BRIEF SUMMARY

NEDOSIRAM-(Aug 2023)

IIndn-      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 m2. 

Comp-    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

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

CI-   None

Pat Inform-

• Instruct 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 a dose is missed.

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U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 40

Name-                      RIVFLOZAtype  9 years and older with primary hyperoxaluria                                                                      type  1 relatively preserve kidney unction                                                                                                                  

Date  of approval                   9/29/2023 

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use                               RIVFLOZA safely and effectively.

See full prescribing information for RIVFLOZA. RIVFLOZATM (nedosiran) injection, for subcutaneous use

Initial U.S. Approval: 2023

INDICATIONS AND USAGE

 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 m2. 

ADVERSE REACTIONS-

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

CONTRAINDICATIONS-

None

DOSAGE AND ADMINISTRATION-

 The recommended dosage is shown below and is administered subcutaneously once monthly.

 Age Adults and adolescents 12 years and older Children 9 to 11 years

Body Weight Greater than or equal to 50 kg Less than 50 kg Greater than or equal to 50 kg Dosing Regimen 160 mg once monthly (Pre-filled Syringe, 1 mL) 128 mg once monthly (Pre-filled Syringe, 0.8 mL) 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)

DOSAGE FORMS AND STRENGTHS-

 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

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

• Instruct 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 a dose is missed.

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

CLINICAL PHARMACOLOGY-

Mechanism of Action-

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.

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 

Cardiac Electrophysiology At the recommended dose, RIVFLOZA does not lead to clinically relevant QT interval prolongation.

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 :

Pharmacokinetic Parameters of Nedosiran Nedosiran General Information Steady State Exposure Cmax [Mean (%CV)] 844 (44) ng/mL AUC0-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 Tmax [Median (Range)] 6 (2 to 12) hours Distributiona 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. 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; Vd/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 m2]) 

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 olde

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.

USE IN SPECIFIC POPULATIONS

1. Pregnancy 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 Reference ID: 5253599 sodium) per dose, based on body surface area (BSA) or upon administration of a mouse-specific (pharmacologically active) analog.

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.

2. Lactation 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.

3. Pediatric Use 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)]. Reference ID: 5253599 The safety and effectiveness of RIVFLOZA in patients younger than 9 years of age have not been established

4.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.

5. 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) 

6. 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).