MIMRYLO

1 INDICATIONS AND USAGE MIMRYLO is indicated for the treatment of erythrocytosis in adults with polycythemia vera (PV). MIMRYLO is a hepcidin mimetic indicated for the treatment of erythrocytosis in adults with polycythemia vera (PV). ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended starting dose: 19 mg by subcutaneous injection once a week. ( 2.1 ) Adjust dose based on efficacy or safety to a maximum of 108 mg weekly. ( 2.1 ) See Full Prescribing Information for instructions on preparation and administration. ( 2.4 ) 2.1 Recommended Dosage MIMRYLO is for subcutaneous use only. The recommended weekly dosage range of MIMRYLO is 9.5 mg to 108 mg. The recommended starting dose of MIMRYLO is 19 mg once a week. Doses above 54 mg will require two injections. Doses greater than 82 mg should be administered on separate days. Administer MIMRYLO subcutaneously on a weekly dosing schedule. See Table 1 . Table 1: MIMRYLO Weekly Dosing Instructions MIMRYLO Weekly Dose Doses higher than 54 mg are administered as 2 injections. If the weekly dosage is greater than 82 mg, administer your first injection on day 1 and the second injection on day 4 or 5. Dosing Instructions Frequency During Each Week 9.5 mg Single injection Once weekly 19 mg 28 mg 41 mg 54 mg 69 mg 28 mg AND 41 mg Once weekly on the Same Day 82 mg 41 mg AND 41 mg Once weekly on the Same Day 95 mg Day 1: 54 mg Day 4 or 5: 41 mg Day 1 and Day 4 or 5 108 mg Day 1: 54 mg Day 4 or 5: 54 mg Adjust the dose of MIMRYLO based on efficacy or safety [see Dosage and Administration (2.2) ] . 2.2 Dose Modifications Monitor complete blood count (CBC) every 2 to 4 weeks or as clinically indicated during dose modifications. Dose increase: After a minimum of 2 weeks at the current weekly dose, dose increase may be considered according to Table 2 and based on medical judgement to reduce or to maintain hematocrit at the recommended level below 45%. Allow a minimum of 2 weeks between dose increases. Table 2: Recommended MIMRYLO Dose Increase to Reduce or to Maintain Hematocrit Below 45% Current Weekly Dose Increase Weekly Dose to 9.5 mg 19 mg 19 mg 28 mg 28 mg 41 mg 41 mg 54 mg 54 mg 69 mg 69 mg 82 mg 82 mg 95 mg 95 mg 108 mg Dose decrease: For Grade ≥2 anemia or for drug-related Grade ≥3 toxicities, reduce the dose of MIMRYLO according to Table 3 . Table 3: Recommended MIMRYLO Dose Decrease for Patients Experiencing Grade ≥2 Anemia or for Drug-Related Grade ≥3 Toxicities Current Weekly Dose Decrease Weekly Dose to 9.5 mg Discontinue treatment 19 mg 9.5 mg 28 mg 19 mg 41 mg 28 mg 54 mg 41 mg 69 mg 54 mg 82 mg 69 mg 95 mg 82 mg 108 mg 95 mg 2.3 Missed Dose For patients injecting once a week If the injection is missed by 1 to 4 days, take the missed injection immediately and then resume regular dosing schedule. If the injection is missed by more than 4 days, take the missed injection immediately. Take the next injection 3 days later and then resume the regular dosing schedule. For patients injecting two times a week If the injection is missed by 1 to 2 days, take the missed injection immediately and take the next injection 3 days later. Then resume the regular dosing schedule. If the injection is missed by more than 2 days, skip the missed injection and continue the regular dosing schedule. 2.4 Preparation and Administration Instructions Prior to treatment initiation, healthcare providers should show patient and/or caregivers how to prepare and inject MIMRYLO subcutaneously into the abdomen, thigh, or upper arm. Advise patients and/or caregivers to contact healthcare providers with questions. For detailed instructions on the preparation and administration of MIMRYLO, see the Instructions for Use provided in the product carton. Preparation : Determine the number of vial(s) of MIMRYLO needed for the full dose. MIMRYLO must be reconstituted using the provided diluent prefilled syringe. Attach the vial adapter to the vial(s). Attach the diluent syringe to the vial adapter. Inject all of the diluent from the attached syringe into the vial containing lyophilized powder. Do not remove the syringe from the vial adapter. Gently swirl the vial to reconstitute. This may take about 2 minutes. Do not shake. Set the vial on a clean flat surface and let it …

3 DOSAGE FORMS AND STRENGTHS For injection: a sterile, white to off-white lyophilized powder for reconstitution in single-dose vials containing 9.5 mg, 19 mg, 28 mg, 41 mg, and 54 mg rusfertide (provided as rusfertide acetate) per vial, co-packaged with a clear diluent solution. For injection: 9.5 mg, 19 mg, 28 mg, 41 mg, and 54 mg of rusfertide as a lyophilized powder in single-dose vials for reconstitution. ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: New or Worsening Thrombocytosis [see Warnings and Precautions (5.1) ] Injection-Site Reactions [see Warnings and Precautions (5.2) ] Most common adverse reactions (incidence >15%) were injection site reactions (56%), and anemia (16%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals America, Inc. at 1-877-TAKEDA-7 (1-877-825-3327) 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. Polycythemia Vera VERIFY The safety of MIMRYLO was evaluated in VERIFY [see Clinical Studies (14) ] , a Phase 3, randomized double-blind, placebo-controlled study in patients with PV. During the randomized controlled period (Week 0 to Week 32), 145 patients received MIMRYLO and 146 patients received placebo. Following the randomized controlled period, patients in the placebo arm crossed over to MIMRYLO, resulting in a total of 285 patients exposed to MIMRYLO during the study. The median duration of exposure to MIMRYLO was 61 weeks (range; 2 weeks to 133 weeks) with 65% of patients exposed to ≥52 weeks. During the randomized controlled period (Week 0 to Week 32), the most common (>15%) adverse reactions in the MIMRYLO arm were injection site reactions (56%) and anemia (16%). One (0.4%) patient experienced a serious adverse reaction of anemia. Dosage reductions of MIMRYLO due to an adverse reaction occurred in 30 (11%) patients. Adverse reactions which required dosage reduction included anemia in 28 (10%) patients, dyspnea in 2 (0.7%) patients and thrombocytosis in 1 (0.4%) patient. Adverse reactions which resulted in permanent discontinuation of MIMRYLO included injection site reactions in 2 (0.7%) patients, thrombocytosis in 2 (0.7%) patients and anemia in 1 (0.4%) patient. Table 4 summarizes the adverse reactions occurring in ≥5% of the patients with a difference of ≥5 percentage points between the MIMRYLO arm and the placebo arm in the randomized part (Week 0 to Week 32) of the VERIFY study. Table 4: Adverse Reactions Occurring in ≥5% Patients with a Difference of ≥5 Percentage Points Between the MIMRYLO Arm and the Placebo Arm in VERIFY (Week 0 to Week 32) Adverse Reaction MIMRYLO (n = 145) PLACEBO (n = 146) All Grades (%) Grade 3 (%) All Grades (%) Grade 3 (%) Injection site reactions 56 0.7 33 0 Anemia Includes anemia and hemoglobin decreased. 16 0 4.1 0 Thrombocytosis Includes thrombocytosis and platelet count increased. 8 0 0.7 0 Dyspnea Includes dyspnea and dyspnea exertional. 8 0 1.4 0

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding not recommended. ( 8.2 ) 8.1 Pregnancy Risk Summary There are no available data on MIMRYLO use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Based on findings from animal studies, MIMRYLO may cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.3) ] . In animal reproductive studies, subcutaneous administration of rusfertide to pregnant rats and rabbits during organogenesis at exposures lower than the human exposure (based on AUC) at the maximum recommended human dose (MRHD) resulted in malformations and embryo fetal lethality, respectively [see Data ] . The estimated background risk of major birth defects and miscarriage for the indicated population 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 defect and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryo-fetal development study in pregnant rats, rusfertide administered subcutaneously at 0.3, 1, and 3 mg/kg/dose administered every three days from gestation day (GD) 6 to 15 caused dose-dependent increases in the incidence of craniofacial and CNS malformations (narrowed nasopharynx, dilated cerebral ventricles, enlarged olfactory lobes, eye defects and fused ribs) at doses 1 mg/kg/dose and higher at exposures less than the clinical exposures at the MRHD based on AUC. In an embryo-fetal development study in pregnant rabbits, rusfertide administered subcutaneously at 0.03, 0.1, 0.3, and 1 mg/kg/dose from GD 7 to 16 caused embryo-fetal lethality at a dose of 1 mg/kg at exposures less than the clinical exposures at the MRHD based on AUC. 8.2 Lactation Risk Summary There are no data on the presence of rusfertide in either human or animal milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, including impaired iron absorption, advise patients not to breastfeed during treatment with MIMRYLO and for 30 days after the final treatment. 8.3 Females and Males of Reproductive Potential Based on animal data, MIMRYLO may cause fetal malformations at doses with exposures less than the clinical exposure at the MRHD [see Use in Specific Populations (8.1) ] . Pregnancy testing Pregnancy testing is recommended for females of reproductive potential. Contraception Females MIMRYLO may cause fetal harm when administered to pregnant women. Advise female patients of reproductive potential to use effective contraception during treatment with MIMRYLO and for at least 30 days after the final dose of MIMRYLO [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1) ]. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use There were 71 (25%) patients 65 years of age and older that received MIMRYLO in the VERIFY study [see Clinical Studies (14) ] , while 22 (8%) were 75 years of age and older. No overall differences in safety or effectiveness of MIMRYLO have been observed between patients 65 years of age and older and younger adult patients.

12.1 Mechanism of Action Rusfertide is a mimetic of the endogenous hormone hepcidin that blocks the iron transporter ferroportin. Inhibition of ferroportin by rusfertide reduces availability of iron for production of red blood cells resulting in lower hematocrit levels.

11 DESCRIPTION MIMRYLO (rusfertide) for injection, for subcutaneous use, a hepcidin mimetic, is a synthetic cyclic peptide (disulfide) isolated as an acetate salt. The chemical name for rusfertide is S 6 , S 16 -cyclo[ N -isovaleryl-Asp-Thr-His-Phe-Pro-Cys-Ile- Nε -( N -palmitoyl-γ-Glu)-Lys-Phe-Glu-Pro-Arg-Ser-Lys-Gly-Cys-Lys-NH 2 ] acetate. Rusfertide acetate has the following chemical structure: Rusfertide acetate is an amorphous white to off-white powder, light sensitive and hygroscopic with low solubility in ethanol or acetonitrile. The aqueous solubility in pH range of 2.5 to 7.4 is ≥112 mg/mL. The average molecular weight for the free base is 2442.0 u. The molecular formula for the free base is C 114 H 181 N 27 O 28 S 2 . MIMRYLO for injection is supplied as a sterile, preservative-free, white to off-white lyophilized powder in a single-dose glass vial. The 9.5 mg dose strength delivers 9.5 mg of rusfertide (provided as rusfertide acetate), mannitol (25 mg), sodium acetate trihydrate (1.36 mg), and glacial acetic acid/sodium hydroxide for pH adjustment, for subcutaneous injection after reconstitution with the provided diluent. The 19 mg, 28 mg, 41 mg, and 54 mg dose strengths deliver 19 mg, 28 mg, 41 mg and 54 mg of rusfertide (provided as rusfertide acetate), mannitol (20 mg), sodium acetate trihydrate (1.36 mg), and glacial acetic acid/sodium hydroxide for pH adjustment, for subcutaneous injection after reconstitution with the provided diluent. The diluent for MIMRYLO is a sterile, preservative-free solution containing sodium acetate trihydrate (1.36 mg/mL), zinc acetate dihydrate (2.2 mg/mL), and glacial acetic acid for adjusting the pH to nominal pH of 5.4 in Water for Injection, USP. It is a clear, colorless solution, free from visible particles, and is provided in a glass prefilled syringe. After reconstitution, MIMRYLO is a clear and colorless solution free from visible particles. chemical structure

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied MIMRYLO for injection is supplied in a carton for each individual dosage strength comprising a single-dose vial containing a sterile, preservative-free, white to off-white lyophilized powder and a single-dose prefilled syringe containing a clear, colorless solution (diluent) with a luer lock adapter and soft inner tip cap. Not made with natural rubber latex. Dosage Strength (mg/vial) Color Cap Indicator Vial NDC Number Carton NDC Number 9.5 Blue 63020-710-10 63020-715-10 19 Lime 63020-720-20 63020-725-20 28 Burgundy 63020-730-30 63020-735-30 41 Yellow 63020-740-40 63020-745-40 54 White 63020-760-60 63020-765-60 Prefilled Diluent Syringe NDC 63020-600-05 Storage and Handling Store at room temperature between 20°C to 25°C (68°F to 77°F). Do not freeze. Store in the original carton to protect from light. Do not use the vial or the diluent prefilled syringe after the expiration date on the carton. For detailed instructions on the preparation and administration of MIMRYLO, see the Instructions for Use provided in the product carton. After reconstitution, MIMRYLO may be stored at room temperature between 20°C to 25°C (68°F to 77°F) for up to 4 hours. After reconstitution, administer MIMRYLO within 4 hours. Discard reconstituted solution if not used within 4 hours.