 56 (22%) were adolescents (12 to less than 18 years of age), and 68 (26%) were children (6 to less than 12 years of age). Among patients receiving HYMPAVZI, 90% were exposed for 6 months or longer and 82% were exposed for at least 1 year. The median duration of exposure across the studies was 364 days (min, max: 14, 406 days). Table 1 summarizes the adverse reactions reported in ≥2% of patients in all age groups who received HYMPAVZI prophylaxis. Table 1. Adverse Reactions Reported in ≥2% of Patients Treated with HYMPAVZI During BASIS and BASIS KIDS studies 12-month active treatment phase By Age Group Adverse Reaction Number of Patients 6 to less than 18 Years n (%) (N = 124) Number of Patients 18 Years and Older n (%) (N = 135) Number of Patients (All Age Groups) n (%) (N = 259) Injection site reaction Injection site reaction is a grouped term which includes the following terms: injection site pruritus, injection site swelling, injection site erythema, injection site bruising, injection site induration, injection site pain, injection site edema, injection site hematoma, injection site hemorrhage, injection site warmth, and injection site urticaria. 19 (15) 11 (8) 30 (12) Headache Headache is a grouped term which includes migraine. 9 (7) 10 (7) 19 (7) Pyrexia 12 (10) 3 (2) 15 (6) Arthralgia 4 (3) 5 (4) 9 (3) Diarrhea 5 (4) 2 (2) 7 (3) Pruritus 1 (1) 5 (4) 6 (2) Rash 2 (2) 3 (2) 5 (2)

8.1 Pregnancy Risk Summary Based on its mechanism of action, HYMPAVZI may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . 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.