Nedosiran (Monograph)

Drug class: Other Miscellaneous Therapeutic Agents

Introduction

Nedosiran is a double-stranded small interfering RNA (siRNA) conjugated to N-acetyl-D-galactosamine (GalNAc) that targets lactate dehydrogenase A (LDHA).

Uses for Nedosiran

Nedosiran has the following uses:

Nedosiran 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 m².

Nedosiran Dosage and Administration

General

Nedosiran is available in the following dosage form(s) and strength(s):

Single-dose vial: 80 mg (0.5 mL)

Single-dose pre-filled syringes: 128 mg (0.8 mL), 160 mg (1 mL)

Administration

• Administer 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.

• Pre-filled syringe: A healthcare professional, caregiver, or patient 12 years of age and older may inject nedosiran 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 nedosiran using the pre-filled syringe.

• Vials: Nedosiran vials are intended for use under the guidance and supervision of a healthcare professional. A caregiver may administer nedosiran to pediatric patients after proper training in preparing the vials for administration, if a healthcare professional determines that it is appropriate, and with medical follow-up as necessary.

Dosage

Nedosiran is administered subcutaneously once monthly at the recommended doses shown in Table 1.

Dosing is based on actual body weight.

If a dose is missed, administer nedosiran as soon as possible. If the planned dose is missed by >7 days, administer nedosiran as soon as possible and resume monthly dosing from the most recently administered dose.

Related/similar drugs

Rivfloza, Oxlumo

Cautions for Nedosiran

Contraindications

None.

Common Adverse Effects

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

Special Populations

Pregnancy

Available data from reports of pregnancy in clinical trials with nedosiran 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. 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.

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.

Lactation

There are no data on the presence of nedosiran 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 nedosiran and any potential adverse effects on the breastfed infant from nedosiran or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of nedosiran have been established in pediatric patients 9 years of age and older. Use of nedosiran in these age groups is supported by evidence from an adequate and well-controlled trial in adults and pediatric patients 9 years of age and older. The safety and effectiveness of nedosiran in patients younger than 9 years of age have not been established.

Geriatric Use

Clinical studies of nedosiran did not include patients 65 years of age and over to determine whether they respond differently from younger patients. No dose adjustment is recommended in patients ≥65 years of age.

Hepatic Impairment

No dose adjustment of nedosiran 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).

Nedosiran has not been studied in patients with moderate or severe hepatic impairment (total bilirubin > 1.5 ULN with any AST).

Renal Impairment

No dose adjustment is recommended in patients with an estimated glomerular filtration rate (eGFR) of ≥30 mL/min/1.73 m².

Nedosiran has not been studied in primary hyperoxaluria type 1 patients with severe renal impairment (eGFR <30 mL/ min/1.73 m²).

Drug Interactions

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Concomitant use of pyridoxine (vitamin B6) did not have a significant impact on the pharmacokinetics of nedosiran.

In vitro studies demonstrated that nedosiran was not an inhibitor or inducer of cytochrome P-450 (CYP) enzymes and was neither a substrate nor an inhibitor of efflux and uptake transporters.

Actions

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.

Advice to Patients

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

• Instruct patients/caregivers on the appropriate dose of nedosiran to use, the timing of the dose, how and where to inject subcutaneously, and what to do if a dose is missed.

Additional Information

AHFSfirstRelease™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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