ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS 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 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 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 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 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 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 patient (3%).The safety of RIVFLOZA has additionally been evaluated in one single-arm clinical study (PHYOX8) in 15 pediatric patients to less than 12 years of age with PH1 and an eGFR >30 mL/min/1.73 m2. Injection site reactions were reported in patients (13%). Overall, the RIVFLOZA safety profile was similar to that seen in PHYOX2.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CarcinogenicityLong-term studies to assess carcinogenic risk of nedosiran have not been conducted.GenotoxicityNedosiran was not genotoxic in the in vitro bacterial mutagenicity, in vitro micronucleus assays (human peripheral blood lymphocytes) and in vivo bone marrow micronucleus assay in mice.FertilityWeekly subcutaneous administration of nedosiran at doses of 500, 1000, or 2000 mg/kg or of mouse-specific (pharmacologically active) analog at dose of 10 mg/kg to male mice for weeks prior to and throughout mating, and to female mice for weeks prior to and throughout mating and to gestation day did not affect male or female fertility or early embryonic development.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Nedosiran is double-stranded siRNA, conjugated to GalNAc aminosugar residues. After subcutaneous administration, the GalNAc-conjugated sugars bind to asialoglycoprotein receptors (ASGPR) to deliver nedosiran to hepatocytes.Nedosiran reduces levels of hepatic lactate dehydrogenase (LDH) via the degradation of LDHA messenger ribonucleic acid (mRNA) in hepatocytes through RNA interference. The reduction of hepatic LDH by nedosiran reduces the production of oxalate by the liver, thereby reducing subsequent oxalate burden.. 12.2 Pharmacodynamics The pharmacodynamic effects of RIVFLOZA were evaluated after single-dose and monthly-dose administration in patients with PH1. Dose-dependent reductions in urinary oxalate were observed in the single-dose range of 1.5 mg/kg to 6.0 mg/kg. With the recommended monthly dose regimen of RIVFLOZA, onset of effect was observed at the first measurement (30 days after the first dose) and the effect persisted with continued monthly dosing [see Clinical Studies 14.1)].Cardiac Electrophysiology At the recommended dose, RIVFLOZA does not lead to clinically relevant QT interval prolongation.. 12.3 Pharmacokinetics The pharmacokinetic (PK) properties of RIVFLOZA were evaluated following administration of single and multiple dosages in patients with PH1 or PH2 as summarized in Table 2.Table 2: Pharmacokinetic Parameters of NedosiranNedosiranGeneral InformationSteady State ExposureCmax [Mean (%CV)]844 (44) ng/mLAUC0-last [Mean (%CV)] 13600 (36) ngh/mLDose ProportionalityNedosiran exhibited dose-proportional increase in plasma exposure following single subcutaneous doses from 1.5 to 6.0 mg/kg.Nedosiran exhibited time-independent pharmacokinetics with multiple doses of 160 mg once monthly (body weight >=50 kg), 128 mg once monthly (body weight <50 kg), or 3.3 mg/kg once monthly in the age range of to 11 years. AccumulationNo accumulation of nedosiran was observed in plasma following repeated monthly dosing.AbsorptionTmax [Median (Range)]6 (2 to 12) hoursDistributiona Estimated Vz/F126 LProtein Binding85.6%EliminationHalf-Life (Mean (%CV)])15 (68) hoursEstimated CL/F5.7 L/hrMetabolismPrimary PathwayNedosiran is metabolized by endo- and exonucleases to shorter oligonucleotides.ExcretionPrimary PathwayApproximately 27% of the administered nedosiran dose is excreted unchanged into the urine within 24 hours of dosing.a Nedosiran distributes primarily to the liver after subcutaneous administration.Cmax maximum plasma concentration; AUC0-last area under the plasma concentration-time curve from time of administration (0) to the last measurable time point (last); Tmax time to maximum concentration; Vz/F apparent volume of distribution; CV coefficient of variation; CL/F apparent clearance.Specific PopulationsNo clinically significant differences in the pharmacokinetics or pharmacodynamics of nedosiran were observed based on age (2 to 73 years old), sex, race/ethnicity, mild-to-moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2) [see Use in Specific Populations 8.7 )] or mild hepatic impairment as assessed using the National Cancer Institute Organ Dysfunction Working Group criteria (total bilirubin <= ULN and AST ULN; or total bilirubin >1 to 1.5 ULN and any AST) [see Use in Specific Populations 8.6)].Pediatrics: At the recommended clinical dose, PK exposure of nedosiran is similar in adult and pediatric patients years of age and older.Drug Interaction Studies Concomitant use of pyridoxine (vitamin B6) did not have significant impact on the PK of nedosiran. In vitro studies demonstrated that nedosiran was not an inhibitor or inducer of cytochrome P450 (CYP) enzymes and was neither substrate nor an inhibitor of efflux and uptake transporters.. 13600 (36) ngh/mL. 12.6 Immunogenicity As with all oligonucleotides, including RIVFLOZA, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. Across all clinical studies in the nedosiran development program, including patients with PH1 dosed with RIVFLOZA, RIVFLOZA did not induce or boost anti-drug antibodies (ADA). Among 79 patients tested with the ADA assay, none developed treatment-emergent ADA.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1 PHYOX2 PHYOX2 was randomized, double-blind trial comparing RIVFLOZA and placebo in patients aged years or older with PH1 or PH2 and an eGFR >= 30 mL/min/1.73 m2 (NCT03847909). Too few PH2 patients were enrolled to evaluate efficacy in the PH2 population. Therefore, RIVFLOZA is only indicated for patients with PH1 [see Indications and Usage (1)]. Unless otherwise noted, data are presented for the complete study population (PH1 and PH2).Patients received monthly doses of RIVFLOZA (N=23) or placebo (N=12). The RIVFLOZA dose for patients at least 12 years of age weighing at least 50 kg was 160 mg, for patients at least 12 years of age weighing less than 50 kg was 128 mg, and for children to 11 years of age was 3.3 mg/kg (to maximum of 128 mg).The median age was 20 years (range - 46 years), 51% were female, 71% were White, 17% were Asian, 83% had PH1, and 17% had PH2. At baseline, mean 24-hour urinary oxalate excretion, normalized by 1.73 m2 BSA in patients less than 18 years of age, was 1547 umol/24-hour. Mean plasma oxalate was 8.2 umol/L, 43% of patients had an eGFR >= 90 mL/min/1.73 m2, 34% had an eGFR 60 to 90 mL/min/1.73 m2, 23% had an eGFR 30 to 60 mL/min/1.73 m2, and 60% were taking pyridoxine.The primary efficacy endpoint was the area under the curve, from Days 90 to 180, of the percent change from baseline in 24-hour urinary oxalate excretion (AUC24-hour Uox). The least-squares (LS) mean AUC24-hour Uox was -3486 (95% CI: -5025, -1947) in the RIVFLOZA group compared to 1490 (95% CI: 781, 3761) in the placebo group, for between group difference of 4976 (95% CI: 2803, 7149; p<0.0001).The LS mean percent change from baseline in 24-hour urinary oxalate excretion (corrected for BSA in patients 18 years of age) averaged over Days 90, 120, 150 and 180, was -37% (95% CI: -53%, -21%) in the RIVFLOZA group and 12% (95% CI: -12%, 36%) in the placebo group, for between group difference of 49% (95% CI: 26%, 72%) [Figure 1]. Among patients with PH1, the between group difference was 56% (95% CI: 33%, 80%).Figure 1. Mean (95% CI) Percent Change from Baseline in 24-hour Urinary Oxalate in RIVFLOZA and Placebo-Treated Patients in PHYOX2After months of treatment in PHYOX2, patients could enroll in an ongoing single-arm extension study, PHYOX3 (NCT04042402), in which all patients were treated with RIVFLOZA. The reduction in urinary oxalate was maintained in the 13 patients with PH1 who received an additional months of treatment in PHYOX3.. figure1. 14.2 PHYOX8 PHYOX8 (NCT05001269) was single-arm open-label multicenter study that included patients years of age to less than 12 years of age with PH1 and an eGFR >30 mL/min/1.73 m2.The median age of patients at first dose was years (range to 10 years), 33% were female, and 80% were White. total of 15 patients with PH1 completed treatment; patients were to less than years of age, patients were to less than years of age and patients were to 11 years of age. The mean spot urinary oxalate:creatinine ratio at baseline was 0.36 mmol/mmol. The primary endpoint was the percent change from baseline in spot urinary oxalate:creatinine ratio at Month 6. Patients treated with RIVFLOZA had 64% (95% CI: 44, 84) reduction in spot urinary oxalate:creatinine ratio from baseline at Month (Figure 2). The corresponding absolute reduction in spot urinary oxalate:creatinine ratio at Month was 0.25 mmol/mmol (95% CI: 0.21, 0.29).Figure 2. PHYOX8: Mean (95% CI) Percent Change in Spot Urinary Oxalate: Creatinine Ratio from Baseline by MonthAfter months of treatment in PHYOX8, patients could enroll in an ongoing single arm extension study, PHYOX3. The reduction in urinary oxalate:creatinine ratio was maintained in the patients who received an additional months of treatment in PHYOX3.. figure-2.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS None.. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION RIVFLOZA injection contains nedosiran, double-stranded small interfering RNA (siRNA) with four covalently attached N-acetyl-D-galactosamine (GalNAc) residues. Nedosiran targets lactate dehydrogenase (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 C662H808F19N231O413P57S6Na57 with molecular weight of 22,238 Da. Nedosiran sodium is freely soluble in water.RIVFLOZA Pre-filled Syringe is supplied as 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 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 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.. structuralformula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION The recommended dosage is shown below and is administered subcutaneously once monthly. (2.1)Body weightLess than 39 kg39 kg to less than 50 kg50 kg and aboveAge to less than 12 years3.3 mg/kg128 mg160 mgAge 12 years and older128 mg160 mgSee 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 weightLess than 39 kg39 kg to less than 50 kg50 kg and aboveAge to less than 12 years3.3 mg/kg128 mg160 mgAge 12 years and older128 mg160 mgMissed DoseIf planned dose is missed, administer RIVFLOZA as soon as possible. If the planned dose is missed by more than days, administer RIVFLOZA as soon as possible and resume monthly dosing from the most recently administered dose.. 2.2 Administration Instructions Pre-filled syringe: healthcare provider, caregiver, or patient 12 years of age and older may inject RIVFLOZA using the pre-filled syringe. In pediatric patients to less than 12 years of age who weigh >=39 kg, 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 healthcare provider. Adult patients or caregivers may administer RIVFLOZA after proper training in preparing RIVFLOZA vials for administration, if healthcare provider determines that it is appropriate, and with medical follow-up as necessary.Administer RIVFLOZA by subcutaneous injection to the abdomen (at least inches from the navel) or the upper thigh. Do not inject into 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS RIVFLOZA Injection 160 mg/mL (present as 170 mg nedosiran sodium) is clear, colorless-to-yellow solution available as follows:o80 mg/0.5 mL single-dose vialo128 mg/0.8 mL single-dose Pre-filled Syringeo160 mg/ mL single-dose Pre-filled Syringe. o80 mg/0.5 mL single-dose vial. o128 mg/0.8 mL single-dose Pre-filled Syringe. o160 mg/ mL single-dose Pre-filled Syringe. RIVFLOZA Injection 160 mg/mL is clear, colorless-to-yellow solution available as follows:o80 mg/0.5 mL single-dose vialo128 mg/0.8 mL single-dose Pre-filled Syringe o160 mg/ mL single-dose Pre-filled Syringe (3). o80 mg/0.5 mL single-dose vial. o128 mg/0.8 mL single-dose Pre-filled Syringe o160 mg/ mL single-dose Pre-filled Syringe (3).

GERIATRIC USE SECTION.

8.5 Geriatric Use Clinical studies of RIVFLOZA did not include patients aged 65 and over to determine whether they respond differently from younger patients. No dose adjustment is recommended in patients >=65 years old [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied RIVFLOZA is clear, sterile, preservative-free, colorless-to-yellow solution available in single-dose pre-filled syringes and single-dose vials in cartons containing one unit each. Table 3: RIVFLOZA PresentationsRIVFLOZA PresentationTotal VolumeTotal amount available in presentation Concentration NDC numberSingle-dose vial0.5 mL80 mg160 mg/mLNDC 0169-5308-01Single-dosePre-filled Syringe0.8 mL128 mg160 mg/mLNDC 0169-5307-08Single-dosePre-filled Syringe1 mL160 mg160 mg/mLNDC 0169-5306-10. Table 3: RIVFLOZA Presentations. 16.2 Storage and Handling Store refrigerated at 2C to 8C (36F to 46F). RIVFLOZA can be stored, if needed, at 15C to 30C (59F to 86F) for maximum of 28 days (4 weeks). Do not freeze. Store in original carton, away from direct heat and light. Table 4: Storage Conditions for RIVFLOZARefrigerated2C to 8C (36F to 46F)Room Temperature at 15C to 30C(59F to 86F)RIVFLOZAUntil expiration dateMaximum 28 days (4 weeks). Table 4: Storage Conditions for RIVFLOZA.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE RIVFLOZA is indicated to lower urinary oxalate levels in children years of age and older and adults with primary hyperoxaluria type (PH1) and relatively preserved kidney function, e.g., eGFR >=30 mL/min/1.73 m2 [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 years of age and older and adults with primary hyperoxaluria type (PH1) and relatively preserved kidney function, e.g., eGFR >=30 mL/min/1.73 m2. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).oInstruct patients/caregivers on the appropriate dose of RIVFLOZA to use, the timing of the dose, how and where to inject subcutaneously, and what to do if dose is missed.For more information contact:Dicerna Pharmaceuticals, Inc.A Novo Nordisk companyNovo Nordisk Inc.800 Scudders Mill RoadPlainsboro, NJ 085361-844-906-5099Manufactured byPyramid Laboratories3598 Cadillac AveCosta Mesa, CA 92626. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).. oInstruct patients/caregivers on the appropriate dose of RIVFLOZA to use, the timing of the dose, how and where to inject subcutaneously, and what to do if dose is missed.

INSTRUCTIONS FOR USE SECTION.

Instructions for Use Pre-filled Syringe INSTRUCTIONS FOR USERIVFLOZA(R) (Riv-flo-za) (nedosiran)injection, for subcutaneous useSingle-dose Pre-filled SyringeThis Instructions for Use contains information on how to inject RIVFLOZA.Read the Instructions for Use before using RIVFLOZA Pre-filled Syringe and each time you get refill. There may be new information. Ask your or your childs healthcare provider if you have any questions.RIVFLOZA Pre-filled Syringe PartsRIVFLOZA Pre-filled Syringe is available in dose strengths. You should check the label on the carton that comes with the RIVFLOZA Pre-filled Syringe to make sure you have the right Pre-filled Syringe for the prescribed dose.For adults and children 12 years of age and older weighing less than 110 pounds (50 kilograms)andFor children years of age to less than 12 years of age weighing between 86 pounds (39 kilograms) and less than 110 pounds (50 kilograms):RIVFLOZA(R) (nedosiran) injectionFor subcutaneous injection onlyFor adults and children years of age and older weighing 110 pounds (50 kilograms) or more:RIVFLOZA(R) (nedosiran) injectionFor subcutaneous injection onlyImportant information you need to know before injecting RIVFLOZA.oYour or your childs healthcare provider will show you how to prepare and inject RIVFLOZA before you use the Pre-filled Syringe for the first time. oUse RIVFLOZA Pre-filled Syringe exactly as your or your childs healthcare provider tells you to.oIn children years of age to less than 12 years of age it is recommended that RIVFLOZA Pre-filled Syringe be given by healthcare provider or caregiver.oYour or your childs healthcare provider will tell you when and how to inject RIVFLOZA.oRIVFLOZA Pre-filled Syringe is single-dose Pre-filled Syringe for one-time (single) use only. Do not reuse the Pre-filled Syringe.oDo not use the Pre-filled Syringe if the carton is damaged or if the tamper-proof seal is not intact.oDo not use if the expiration date on the carton has passed.oRIVFLOZA Pre-filled Syringe is for injection under the skin (subcutaneous injection) only. Do not inject RIVFLOZA into vein.Supplies needed to give the injection:o1 RIVFLOZA Pre-filled Syringe The following supplies are not included in the carton:oAlcohol wipeoCotton balls or gauzeoPuncture resistant sharps disposal container. See Step 12 Throw away (dispose of) the used RIVFLOZA Pre-filled Syringe at the end of this Instructions for Use. How should store RIVFLOZA Pre-filled SyringeoStore unused RIVFLOZA Pre-filled Syringes in the refrigerator between 36F to 46F (2C to 8C).oIf needed, RIVFLOZA Pre-filled Syringes can be stored between 59F to 86F (15C to 30C) for no longer than 28 days (4 weeks). Record the date RIVFLOZA was removed from the refrigerator on the carton and throw away (dispose of) if not used within 28 days. oStore RIVFLOZA Pre-filled Syringes in the original carton.oKeep RIVFLOZA Pre-filled Syringes away from direct heat and light. oDo not freeze. Keep RIVFLOZA Pre-filled Syringe and all medicines out of the reach of children.INSTRUCTIONS FOR USEA. Preparing for the injectionStep 1. Gather the supplies and place the supplies on clean, flat surface in well-lit area.Step 2. Remove the RIVFLOZA Pre-filled Syringe carton from the refrigerator.oMake sure the carton contains the correct dose. oCheck the expiration date on the carton. Do not use if the expiration date has passed. oWait 30 minutes before injecting to allow the medicine in the Pre-filled Syringe to warm to room temperature.Caution:oKeep the RIVFLOZA Pre-filled Syringe in the carton and out of direct heat and sunlight.oDo not warm the Pre-filled Syringe using any heat sources such as hot water or microwave.Step 3. Wash your hands with soap and water.Step 4. Open the carton and remove the RIVFLOZA Pre-filled Syringe.oGrip the barrel of the Pre-filled Syringe and remove it from the carton.Step 5. Inspect the RIVFLOZA Pre-filled Syringe.oLook at the medicine in the Pre-filled Syringe. The medicine should be colorless to yellow and free of particles. oDo not use the Pre-filled Syringe if the medicine looks cloudy, discolored, or contains particles.oThe Pre-filled Syringe should not look damaged.oDo not use the Pre-filled Syringe if it looks damaged.You may see small air bubbles in the liquid. This is normal.Step 6. Choose the injection site.You may inject into skin of:othe stomach area (abdomen) at least inches from the belly button, orothe upper thigh.Caution:oDo not inject into scarred or bruised skin.Step 7. Clean the injection site. oClean the injection site with an alcohol wipe and let it air dry. oDo not touch, wipe with other material, fan, or blow on the cleaned injection site.B. Giving the injectionStep 8. Remove the needle cap and throw it away in the sharps disposal container.oHold the Pre-filled Syringe with hand and the needle pointed away from you. Pull the needle cap straight off with your other hand as shown.Caution:oIf the needle appears to be bent or damaged, do not use the Pre-filled Syringe.oDo not touch or recap the needle.oDo not touch the plunger rod until you are ready to inject.Step 9. Pinch the skin and fully insert the needle.oPinch the skin around the clean injection site with hand.oGrasp the finger grip of the Pre-filled Syringe with your other hand and fully insert the needle into the injection site at 45-degree angle.Step 10. Slowly inject all the medicine. oGently push the plunger rod all the way down until the Pre-filled Syringe is empty.oYou will see the rubber stopper inside the Pre-filled Syringe move to the bottom of the barrel as the medicine is injected.Step 11. Remove the RIVFLOZA Pre-filled Syringe from the injection site.Caution:oDo not recap the needle.If there is bleeding, lightly press cotton ball or gauze over the injection site.C. After the injectionStep 12. Throw away (dispose of) the used RIVFLOZA Pre-filled Syringe.oPut the used RIVFLOZA Pre-filled Syringe in an FDA-cleared sharps disposal container right away after use.oDo not throw away (dispose of) RIVFLOZA Pre-filled Syringes and needle caps in your household trash.oIf you do not have an FDA-cleared sharps disposal container, you may use household container that is:omade of heavy-duty plastic,ocan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out, oupright and stable during use, oleak-resistant, and oproperly labeled to warn of hazardous waste inside the container. oWhen the sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. oFor more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal. oDo not dispose of the used sharps disposal container in your household trash unless your community guidelines permit this. oDo not recycle the used sharps disposal container.Flip Page for more Information Frequently asked questionsWhat if dose is missedoIf dose of RIVFLOZA is missed, inject the dose as soon as possible.oIf dose of RIVFLOZA is missed by more than days, inject the dose as soon as possible and resume monthly dosing from the most recently injected dose.If you have any questions about missed dose, call your healthcare provider or pharmacist.What if damage or break the RIVFLOZA Pre-filled SyringeoDo not use broken or damaged Pre-filled Syringe. Call the pharmacy for replacement.Do inject the full volume of the Pre-filled SyringeoYes, the Pre-filled Syringe is for one-time (single) use and contains complete dose.Pull Out panel (on front of IFU)INSTRUCTIONS FOR USE Read Entire Instructions Before Use Follow Instructions Carefully Contact Novo Nordisk for any QuestionsRIVFLOZA(R) (Riv-flo-za) (nedosiran) injection,for subcutaneous useSingle-dose Pre-filled SyringeAddress PanelFor more information go to https://www.rivfloza.com/ or call 1-844-906-5099. Dicerna Pharmaceuticals, Inc.A Novo Nordisk companyNovo Nordisk Inc.800 Scudders Mill RoadPlainsboro, NJ 08536 USA1-888-906-5099Manufactured by:Pyramid Laboratories3598 Cadillac AvenueCosta Mesa, CA 92626 USAVersion: 3(C) 2025 Novo NordiskThis Instructions for Use has been approved by the U.S. Food and Drug Administration.Revised: 03/2025Flip Page for Instructions for Use. oYour or your childs healthcare provider will show you how to prepare and inject RIVFLOZA before you use the Pre-filled Syringe for the first time. oUse RIVFLOZA Pre-filled Syringe exactly as your or your childs healthcare provider tells you to.. oIn children years of age to less than 12 years of age it is recommended that RIVFLOZA Pre-filled Syringe be given by healthcare provider or caregiver.. oYour or your childs healthcare provider will tell you when and how to inject RIVFLOZA.. oRIVFLOZA Pre-filled Syringe is single-dose Pre-filled Syringe for one-time (single) use only. Do not reuse the Pre-filled Syringe.. oDo not use the Pre-filled Syringe if the carton is damaged or if the tamper-proof seal is not intact.. oDo not use if the expiration date on the carton has passed.. oRIVFLOZA Pre-filled Syringe is for injection under the skin (subcutaneous injection) only. Do not inject RIVFLOZA into vein.. o1 RIVFLOZA Pre-filled Syringe. The following supplies are not included in the carton:. oAlcohol wipe. oCotton balls or gauze. oPuncture resistant sharps disposal container. See Step 12 Throw away (dispose of) the used RIVFLOZA Pre-filled Syringe at the end of this Instructions for Use. oStore unused RIVFLOZA Pre-filled Syringes in the refrigerator between 36F to 46F (2C to 8C).. oIf needed, RIVFLOZA Pre-filled Syringes can be stored between 59F to 86F (15C to 30C) for no longer than 28 days (4 weeks). Record the date RIVFLOZA was removed from the refrigerator on the carton and throw away (dispose of) if not used within 28 days. oStore RIVFLOZA Pre-filled Syringes in the original carton.. oKeep RIVFLOZA Pre-filled Syringes away from direct heat and light. oDo not freeze. oMake sure the carton contains the correct dose. oCheck the expiration date on the carton. Do not use if the expiration date has passed. oWait 30 minutes before injecting to allow the medicine in the Pre-filled Syringe to warm to room temperature.. oKeep the RIVFLOZA Pre-filled Syringe in the carton and out of direct heat and sunlight.. oDo not warm the Pre-filled Syringe using any heat sources such as hot water or microwave.. oGrip the barrel of the Pre-filled Syringe and remove it from the carton.. oLook at the medicine in the Pre-filled Syringe. The medicine should be colorless to yellow and free of particles. oDo not use the Pre-filled Syringe if the medicine looks cloudy, discolored, or contains particles.. oThe Pre-filled Syringe should not look damaged.oDo not use the Pre-filled Syringe if it looks damaged.. oDo not use the Pre-filled Syringe if it looks damaged.. othe stomach area (abdomen) at least inches from the belly button, or. othe upper thigh.. oDo not inject into scarred or bruised skin.. oClean the injection site with an alcohol wipe and let it air dry. oDo not touch, wipe with other material, fan, or blow on the cleaned injection site.. oHold the Pre-filled Syringe with hand and the needle pointed away from you. Pull the needle cap straight off with your other hand as shown.. oIf the needle appears to be bent or damaged, do not use the Pre-filled Syringe.. oDo not touch or recap the needle.. oDo not touch the plunger rod until you are ready to inject.. oPinch the skin around the clean injection site with hand.. oGrasp the finger grip of the Pre-filled Syringe with your other hand and fully insert the needle into the injection site at 45-degree angle.. oGently push the plunger rod all the way down until the Pre-filled Syringe is empty.. oYou will see the rubber stopper inside the Pre-filled Syringe move to the bottom of the barrel as the medicine is injected.. oDo not recap the needle.. oPut the used RIVFLOZA Pre-filled Syringe in an FDA-cleared sharps disposal container right away after use.. oDo not throw away (dispose of) RIVFLOZA Pre-filled Syringes and needle caps in your household trash.. oIf you do not have an FDA-cleared sharps disposal container, you may use household container that is:. omade of heavy-duty plastic,. ocan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out, oupright and stable during use, oleak-resistant, and oproperly labeled to warn of hazardous waste inside the container. oWhen the sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. oFor more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal. oDo not dispose of the used sharps disposal container in your household trash unless your community guidelines permit this. oDo not recycle the used sharps disposal container.. oIf dose of RIVFLOZA is missed, inject the dose as soon as possible.. oIf dose of RIVFLOZA is missed by more than days, inject the dose as soon as possible and resume monthly dosing from the most recently injected dose.. oDo not use broken or damaged Pre-filled Syringe. Call the pharmacy for replacement.. oYes, the Pre-filled Syringe is for one-time (single) use and contains complete dose.. image03. image04. image-5. image06. image07. image08. image09. image10. image11. image12. image13. image14. image15. image16. image17. image18. image19. flip-arrow. pull-out-arrow. image20. image21. image22. 128-160-2. flip-arrow-1.

LACTATION SECTION.

8.2 Lactation Risk SummaryThere are no data on the presence of RIVFLOZA in human or animal milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for RIVFLOZA and any potential adverse effects on the breastfed infant from RIVFLOZA or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Nedosiran is double-stranded siRNA, conjugated to GalNAc aminosugar residues. After subcutaneous administration, the GalNAc-conjugated sugars bind to asialoglycoprotein receptors (ASGPR) to deliver nedosiran to hepatocytes.Nedosiran reduces levels of hepatic lactate dehydrogenase (LDH) via the degradation of LDHA messenger ribonucleic acid (mRNA) in hepatocytes through RNA interference. The reduction of hepatic LDH by nedosiran reduces the production of oxalate by the liver, thereby reducing subsequent oxalate burden.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CarcinogenicityLong-term studies to assess carcinogenic risk of nedosiran have not been conducted.GenotoxicityNedosiran was not genotoxic in the in vitro bacterial mutagenicity, in vitro micronucleus assays (human peripheral blood lymphocytes) and in vivo bone marrow micronucleus assay in mice.FertilityWeekly subcutaneous administration of nedosiran at doses of 500, 1000, or 2000 mg/kg or of mouse-specific (pharmacologically active) analog at dose of 10 mg/kg to male mice for weeks prior to and throughout mating, and to female mice for weeks prior to and throughout mating and to gestation day did not affect male or female fertility or early embryonic development.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL Pre-filled Syringe 128 mg/0.8 mL NDC: 0169-5307-08List 530708rivfloza(TM) (nedosiran) injection128 mg/0.8 mLFor subcutaneous injection only1 0.8 mL Sterile Single-dose Pre-filled SyringeDo not use the Pre-filled Syringe if the carton is damaged or if the tamper proof seal is not intact.Rx OnlyDicerna(TM)a Novo Nordisk company. sleeve128mg.

PEDIATRIC USE SECTION.

8.4 Pediatric Use The safety and effectiveness of RIVFLOZA have been established in pediatric patients aged years and older. Use of RIVFLOZA in these age groups is supported by evidence from an adequate and well-controlled trial in adult and pediatric patients years of age and older (PHYOX2), and single-arm study in pediatric patients to less than 12 years of age (PHYOX8) [see Clinical Studies 14)]. The safety and effectiveness of RIVFLOZA in patients younger than years of age have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics The pharmacodynamic effects of RIVFLOZA were evaluated after single-dose and monthly-dose administration in patients with PH1. Dose-dependent reductions in urinary oxalate were observed in the single-dose range of 1.5 mg/kg to 6.0 mg/kg. With the recommended monthly dose regimen of RIVFLOZA, onset of effect was observed at the first measurement (30 days after the first dose) and the effect persisted with continued monthly dosing [see Clinical Studies 14.1)].Cardiac Electrophysiology At the recommended dose, RIVFLOZA does not lead to clinically relevant QT interval prolongation.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics The pharmacokinetic (PK) properties of RIVFLOZA were evaluated following administration of single and multiple dosages in patients with PH1 or PH2 as summarized in Table 2.Table 2: Pharmacokinetic Parameters of NedosiranNedosiranGeneral InformationSteady State ExposureCmax [Mean (%CV)]844 (44) ng/mLAUC0-last [Mean (%CV)] 13600 (36) ngh/mLDose ProportionalityNedosiran exhibited dose-proportional increase in plasma exposure following single subcutaneous doses from 1.5 to 6.0 mg/kg.Nedosiran exhibited time-independent pharmacokinetics with multiple doses of 160 mg once monthly (body weight >=50 kg), 128 mg once monthly (body weight <50 kg), or 3.3 mg/kg once monthly in the age range of to 11 years. AccumulationNo accumulation of nedosiran was observed in plasma following repeated monthly dosing.AbsorptionTmax [Median (Range)]6 (2 to 12) hoursDistributiona Estimated Vz/F126 LProtein Binding85.6%EliminationHalf-Life (Mean (%CV)])15 (68) hoursEstimated CL/F5.7 L/hrMetabolismPrimary PathwayNedosiran is metabolized by endo- and exonucleases to shorter oligonucleotides.ExcretionPrimary PathwayApproximately 27% of the administered nedosiran dose is excreted unchanged into the urine within 24 hours of dosing.a Nedosiran distributes primarily to the liver after subcutaneous administration.Cmax maximum plasma concentration; AUC0-last area under the plasma concentration-time curve from time of administration (0) to the last measurable time point (last); Tmax time to maximum concentration; Vz/F apparent volume of distribution; CV coefficient of variation; CL/F apparent clearance.Specific PopulationsNo clinically significant differences in the pharmacokinetics or pharmacodynamics of nedosiran were observed based on age (2 to 73 years old), sex, race/ethnicity, mild-to-moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2) [see Use in Specific Populations 8.7 )] or mild hepatic impairment as assessed using the National Cancer Institute Organ Dysfunction Working Group criteria (total bilirubin <= ULN and AST ULN; or total bilirubin >1 to 1.5 ULN and any AST) [see Use in Specific Populations 8.6)].Pediatrics: At the recommended clinical dose, PK exposure of nedosiran is similar in adult and pediatric patients years of age and older.Drug Interaction Studies Concomitant use of pyridoxine (vitamin B6) did not have significant impact on the PK of nedosiran. In vitro studies demonstrated that nedosiran was not an inhibitor or inducer of cytochrome P450 (CYP) enzymes and was neither substrate nor an inhibitor of efflux and uptake transporters.. 13600 (36) ngh/mL.

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryAvailable data from reports of pregnancy in clinical trials with RIVFLOZA are insufficient to evaluate for drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed when nedosiran was administered to pregnant mice at doses up to approximately 58 times the maximum recommended human dose (MRHD) of 160 mg nedosiran (equivalent to 170 mg nedosiran sodium) per dose, based on body surface area (BSA) or upon administration of mouse-specific (pharmacologically active) analog. Subcutaneous administration of nedosiran to pregnant rabbits during the period of organogenesis at doses approximating the MRHD resulted in increased fetal loss in the presence of maternal toxicity. Adverse developmental outcomes (fetal cardiovascular and skeletal malformations) were observed at dose approximately times the MRHD (see Data). Nedosiran is not pharmacologically active in rabbits or mice. The cause for the embryo-fetal toxicities observed in rabbits remains unclear.The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have 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.DataAnimal DataIn mice, subcutaneous administration of nedosiran at doses up to 2000 mg/kg/dose (approximately 58 times the MRHD based on BSA) or mouse-specific (pharmacologically active) analog (10 mg/kg/dose) during organogenesis (dosing on gestation days 6, 8, 10, 12, and 14 for nedosiran; gestation days and 10 for the analog) did not have adverse effects on embryo-fetal development.Subcutaneous administration of nedosiran (0, 2, or 20 mg/kg/dose) to pregnant rabbits during organogenesis (dosing on gestation days 7, 9, 11, 13, 15, 17, and 19) resulted in maternal toxicity on the basis of body weight loss of up to 6.5% following the first dose in the and 20 mg/kg/dose groups. Higher post-implantation loss and lower numbers of live fetuses occurred at >=6 mg/kg/dose (exposures equivalent to the MRHD based on BSA), and fetal cardiovascular and skeletal malformations occurred at the 20 mg/kg/dose (2 times the MRHD based on BSA). At the mg/kg/dose, which is below the MRHD, no adverse findings were seen.In pre- and postnatal study in mice, subcutaneous administration of nedosiran (0, 250, 500, or 1000 mg/kg/dose) or mouse-specific (pharmacologically active) analog (10 mg/kg/dose) from implantation (dosing on gestational days 6, 8, 10, 12, 14, 16) to weaning (dosing on lactation days 1, 8, 15, 20) did not have adverse effects on the growth, viability, development and reproductive performance of the offspring.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Package Insert PATIENT INFORMATIONRIVFLOZA(R) (Riv-flo-za)(nedosiran)injection, for subcutaneous useWhat is RIVFLOZARIVFLOZA is prescription medicine used to lower urinary oxalate levels in children years of age and older and adults with primary hyperoxaluria type (PH1) and relatively preserved kidney function.It is not known if RIVFLOZA is safe and effective in children younger than years of age.Before using RIVFLOZA, tell your healthcare provider about all of your medical conditions, including if you:oare pregnant or plan to become pregnant. It is not known if RIVFLOZA will harm your unborn baby.oare breastfeeding or plan to breastfeed. It is not known if RIVFLOZA passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with RIVFLOZA.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How should use RIVFLOZAoRead the detailed Instructions for Use that comes with RIVFLOZA about the right way to prepare and inject RIVFLOZA.oUse RIVFLOZA exactly as your healthcare provider tells you to.oInject RIVFLOZA under your skin (subcutaneous injection).oUse RIVFLOZA time each month.oYour healthcare provider will prescribe the dose of RIVFLOZA that is right for you or your child based on your or your childs body weight.oRIVFLOZA comes as single-dose Pre-filled Syringe and as single-dose vial.oYour healthcare provider will show you or your caregiver how to prepare and inject RIVFLOZA. Do not try to inject RIVFLOZA until you or your caregiver have been shown the right way by your healthcare provider.oIn children years of age to less than 12 years of age weighing 86 pounds (39 kilograms) or more, it is recommended that RIVFLOZA Pre-filled Syringe be given by healthcare provider or caregiver.oIf you miss dose of RIVFLOZA, inject the dose as soon as possible. If you miss dose of RIVFLOZA by more than days, inject the dose as soon as possible and resume monthly dosing from the most recently injected dose. If you have any questions about missed dose, call your healthcare provider or pharmacist.What are the possible side effects of RIVFLOZAThe most common side effects of RIVFLOZA include injection site reactions, such as reddening, pain, bruising, rash, or dimple at the site of injection.These are not all the possible side effects of RIVFLOZA.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.You may also report side effects to Novo Nordisk at 1-844-906-5099.How should store RIVFLOZAoStore RIVFLOZA in the refrigerator between 36F to 46F (2C to 8C).oIf needed, RIVFLOZA can be stored between 59F to 86F (15C to 30C) for up to 28 days (4 weeks). Record the date RIVFLOZA was removed from the refrigerator on the carton and throw away (dispose of) if not used within 28 days.oDo not freeze RIVFLOZA.oStore RIVFLOZA in the original carton.oKeep RIVFLOZA away from direct heat and light.Keep RIVFLOZA and all medicines out of the reach of children.General information about the safe and effective use of RIVFLOZA.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use RIVFLOZA for condition for which it was not prescribed. Do not give RIVFLOZA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about RIVFLOZA that is written for health professionals.What are the ingredients in RIVFLOZAActive ingredient: nedosiranInactive ingredients: water for injection and sodium hydroxide and/or hydrochloric acid.For more information contact: Dicerna Pharmaceuticals, Inc., Novo Nordisk companyNovo Nordisk Inc., 800 Scudders Mill Road, Plainsboro, NJ 085361-844-906-5099Manufactured by: Pyramid Laboratories, 3598 Cadillac Ave, Costa Mesa, CA 92626For more information, go to https://www.rivfloza.com/ or call 1-844-906-5099.This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 03/2025. oare pregnant or plan to become pregnant. It is not known if RIVFLOZA will harm your unborn baby.. oare breastfeeding or plan to breastfeed. It is not known if RIVFLOZA passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with RIVFLOZA.. oRead the detailed Instructions for Use that comes with RIVFLOZA about the right way to prepare and inject RIVFLOZA.. oUse RIVFLOZA exactly as your healthcare provider tells you to.. oInject RIVFLOZA under your skin (subcutaneous injection).. oUse RIVFLOZA time each month.. oYour healthcare provider will prescribe the dose of RIVFLOZA that is right for you or your child based on your or your childs body weight.. oRIVFLOZA comes as single-dose Pre-filled Syringe and as single-dose vial.. oYour healthcare provider will show you or your caregiver how to prepare and inject RIVFLOZA. Do not try to inject RIVFLOZA until you or your caregiver have been shown the right way by your healthcare provider.. oIn children years of age to less than 12 years of age weighing 86 pounds (39 kilograms) or more, it is recommended that RIVFLOZA Pre-filled Syringe be given by healthcare provider or caregiver.. oIf you miss dose of RIVFLOZA, inject the dose as soon as possible. If you miss dose of RIVFLOZA by more than days, inject the dose as soon as possible and resume monthly dosing from the most recently injected dose. If you have any questions about missed dose, call your healthcare provider or pharmacist.. oStore RIVFLOZA in the refrigerator between 36F to 46F (2C to 8C).. oIf needed, RIVFLOZA can be stored between 59F to 86F (15C to 30C) for up to 28 days (4 weeks). Record the date RIVFLOZA was removed from the refrigerator on the carton and throw away (dispose of) if not used within 28 days.. oDo not freeze RIVFLOZA.. oStore RIVFLOZA in the original carton.. oKeep RIVFLOZA away from direct heat and light.

SPL UNCLASSIFIED SECTION.

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 weightLess than 39 kg39 kg to less than 50 kg50 kg and aboveAge to less than 12 years3.3 mg/kg128 mg160 mgAge 12 years and older128 mg160 mgMissed DoseIf planned dose is missed, administer RIVFLOZA as soon as possible. If the planned dose is missed by more than days, administer RIVFLOZA as soon as possible and resume monthly dosing from the most recently administered dose.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk SummaryAvailable data from reports of pregnancy in clinical trials with RIVFLOZA are insufficient to evaluate for drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed when nedosiran was administered to pregnant mice at doses up to approximately 58 times the maximum recommended human dose (MRHD) of 160 mg nedosiran (equivalent to 170 mg nedosiran sodium) per dose, based on body surface area (BSA) or upon administration of mouse-specific (pharmacologically active) analog. Subcutaneous administration of nedosiran to pregnant rabbits during the period of organogenesis at doses approximating the MRHD resulted in increased fetal loss in the presence of maternal toxicity. Adverse developmental outcomes (fetal cardiovascular and skeletal malformations) were observed at dose approximately times the MRHD (see Data). Nedosiran is not pharmacologically active in rabbits or mice. The cause for the embryo-fetal toxicities observed in rabbits remains unclear.The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have 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.DataAnimal DataIn mice, subcutaneous administration of nedosiran at doses up to 2000 mg/kg/dose (approximately 58 times the MRHD based on BSA) or mouse-specific (pharmacologically active) analog (10 mg/kg/dose) during organogenesis (dosing on gestation days 6, 8, 10, 12, and 14 for nedosiran; gestation days and 10 for the analog) did not have adverse effects on embryo-fetal development.Subcutaneous administration of nedosiran (0, 2, or 20 mg/kg/dose) to pregnant rabbits during organogenesis (dosing on gestation days 7, 9, 11, 13, 15, 17, and 19) resulted in maternal toxicity on the basis of body weight loss of up to 6.5% following the first dose in the and 20 mg/kg/dose groups. Higher post-implantation loss and lower numbers of live fetuses occurred at >=6 mg/kg/dose (exposures equivalent to the MRHD based on BSA), and fetal cardiovascular and skeletal malformations occurred at the 20 mg/kg/dose (2 times the MRHD based on BSA). At the mg/kg/dose, which is below the MRHD, no adverse findings were seen.In pre- and postnatal study in mice, subcutaneous administration of nedosiran (0, 250, 500, or 1000 mg/kg/dose) or mouse-specific (pharmacologically active) analog (10 mg/kg/dose) from implantation (dosing on gestational days 6, 8, 10, 12, 14, 16) to weaning (dosing on lactation days 1, 8, 15, 20) did not have adverse effects on the growth, viability, development and reproductive performance of the offspring. 8.2 Lactation Risk SummaryThere are no data on the presence of RIVFLOZA in human or animal milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for RIVFLOZA and any potential adverse effects on the breastfed infant from RIVFLOZA or from the underlying maternal condition.. 8.4 Pediatric Use The safety and effectiveness of RIVFLOZA have been established in pediatric patients aged years and older. Use of RIVFLOZA in these age groups is supported by evidence from an adequate and well-controlled trial in adult and pediatric patients years of age and older (PHYOX2), and single-arm study in pediatric patients to less than 12 years of age (PHYOX8) [see Clinical Studies 14)]. The safety and effectiveness of RIVFLOZA in patients younger than years of age have not been established.. 8.5 Geriatric Use Clinical studies of RIVFLOZA did not include patients aged 65 and over to determine whether they respond differently from younger patients. No dose adjustment is recommended in patients >=65 years old [see Clinical Pharmacology (12.3)]. 8.6 Hepatic Impairment No dose adjustment of RIVFLOZA is recommended for patients with mild hepatic impairment (total bilirubin <= upper limit of normal [ULN] and aspartate aminotransferase [AST] ULN or total bilirubin >1 to 1.5 times ULN and any AST). RIVFLOZA has not been studied in patients with moderate or severe hepatic impairment (total bilirubin >1.5 ULN with any AST) [see Clinical Pharmacology 12.3)].. 8.7 Renal Impairment No dose adjustment is recommended in patients with an estimated glomerular filtration rate (eGFR) of >=30 mL/min/1.73 m2 [see Clinical Pharmacology (12.3)].RIVFLOZA has not been studied in PH1 patients with severe renal impairment (eGFR <30 mL/min/1.73 m2).