DailyMed Label: RIVFLOZA

DailyMed Label: RIVFLOZA

2023

DailyMed Prescription

RIVFLOZA

nedosiran

Novo Nordisk

NDC: 0169-5306

NDC: 0169-5306

NDC: 0169-5307

NDC: 0169-5307

NDC: 0169-5308

NDC: 0169-5308

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 9 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 9 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 ) Age Body Weight Dosing Regimen Adults and adolescents 12 years and older Greater than or equal to 50 kg 160 mg once monthly (Pre-filled Syringe, 1 mL) Less than 50 kg 128 mg once monthly (Pre-filled Syringe, 0.8 mL) Children 9 to 11 years Greater than or equal to 50 kg 160 mg once monthly (Pre-filled Syringe, 1 mL) Less than 50 kg 3.3 mg/kg once monthly, not to exceed 128 mg (Vial, dose volume rounded to nearest 0.1 mL) See full Prescribing Information for important administration instructions. (‎ 2.2 ) 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 (9 years of age and older) Age Body Weight Dosing Regimen Adults and adolescents 12 years and older Greater than or equal to 50 kg 160 mg once monthly (Pre-filled Syringe, 1 mL) Less than 50 kg 128 mg once monthly (Pre-filled Syringe, 0.8 mL) Children 9 to 11 years Greater than or equal to 50 kg 160 mg once monthly (Pre-filled Syringe, 1 mL) Less than 50 kg 3.3 mg/kg once monthly, not to exceed 128 mg (Vial, dose volume rounded to nearest 0.1 mL) 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. Pre-filled syringe: A healthcare professional, caregiver, or patient 12 years of age and older may inject RIVFLOZA using the pre-filled syringe. In pediatric patients 9 to 11 years of age who weigh ≥50 kg, a healthcare professional 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 professional. A caregiver may administer RIVFLOZA to pediatric patients after proper training in preparing RIVFLOZA vials for administration, if a healthcare professional 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.

RIVFLOZA Injection 160 mg/mL (present as 170 mg nedosiran sodium salt) is a clear, colorless-to-yellow solution available as follows: • 80 mg (0.5 mL) single-dose Vial • 128 mg (0.8 mL) single-dose Pre-filled Syringe • 160 mg (1 mL) single-dose Pre-filled Syringe RIVFLOZA Injection 160 mg/mL is a clear, colorless-to-yellow solution available as follows: • 80 mg (0.5 mL) single-dose Vial • 128 mg (0.8 mL) single-dose Pre-filled Syringe • 160 mg (1 mL) single-dose Pre-filled Syringe (‎ 3 )

None. None. ( 4 )

Most common adverse reaction (reported in ≥20% of patients) is injection site reactions. (‎

Risk Summary Available data from reports of pregnancy in clinical trials with RIVFLOZA are insufficient to evaluate for a 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 a 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 a dose approximately 2 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 a 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. Data Animal Data In mice, subcutaneous administration of nedosiran at doses up to 2000 mg/kg/dose (approximately 58 times the MRHD based on BSA) or a 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 3 and 10 for the analog) did not have adverse effects on embryo-fetal development. Subcutaneous administration of nedosiran (0, 2, 6 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 6 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 2 mg/kg/dose, which is below the MRHD, no adverse findings were seen. In a pre- and postnatal study in mice, subcutaneous administration of nedosiran (0, 250, 500, or 1000 mg/kg/dose) or a 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 . Risk Summary There 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 mother’s clinical need for RIVFLOZA and any potential adverse effects on the breastfed infant from RIVFLOZA or from the underlying maternal condition. The safety and effectiveness of RIVFLOZA have been established in pediatric patients aged 9 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 9 years of age and older [see Clinical Studies ( ‎ 14 )] . The safety and effectiveness of RIVFLOZA in patients younger than 9 years of age have not been established. 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 )]. 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 )] . No dose adjustment is recommended in patients with an estimated glomerular filtration rate (eGFR) of ≥30 mL/min/1.73 m 2 [see Clinical Pharmacology (‎ 12.3 )] . RIVFLOZA has not been studied in PH1 patients with severe renal impairment (eGFR <30 mL/min/1.73 m 2 ).

How Supplied RIVFLOZA is a 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 Presentations RIVFLOZA Presentation Total Volume Total amount available in presentation Concentration NDC Number Single-dose Vial 0.5 mL 80 mg 160 mg/mL NDC 0169-5308-01 Single-dose Pre-filled Syringe 0.8 mL 128 mg 160 mg/mL NDC 0169-5307-08 Single-dose Pre-filled Syringe 1 mL 160 mg 160 mg/mL NDC 0169-5306-10 Storage and Handling Store refrigerated at 2°C to 8°C (36°F to 46°F). RIVFLOZA can be stored, if needed, at 15°C to 30°C (59°F to 86°F) for a maximum of 28 days (4 weeks). Do not freeze. Store in original carton, away from direct heat and light.   Table 4: Storage Conditions for RIVFLOZA Refrigerated 2°C to 8°C (36°F to 46°F) Room Temperature at 15°C to 30°C (59°F to 86°F) RIVFLOZA Until expiration date Maximum 28 days (4 weeks)

Nedosiran is a 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. 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. 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 Nedosiran Nedosiran General Information Steady State Exposure C max [Mean (%CV)] 844 (44) ng/mL AUC 0-last [Mean (%CV)]   13600 (36) ng * h/mL Dose Proportionality Nedosiran exhibited a 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 6 to 11 years. Accumulation No accumulation of nedosiran was observed in plasma following repeated monthly dosing. Absorption T max [Median (Range)] 6 (2 to 12) hours Distribution a Estimated Vz/F 126 L Protein Binding 85.6% Elimination Half-Life (Mean (%CV)]) 15 (68) hours Estimated CL/F 5.7 L/hr Metabolism Primary Pathway Nedosiran is metabolized by endo- and exonucleases to shorter oligonucleotides. Excretion Primary Pathway Approximately 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. C max = maximum plasma concentration; AUC 0-last = area under the plasma concentration-time curve from time of administration (0) to the last measurable time point (last); T max = time to maximum concentration; Vz/F = apparent volume of distribution; CV = coefficient of variation; CL/F = apparent clearance. Specific Populations No clinically significant differences in the pharmacokinetics or pharmacodynamics of nedosiran were observed based on age (9 to 73 years old), sex, race/ethnicity, mild-to-moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m 2 ) [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 9 years of age and older. Drug Interaction Studies Concomitant use of pyridoxine (vitamin B6) did not have a 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 a substrate nor an inhibitor of efflux and uptake transporters. As with all oligonucleotides, including RIVFLOZA, there is a 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 59 patients tested with the ADA assay, none developed treatment-emergent ADA.

Carcinogenicity Long-term studies to assess carcinogenic risk of nedosiran have not been conducted. Genotoxicity Nedosiran 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. Fertility Weekly subcutaneous administration of nedosiran at doses of 500, 1000, or 2000 mg/kg or of a mouse-specific (pharmacologically active) analog at a dose of 10 mg/kg to male mice for 4 weeks prior to and throughout mating, and to female mice for 2 weeks prior to and throughout mating and to gestation day 7 did not affect male or female fertility or early embryonic development.

PHYOX2 was a randomized, double-blind trial comparing RIVFLOZA and placebo in patients aged 6 years or older with PH1 or PH2 and an eGFR ≥30 mL/min/1.73 m 2 (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 6 to 11 years of age was 3.3 mg/kg (to a maximum of 128 mg). The median age was 20 years (range 9 to 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 m 2 BSA in patients less than 18 years of age, was 1547 µmol/24-hour. Mean plasma oxalate was 8.2 µmol/L, 43% of patients had an eGFR ≥90 mL/min/1.73 m 2 , 34% had an eGFR 60 to <90 mL/min/1.73 m 2 , 23% had an eGFR 30 to <60 mL/min/1.73 m 2 , 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 (AUC 24-hour Uox ). The least-squares (LS) mean AUC 24‑hour Uox was -3486 (95% CI: -5025, -1947) in the RIVFLOZA group compared to 1490 (95% CI: 781, 3761) in the placebo group, for a 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 a 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 PHYOX2 After 6 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 6 months of treatment in PHYOX3. figure_1

PATIENT INFORMATION RIVFLOZA ™ (Riv-flo-za) (nedosiran) injection, for subcutaneous use What is RIVFLOZA? RIVFLOZA is a prescription medicine used to lower urinary oxalate levels in children 9 years of age and older and adults with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function. It is not known if RIVFLOZA is safe and effective in children younger than 9 years of age. Before using RIVFLOZA, tell your healthcare provider about all of your medical conditions, including if you: • are pregnant or plan to become pregnant. It is not known if RIVFLOZA will harm your unborn baby. • are 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 I use RIVFLOZA? • Read the detailed Instructions for Use that comes with RIVFLOZA about the right way to prepare and inject RIVFLOZA. • Use RIVFLOZA exactly as your healthcare provider tells you to. • Inject RIVFLOZA under your skin (subcutaneous injection). • Use RIVFLOZA 1 time each month. • Your healthcare provider will prescribe the dose of RIVFLOZA that is right for you based on your body weight. • RIVFLOZA comes as a single-dose Pre-filled Syringe and as a single-dose vial. • Your healthcare provider will show you how to prepare and inject RIVFLOZA. Do not try to inject RIVFLOZA until you have been shown the right way by your healthcare provider. • In children 9 to 11 years of age weighing 110 pounds (50 kilograms) or more, it is recommended that RIVFLOZA Pre-filled Syringe be given by a healthcare provider or caregiver. • If you miss a dose of RIVFLOZA, inject the dose as soon as possible. If you miss a dose of RIVFLOZA by more than 7 days, inject the dose as soon as possible and resume monthly dosing from the most recently injected dose. If you have any questions about a missed dose, call your healthcare provider or pharmacist. What are the possible side effects of RIVFLOZA? The 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 I store RIVFLOZA? • Store RIVFLOZA in the refrigerator between 36°F to 46°F (2°C to 8°C). • If needed, RIVFLOZA can be stored between 59°F to 86°F (15°C to 30°C) 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. • Do not freeze RIVFLOZA. • Store RIVFLOZA in the original carton. • Keep 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 a Patient Information leaflet. Do not use RIVFLOZA for a 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 RIVFLOZA? Active ingredient: nedosiran Inactive ingredients: water for injection and sodium hydroxide and/or hydrochloric acid. For more information contact: Dicerna Pharmaceuticals, Inc., A Novo Nordisk company Novo Nordisk Inc, 800 Scudders Mill Road, Plainsboro, NJ 08536 1-844-906-5099 Manufactured by: Pyramid Laboratories, 3598 Cadillac Ave, Costa Mesa, CA 92626 For more information, go to https://www.novonordisk-us.com/ or call 1-844-906-5099. This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 09/2023

NDC: 0169-5307-08 List 530708 rivfloza ™ (nedosiran) injection 128 mg/0.8 mL For subcutaneous injection only 1 x 0.8 mL Sterile Single-dose Pre-filled Syringe Do not use the Pre-filled Syringe if the carton is damaged or if the tamper proof seal is not intact. Rx Only Dicerna ™ a Novo Nordisk company sleeve_128mg