AMVUTTRA

1 INDICATIONS AND USAGE AMVUTTRA is a transthyretin-directed small interfering RNA indicated for the treatment of: the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults ( 1.1 ) the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality, cardiovascular hospitalizations and urgent heart failure visits ( 1.2 ) 1.1 Polyneuropathy of Hereditary Transthyretin-mediated Amyloidosis AMVUTTRA is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults. 1.2 Cardiomyopathy of Wild-type or Hereditary Transthyretin-mediated Amyloidosis AMVUTTRA is indicated for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality, cardiovascular hospitalizations and urgent heart failure visits.

2 DOSAGE AND ADMINISTRATION The recommended dosage of AMVUTTRA is 25 mg administered by subcutaneous injection once every 3 months. ( 2.1 ) AMVUTTRA is for subcutaneous use only and should be administered by a healthcare professional. ( 2.2 ) 2.1 Recommended Dosage The recommended dosage of AMVUTTRA is 25 mg administered by subcutaneous injection once every 3 months [see Dosage and Administration (2.2) ] . Missed Dose If a dose is missed, administer AMVUTTRA as soon as possible. Resume dosing every 3 months from the most recently administered dose. 2.2 Administration Instructions AMVUTTRA is for subcutaneous use only and should be administered by a healthcare professional. Syringe Appearance Before and After Use Before Use After Use Image Image Preparation and Administration 1. Prepare the syringe If stored cold, allow the syringe to warm to room temperature for 30 minutes prior to use. Remove the syringe from the packaging by gripping the syringe body. Do not touch the plunger rod until ready to inject. Visually inspect the drug solution for discoloration and particulate matter prior to administration. AMVUTTRA is a sterile, preservative-free, clear, colorless-to-yellow solution. Do not use if it contains particulate matter or if it is cloudy or discolored. Check the following: Syringe is not damaged, such as cracked or leaking Needle cap is attached to the syringe Expiration date on syringe label Do not use the syringe if any issues are found while checking the syringe. 2. Choose and prepare the injection site Choose an injection site from the following areas: the abdomen, thighs, or upper arms. Avoid the following: 5-cm area around the navel Scar tissue or areas that are reddened, inflamed, or swollen Clean the chosen injection site. 3. Prepare the syringe for injection Hold the syringe body with one hand. Pull the needle cap straight off with other hand and dispose of needle cap immediately. It is normal to see a drop of liquid at the tip of the needle. Do not touch the needle or let it touch any surface. Do not recap the syringe. Do not use the syringe if it is dropped. 4. Perform the injection Pinch the cleaned skin. Fully insert the needle into the pinched skin at a 45°-90° angle. Inject all of the medication. Push the plunger rod as far as it will go to administer the dose and activate the needle shield. Release the plunger rod to allow the needle shield to cover the needle. Do not block plunger rod movement. 5. Dispose of the syringe Immediately dispose of the used syringe into a sharps container. Image Image Image Image Image

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Reduced serum vitamin A levels and recommended supplementation: Supplement with the recommended daily allowance of vitamin A. Refer to an ophthalmologist if ocular symptoms suggestive of vitamin A deficiency occur. ( 5.1 ) 5.1 Reduced Serum Vitamin A Levels and Recommended Supplementation AMVUTTRA treatment leads to a decrease in serum vitamin A levels [see Adverse Reactions (6.1) and Clinical Pharmacology (12.2) ] . Supplementation at the recommended daily allowance of vitamin A is advised for patients taking AMVUTTRA. Higher doses than the recommended daily allowance of vitamin A should not be given to try to achieve normal serum vitamin A levels during treatment with AMVUTTRA, as serum vitamin A levels do not reflect the total vitamin A in the body. Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness).

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) ] The most common adverse reactions (≥5%) were pain in extremity, arthralgia, dyspnea, and vitamin A decreased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alnylam Pharmaceuticals at 1-877-256-9526 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 AMVUTTRA cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Two Phase 3 randomized, multi-center studies evaluated the safety of AMVUTTRA in 448 transthyretin-mediated amyloidosis (ATTR) patients, including 122 patients with hATTR-PN (HELIOS-A) and 326 patients with ATTR-CM (HELIOS-B) [see Clinical Studies (14) ] . In both studies, patients were instructed to take the recommended daily allowance of vitamin A [see Warnings and Precautions (5.1) ] . Polyneuropathy of Hereditary Transthyretin-mediated Amyloidosis In HELIOS-A, 118 patients received at least 18 months of treatment. The mean duration of treatment was 18.8 months (range: 1.7 to 19.4 months). The median patient age at baseline was 60 years and 65% of the patients were male. Seventy percent of AMVUTTRA-treated patients were Caucasian, 17% were Asian, 3% were Black, and 9% were reported as Other. Forty-four percent of patients had the Val30Met mutation in the transthyretin gene; the remaining patients had one of 21 other mutations. At baseline, 70% of patients were in Stage 1 of the disease and 30% were in Stage 2. The most common adverse reactions (at least 5%) were pain in extremity, arthralgia, dyspnea, and vitamin A decreased (see Table 1 ) . Seventy-four percent of patients treated with AMVUTTRA had normal vitamin A levels at baseline, and 98% of those with a normal baseline developed low vitamin A levels. In some cases, the decreased vitamin A level was reported as an adverse reaction (see Table 1 ) . Table 1: Adverse Reactions Reported in at least 5% of Patients Treated with AMVUTTRA in HELIOS-A Adverse Reaction AMVUTTRA N=122 % Pain in extremity 15 Arthralgia Comprised of several similar terms 11 Dyspnea 7 Vitamin A decreased Percentage only reflects those reported as an adverse reaction 7 In HELIOS-A, two serious adverse reactions of atrioventricular (AV) heart block (1.6%) occurred in patients treated with AMVUTTRA, including one case of complete AV block. Injection site reactions were reported in 5 (4%) patients treated with AMVUTTRA. Reported symptoms included bruising, erythema, pain, pruritus, and warmth. Injection site reactions were mild and transient. Cardiomyopathy of Wild-type or Hereditary Transthyretin-mediated Amyloidosis In HELIOS-B, safety was evaluated in 654 patients with ATTR-CM, which included 257 patients treated with AMVUTTRA for ≥30 months, and 77 patients treated with AMVUTTRA for ≥36 months [see Clinical Studies (14) ] . No new safety issues were identified. Eighty-two percent of patients treated with AMVUTTRA had normal vitamin A levels at baseline, and 80% of those with a normal baseline developed low vitamin A levels.

8.1 Pregnancy Risk Summary There are no available data on AMVUTTRA use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. AMVUTTRA treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised for patients taking AMVUTTRA. Vitamin A is essential for normal embryofetal development; however, excessive levels of vitamin A are associated with adverse developmental effects. The effects on the fetus of a reduction in maternal serum TTR caused by AMVUTTRA and of vitamin A supplementation are unknown [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2) ] . In animal studies, subcutaneous administration of vutrisiran to pregnant rats resulted in developmental toxicity (reduced fetal body weight and embryofetal mortality) at doses associated with maternal toxicity (see Data ) . 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. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Subcutaneous administration of vutrisiran (0, 3, 10, or 30 mg/kg/day) to pregnant rats during the period of organogenesis resulted in embryofetal mortality at the high dose and reduced fetal body weight at the mid and high doses, which were associated with maternal toxicity. Subcutaneous administration of vutrisiran (0, 3, 10, or 30 mg/kg/day) to pregnant rabbits resulted in no adverse effects on embryofetal development. Subcutaneous administration of vutrisiran (0, 5, 10, or 20 mg/kg) to pregnant rats every 6 days throughout pregnancy and lactation resulted in no adverse developmental effects on the offspring.