WAINUA

Dosage and Administration ( 2.2 , 2.4 ) 04/2026

1 INDICATIONS AND USAGE WAINUA is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. WAINUA is a transthyretin-directed antisense oligonucleotide indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. ( 1 )

2 DOSAGE AND ADMINISTRATION • The recommended dosage of WAINUA is 45 mg administered by subcutaneous injection once monthly. ( 2.1 ) • Administer WAINUA into the abdomen or upper thigh region; the back of the upper arm can be used if a healthcare provider or caregiver administers the injection. ( 2.2 ) • The prefilled syringe must be administered by a healthcare provider. ( 2.4 ) 2.1 Recommended Dosage The recommended dosage of WAINUA is 45 mg administered by subcutaneous injection once monthly [see Dosage and Administration (2.2) ] . Missed Dose Administer WAINUA as soon as possible after a missed dose. Resume dosing at monthly intervals from the date of the most recently administered dose. 2.2 General Administration Instructions Each autoinjector and prefilled syringe contains a single dose of WAINUA. Prior to administration of the autoinjector or prefilled syringe: • Do not use if WAINUA has been dropped or damaged, appears to be tampered with, or if the expiration date has passed. • Remove WAINUA from the refrigerator 30 minutes prior to the injection to reach room temperature. Do not use other warming methods. • Visually inspect WAINUA before use. The solution should appear colorless to yellow. Do not use if cloudiness, particulate matter, or discoloration is observed. To deliver a 45 mg dose of WAINUA, administer the entire contents of one autoinjector or prefilled syringe [see Dosage and Administration (2.3) , (2.4) ] , as a subcutaneous injection in the upper thigh or the abdomen. The back of the upper arm can also be used as an injection site if a healthcare provider or caregiver administers the injection. Do not inject WAINUA into the area 2 inches (5 cm) around the navel or into areas where the skin is red, warm, tender, bruised, scaly or hard. Rotate the injection site with each injection . 2.3 Administration Instructions for WAINUA Autoinjector The autoinjector is intended for self-administration by patients or administration by caregivers. Prior to initiation, train patients and/or caregivers on proper preparation and administration of WAINUA autoinjector [see Instructions for Use ] . 2.4 Administration Instructions for WAINUA Prefilled Syringe (Healthcare Providers Only) The prefilled syringe must be administered by a healthcare provider. Refer to Figure 1 to identify the prefilled syringe components for use in the administration steps. Do not remove the needle cover until you are ready to inject WAINUA. Do not touch the needle guard activation clips to prevent premature activation of the needle safety guard. Figure 1: WAINUA Prefilled Syringe Components Administration Steps Step 1 Remove the prefilled syringe from its tray. Hold the syringe body and remove the needle cover by pulling straight off. Do not recap. If small air bubbles are present, do not expel them prior to administration. Step 2 Choose an injection site (i.e., back of upper arm, upper thigh, or abdomen). Gently pinch the skin and insert the needle subcutaneously at approximately a 45° angle into the chosen injection site. Step 3 Once the entire dose has been injected, the needle safety device will be triggered. As you let go of the plunger, the needle is automatically pulled from the skin, and into the device; the entire needle will be covered by the needle guard. Figure_1

3 DOSAGE FORMS AND STRENGTHS Injection: 45 mg/0.8 mL of eplontersen as a clear, colorless-to-yellow solution available in a single dose autoinjector or a single-dose prefilled syringe. Injection: • 45 mg/0.8 mL in a single-dose autoinjector. ( 3 ) • 45 mg/0.8 mL in a single-dose prefilled syringe. ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: • Reduced Serum Vitamin A Levels and Recommended Supplementation [see Warnings and Precautions (5.1) ]. Most common adverse reactions (that occurred in at least 9% of patients treated with WAINUA) were vitamin A decreased and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 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 WAINUA cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In Study 1 [see Clinical Studies (14) ] , a total of 144 patients with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) were randomized to WAINUA and received at least one dose of WAINUA. Of these, 141 patients received at least 6 months of treatment and 107 patients received at least 12 months of treatment. The mean duration of treatment was 15 months (range: 1.9 to 19.4 months). The median patient age at baseline was 52 years and 69% of the patients were male. Seventy-eight percent of patients treated with WAINUA were White, 15% were Asian, 4% were Black, 2% were reported as other races, and <1% were multiple races. Fifty-nine percent of patients had the Val30Met variant in the transthyretin gene; the remaining patients had one of 19 other variants. At baseline, 80% of patients were in Stage 1 of the disease and 20% were in Stage 2 with a mean duration from polyneuropathy diagnosis of 47 months. The mean duration from onset of polyneuropathy symptoms was 68 months. Table 1 lists the adverse reactions that occurred in at least 5% of patients treated with WAINUA in Study 1. Table 1: Adverse Reactions Reported in at least 5% of Patients Treated with WAINUA (Study 1) Adverse Reaction WAINUA N=144 % Vitamin A decreased Vitamin A decreased includes vitamin A deficiency and vitamin A decrease. 15 Vomiting 9 Proteinuria 8 Injection site reactions Injection site reactions includes erythema, pain, and pruritus. 7 Blurred vision 6 Cataract 6 Three serious adverse reactions of atrioventricular (AV) heart block (2%) occurred in WAINUA-treated patients, including 1 case of complete AV block. Laboratory Tests Vitamin A Decrease In Study 1, patients were instructed to take the recommended daily allowance of vitamin A [see Warnings and Precautions (5.1) ] . All patients treated with WAINUA had normal vitamin A levels at baseline, 95% of patients developed low vitamin A levels during the study. In some cases, the decreased vitamin A level was reported as an adverse reaction.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on WAINUA use in pregnant women to inform drug-associated risk of adverse developmental outcomes. WAINUA treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised for patients taking WAINUA. Vitamin A is essential for normal embryofetal development; however, excessive levels of vitamin A are associated with adverse developmental effects. The effect of vitamin A supplementation on the fetus in the setting of a reduction in maternal serum TTR caused by WAINUA administration is unknown [see Clinical Pharmacology (12.2) and Warnings and Precautions (5.1) ] . No adverse developmental effects were observed when eplontersen or a mouse-specific surrogate was administered to mice prior to mating and continuing throughout organogenesis [see Animal Data ] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Subcutaneous administration of eplontersen (0, 5, 25, or 75 mg/kg) or a mouse-specific surrogate (25 mg/kg) to male and female mice weekly prior to and during mating and administration continued every other day in females throughout the period of organogenesis resulted in no adverse effects on embryofetal development. 8.2 Lactation Risk Summary There is no information regarding the presence of eplontersen in human milk, the effects on the breast-fed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for WAINUA and any potential adverse effects on the breast-fed infant from WAINUA or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use No dose adjustment is required in patients ≥65 years of age [see Clinical Pharmacology (12.3) ] . In Study 1 [see Clinical Studies (14) ] , 44 (31%) patients were 65 to 74 years of age, and 8 (5.6%) patients were ≥75 years of age. No overall differences in safety or effectiveness were observed between these patients and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal Impairment No dose adjustment is necessary in patients with mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] ≥30 to 1 x ULN, or total bilirubin >1.0 to 1.5 x ULN and any AST) [see Clinical Pharmacology (12.3) ] . WAINUA has not been studied in patients with moderate or severe hepatic impairment.

12.1 Mechanism of Action Eplontersen is an antisense oligonucleotide-GalNAc conjugate that causes degradation of mutant and wild-type TTR mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues.

11 DESCRIPTION Eplontersen is a transthyretin-directed antisense oligonucleotide (ASO), covalently linked to a ligand containing three N-acetyl galactosamine (GalNAc) residues to enable delivery of the ASO to hepatocytes. WAINUA contains eplontersen sodium as the active ingredient. Eplontersen sodium is a white to yellow solid and it is freely soluble in water and in phosphate buffer. The molecular formula of eplontersen sodium is C 296 H 417 N 77 O 156 P 20 S 13 Na 20 and the molecular weight is 9046.1 daltons. The chemical name of eplontersen sodium is DNA, d([2′-O-(2-methoxyethyl)]m5rU-sp-[2′-O-(2-methoxyethyl)]m5rC-[2′-O-(2-methoxyethyl)]m5rU-[2′-O-(2-methoxyethyl)]m5rU-[2′-O-(2-methoxyethyl)]rG-G-sp-T-sp-T-sp-A-sp-m5C-sp-A-sp-T-sp-G-sp-A-sp-A-sp-[2′-O-(2-methoxyethyl)]rA-[2′-O-(2-methoxyethyl)]m5rU-[2′-O-(2-methoxyethyl)]m5rC-sp-[2′-O-(2-methoxyethyl)]m5rC-sp-[2′-O-(2-methoxyethyl)]m5rC), 5′-[26-[[2-(acetylamino)-2-deoxy-β-D-galactopyranosyl]oxy]-14,14-bis[[3-[[6-[[2-(acetylamino)-2-deoxy-β-D-galactopyranosyl]oxy]hexyl]amino]-3-oxopropoxy]methyl]-8,12,19-trioxo-16-oxa-7,13,20-triazahexacos-1-yl hydrogen phosphate], sodium salt (1:20). The structure of eplontersen sodium is presented below: WAINUA is a sterile, preservative-free, aqueous solution for subcutaneous injection supplied in a single dose autoinjector or single-dose prefilled syringe. Each dose contains 45 mg eplontersen (equivalent to 47 mg eplontersen sodium) in 0.8 mL of solution. The solution also contains 0.868 mg dibasic sodium phosphate, anhydrous (buffering agent); 0.238 mg monobasic sodium phosphate, dihydrate (buffering agent); 4.2 mg sodium chloride (tonicity modifier); water for injection; and may include hydrochloric acid and/or sodium hydroxide for pH adjustment between 6.9 - 7.9. Each dose of WAINUA injection contains less than 5 mg of sodium and less than 5 mg of phosphorus. Chemical_Structure

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied WAINUA (eplontersen) injection is a sterile, preservative-free, clear, colorless to yellow solution. WAINUA is available as: • carton containing one 45 mg/0.8 mL single-dose autoinjector (NDC 0310-9400-01) • carton containing one 45 mg/0.8 mL single dose prefilled syringe (NDC 0310-9420-01) 16.2 Storage and Handling Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton protected from light. If needed, WAINUA can be kept at room temperature (up to 30°C [86°F]) in the original carton for up to 6 weeks. If not used within the 6 weeks stored at room temperature, discard WAINUA. Do not freeze. Do not expose to heat.