RIVFLOZA

RIVFLOZA injection contains nedosiran, a double-stranded small interfering RNA (siRNA) with four covalently attached N -acetyl-D-galactosamine (GalNAc) residues. Nedosiran targets lactate dehydrogenase A (LDHA) in hepatocytes via GalNAc-mediated delivery. The structural formula of the nedosiran sodium drug substance is presented below: The molecular formula of nedosiran sodium is C 662 H 808 F 19 N 231 O 413 P 57 S 6 Na 57 with a molecular weight of 22,238 Da. Nedosiran sodium is freely soluble in water. RIVFLOZA Pre-filled Syringe is supplied as a clear, sterile, preservative-free, colorless‑to‑yellow solution for subcutaneous injection containing either the equivalent of 160 mg (present as 170 mg nedosiran sodium salt) nedosiran in 1 mL or the equivalent of 128 mg (present as 136 mg nedosiran sodium salt) nedosiran in 0.8 mL of water for injection and sodium hydroxide and/or hydrochloric acid to adjust the pH to ~7.2. RIVFLOZA vial is supplied as a clear, sterile, preservative-free, colorless-to-yellow solution for subcutaneous injection containing the equivalent of 80 mg (present as 85 mg nedosiran sodium salt) nedosiran in 0.5 mL of water for injection and sodium hydroxide and/or hydrochloric acid to adjust the pH to ~7.2. structural_formula

RIVFLOZA is indicated to lower urinary oxalate levels in children 2 years of age and older and adults with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function, e.g., eGFR ≥30 mL/min/1.73 m 2 [see Clinical Pharmacology (‎ 12.3 )], Clinical Studies (‎ 14.1 )]. RIVFLOZA is an LDHA -directed small interfering RNA indicated to lower urinary oxalate levels in children 2 years of age and older and adults with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function, e.g., eGFR ≥30 mL/min/1.73 m 2 . (‎ 1 )

The recommended dosage is shown below and is administered subcutaneously once monthly. (‎ 2.1 ) Body weight Less than 39 kg 39 kg to less than 50 kg 50 kg and above Age 2 to less than 12 years 3.3 mg/kg 128 mg 160 mg Age 12 years and older 128 mg 160 mg See full Prescribing Information for important administration instructions. (‎ 2.2 ) 2.1 Recommended Dosage RIVFLOZA is administered subcutaneously once monthly at the recommended doses shown in Table 1 . Dosing is based on actual body weight. Table 1: RIVFLOZA Dose Regimen in Adults and Pediatric Patients (2 years of age and older) Body weight Less than 39 kg 39 kg to less than 50 kg 50 kg and above Age 2 to less than 12 years 3.3 mg/kg 128 mg 160 mg Age 12 years and older 128 mg 160 mg Missed Dose If a planned dose is missed, administer RIVFLOZA as soon as possible. If the planned dose is missed by more than 7 days, administer RIVFLOZA as soon as possible and resume monthly dosing from the most recently administered dose. 2.2 Administration Instructions Pre-filled syringe: A healthcare provider, caregiver, or patient 12 years of age and older may inject RIVFLOZA using the pre-filled syringe. In pediatric patients 2 to less than 12 years of age who weigh ≥39 kg, a healthcare provider or caregiver may inject RIVFLOZA using the pre-filled syringe. Vials: RIVFLOZA vials are intended for use under the guidance and supervision of a healthcare provider. Adult patients or caregivers may administer RIVFLOZA after proper training in preparing RIVFLOZA vials for administration, if a healthcare provider determines that it is appropriate, and with medical follow-up as necessary. Administer RIVFLOZA by subcutaneous injection to the abdomen (at least 2 inches from the navel) or the upper thigh. Do not inject into a vein or into scarred or bruised skin. Inspect visually for particulate matter and discoloration prior to injection. RIVFLOZA should be colorless-to-yellow and particle free. If the solution is cloudy or contains particulate matter, do not use. Instructions for delivering the dosage are provided in the Instructions for Use leaflets enclosed with the RIVFLOZA Pre-filled Syringe and single-dose vial. Discard the unused portion of the drug.

None. None. ( 4 )

Most common adverse reactions (reported in ≥20% of patients) are injection site reactions. (‎ 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-844-906-5099 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 RIVFLOZA has been evaluated in one placebo-controlled clinical trial (PHYOX2) and one open-label extension study (PHYOX3). Across these studies, 29 adults and 12 children with PH1 have been treated with RIVFLOZA. Patients with PH1 in these studies ranged in age from 9 to 46 years at first dose. The median duration of exposure was approximately 15 months (range 1-29 months). Overall, 38 patients with PH1 were treated for at least 6 months, 24 patients for at least 12 months, and 16 patients for at least 18 months. In the randomized, placebo-controlled, double-blind PHYOX2 trial in pediatric and adult patients 9 to 46 years of age, 18 patients with PH1 received RIVFLOZA and 11 patients received placebo. Of the 18 patients treated with RIVFLOZA, 17 patients received ≥5 months of active treatment. The most common adverse reactions were injection site reactions, which were reported in 7 patients with PH1 (39%) on RIVFLOZA as compared to no patients on placebo. Injection site reactions included erythema, pain, bruising, and rash and were generally mild and did not lead to discontinuation of treatment. In the single-arm extension study (PHYOX3) that included 40 patients with PH1, additional injection site reactions included atrophy in 1 patient (3%). The safety of RIVFLOZA has additionally been evaluated in one single-arm clinical study (PHYOX8) in 15 pediatric patients 2 to less than 12 years of age with PH1 and an eGFR > 30 mL/min/1.73 m 2 . Injection site reactions were reported in 2 patients (13%). Overall, the RIVFLOZA safety profile was similar to that seen in PHYOX2.