Nedosiran is a subcutaneously administered lactate dehydrogenase A-directed small interfering ribonucleic acid (siRNA) indicated for the treatment of primary hyperoxaluria type 1 (PH1) in persons with relatively preserved kidney function (e.g., eGFR of 30 mL/minute/1.73 m2 or more) to lower urinary oxalate concentrations. PH1 is an autosomal recessive disease caused by mutations in the AGXT gene that encodes the hepatic peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT). Defects in the AGT enzyme increase glyoxylate and oxalate production. An increase in oxylate production leads to the development of kidney stones and nephrocalcinosis due to low solubility when it combines with calcium in the kidney. Symptoms and age at diagnosis of PH1 vary from severe forms that present in infants and lead to kidney failure during the first months of life to forms that present in adults with moderate to advanced chronic kidney disease, including kidney failure, nephrocalcinosis, and recurrent bilateral kidney stones. The efficacy and safety of nedosiran were evaluated in a double-blind, placebo-controlled trial (PHYOX2) in subjects 6 years and older (n = 35) with primary hyperoxaluria type 1 (PH1) (n = 29) or primary hyperoxaluria type 2 (PH2) (n = 6) who had a 24-hour urinary oxylate excretion of 0.7 mmol or more (per 1.73 m2 body surface area in those younger than 18 years) and an eGFR of 30 mL/minute/1.73 m2 or more. The primary efficacy endpoint was the percent change from baseline in 24-hour urinary oxalate excretion, as assessed by the area under the curve (AUC (24-hour Uox)) from days 90 to 180. The least-squares (LS) mean AUC (24-hour Uox) was 3,507 (95% CI 1,962 to 5,053) in the nedosiran group compared to -1,664 (95% CI -3,397 to -668) in the placebo group, for a between group LS mean difference of 5,172 (95% CI 2,929 to 7,414; p less than 0.001). After 6 months of treatment in the PHYOX2 trial, subjects could enroll in an ongoing single-arm (nedosiran) extension study (PHYOX3). The reduction in urinary oxalate was maintained in the 13 subjects with PH1 who received an additional 6 months of treatment with nedosiran in PHYOX3. Nedosiran has not been studied in persons with severe renal impairment or moderate to severe hepatic impairment.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Nedosiran is colorless-to-yellow and particle free. Do not use if the solution is cloudy, discolored, or contains particulate matter. Do not use if the pre-filled syringe or vial looks damaged.
-Nedosiran is preservative-free. Both the pre-filled syringe and vial are for single use only.
-Storage: Store unused nedosiran pre-filled syringes or vials in the refrigerator at 36 to 46 degrees F (2 to 8 degrees C). If needed, nedosiran pre-filled syringes or vials can be stored at 59 to 86 degrees F (15 to 30 degrees C) for no longer than 28 days (4 weeks). Record the date of removal from the refrigerator on the carton and dispose of if not used within 28 days. Store nedosiran in the original carton away from direct heat and light. Do not warm the pre-filled syringe or vial using any heat sources (e.g., hot water or a microwave). Do not freeze.
-Missed dose: If a dose is missed, administer the dose as soon as possible. If a dose is missed by more than 7 days, administer the dose as soon as possible and resume monthly dosing from the most recently administered dose.
Subcutaneous Administration
Preparation
-Remove the nedosiran pre-filled syringe or vial(s) from refrigeration. Wait 30 minutes before administering to allow the medication in the pre-filled syringe or vial to warm to room temperature.
Pre-filled syringe
-The pre-filled syringe may be self-administered by persons 12 years and older. A health care professional or caregiver may administer nedosiran using a pre-filled syringe for children 9 to 11 years as well as for persons 12 years and older.
-Hold the pre-filled syringe with 1 hand and the needle pointed away. Pull the needle cap straight off with the other hand.
-Do not use the pre-filled syringe if the needle appears to be bent or damaged.
-Do not touch or recap the needle; do not touch the plunger rod until ready for injection.
-Small air bubbles may appear in the liquid of the pre-filled syringe; this is normal.
Vial
-The vial is intended for use under the guidance and supervision of a health care professional. A caregiver may administer nedosiran to a child after proper training in preparing nedosiran vials for administration, if a health care professional determines that it is appropriate and with medical follow-up as needed.
-Remove the cap from the vial(s) and clean the top of the grey rubber stopper with a new alcohol wipe.
-Remove the syringe with the attached needle from the packaging, and remove the needle cap by pulling it straight off and away from the body.
-Insert the needle into the grey rubber stopper on top of the vial; turn the vial and syringe upside down and keep the needle in the medication.
-Hold the syringe and vial in 1 hand and slowly pull back on the plunger rod to withdraw the prescribed dose into the syringe.
-If the dose is more than 80 mg (0.5 mL), withdraw the nedosiran dose from 2 vials using 2 separate syringes.
-Remove any large air bubbles from the syringe by tapping the side of the syringe to move any air bubbles to the top of the syringe. Push the plunger rod up to push the air bubbles back into the vial.
-Turn the vial and syringe back upright and remove the needle from the vial.
Administration
-Choose the injection site from the abdomen (at least 2 inches from the belly button) or the upper thigh. Do not inject into a vein or scarred or bruised skin.
-Clean the injection site with an alcohol wipe and let it air dry. Do not touch, wipe with other material, fan, or blow on the cleaned injection site.
-Pinch the skin around the clean injection site with 1 hand. With the other hand, fully insert the needle into the injection site at a 45-degree angle.
-Gently push the plunger rod all the way down until the syringe is empty.
-Remove the needle from the injection site. Do not recap the needle.
-Lightly press a cotton ball or gauze over the injection site if there is bleeding.
-Dispose of the used syringe(s) and vial(s) in an appropriate sharps disposal container.
Injection site reaction was reported in 39% (n = 7) of nedosiran-treated subjects in clinical trials. Injection site reactions included bruising, erythema, pain, and rash. These reactions were generally mild and did not lead to discontinuation of treatment. Additional injection site reactions reported with nedosiran in 3% of subjects (n = 1) in an extension study included skin atrophy.
Available data from reports of pregnancy in clinical trials with nedosiran are insufficient to determine a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, adverse developmental effects were not observed when nedosiran was administered to pregnant mice at doses up to approximately 58 times the maximum recommended human dose (MRHD) of 160 mg/dose, based on body surface area, 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, including fetal cardiovascular and skeletal malformations, were observed at a dose approximately 2 times the MRHD. Nedosiran is not pharmacologically active in mice or rabbits; the cause for the embryo-fetal toxicities observed in rabbits is unknown. In a pre- and post-natal study in mice, subcutaneous administration of nedosiran up to 1,000 mg/kg/dose or a mouse-specific, pharmacologically active analog at 10 mg/kg/dose from implantation to weaning did not have adverse effects on the growth, viability, development, and reproductive performance of the offspring.
Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for nedosiran and any potential adverse effects on the breast-fed infant from nedosiran or the underlying maternal condition. There are no data on the presence of nedosiran in human or animal milk, the effects on the breast-fed child, or the effects on milk production.
For the treatment of primary hyperoxaluria type 1:
Note: Nedosiran has been designated as an orphan drug for this indication by the FDA.
Subcutaneous dosage:
Adults weighing 50 kg or more: 160 mg subcutaneously once monthly.
Adults weighing less than 50 kg: 128 mg subcutaneously once monthly.
Children and Adolescents 12 to 17 years weighing 50 kg or more: 160 mg subcutaneously once monthly.
Children and Adolescents 12 to 17 years weighing less than 50 kg: 128 mg subcutaneously once monthly.
Children 9 to 11 years weighing 50 kg or more: 160 mg subcutaneously once monthly.
Children 9 to 11 years weighing less than 50 kg: 3.3 mg/kg/dose (Max: 128 mg/dose) subcutaneously once monthly.
Maximum Dosage Limits:
-Adults
weighing 50 kg or more: 160 mg/month subcutaneously
weighing less than 50 kg: 128 mg/month subcutaneously
-Geriatric
weighing 50 kg or more: 160 mg/month subcutaneously.
weighing less than 50 kg: 128 mg/month subcutaneously.
-Adolescents
weighing 50 kg or more: 160 mg/month subcutaneously.
weighing less than 50 kg: 128 mg/month subcutaneously.
-Children
9 to 12 years weighing 50 kg or more: 160 mg/month subcutaneously.
9 to 12 years weighing less than 50 kg: 128 mg/month subcutaneously.
1 to 8 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustment is recommended for persons with mild hepatic impairment (total bilirubin of the upper limit of normal (ULN) or less and aspartate aminotransferase (AST) more than ULN or total bilirubin more than 1 to 1.5 times ULN and any AST elevation). Nedosiran has not been studied in persons with moderate or severe hepatic impairment (total bilirubin more than 1.5 times ULN and any AST).
Patients with Renal Impairment Dosing
No dosage adjustment is recommended in persons with an eGFR of 30 mL/minute/1.73 m2 or more. Nedosiran has not been studied in persons with primary hyperoxaluria type 1 (PH1) and severe renal impairment (eGFR less than 30 mL/minute/1.73 m2).
*non-FDA-approved indication
There are no drug interactions associated with Nedosiran products.
Nedosiran is a double-stranded small interfering ribonucleic acid (siRNA) that is conjugated to GalNAc aminosugar residues. The GalNAc-conjugated sugars bind to asialoglycoprotein receptors (ASGPR) to deliver nedosiran to hepatocytes after subcutaneous administration. Nedosiran reduces concentrations of hepatic lactate dehydrogenase (LDH) by the degradation of lactate dehydrogenase A (LDHA) messenger ribonucleic acid (mRNA) in hepatocytes through RNA interference. The reduction of hepatic LDH by nedosiran decreases the production of oxalate by the liver and leads to a reduction in oxalate burden.
Nedosiran is administered subcutaneously. Plasma protein binding of nedosiran is 85.6% and the apparent Vd is 126 L. Nedosiran primarily distributes to the liver after subcutaneous administration. Nedosiran is metabolized by endo- and exonucleases to shorter oligonucleotides. Approximately 27% of the administered nedosiran dose is excreted unchanged in the urine within 24 hours of dosing. The estimated apparent clearance of nedosiran is 5.7 L/hour and the mean half-life of nedosiran is 15 hours.
Affected cytochrome P450 isoenzymes and drug transporters: none
In vitro studies demonstrated that nedosiran is not an inhibitor or inducer of cytochrome P450 enzymes and is not a substrate or an inhibitor of efflux and uptake transporters.
-Route-Specific Pharmacokinetics
Subcutaneous Route
The median time to maximum concentration (Tmax) for nedosiran is 6 hours (range 2 to 12 hours). The mean maximum plasma concentration (Cmax) at steady-state is 844 ng/mL and the mean overall exposure at steady-state (AUC0-last) is 13,600 nanogram x hour/mL. Nedosiran exhibited a dose-proportional increase in plasma exposure after single subcutaneous doses from 1.5 to 6 mg/kg/dose. Nedosiran exhibited time-independent pharmacokinetics after multiple doses of 3.3 mg/kg/dose up to 160 mg/dose subcutaneously once monthly (dose-adjusted based on age and weight). No accumulation of nedosiran was observed in plasma after repeated monthly dosing. Dose-dependent reductions in urinary oxalate were observed in persons with primary hyperoxaluria 1 (PH1) in the single-dose range of 1.5 to 6 mg/kg/dose subcutaneously; the onset of effect was observed 30 days after the first nedosiran dose, and the effect persisted with continued monthly dosing.
-Special Populations
Hepatic Impairment
No clinically significant differences in the pharmacokinetics or pharmacodynamics of nedosiran were observed based on mild hepatic impairment as assessed using the National Cancer Institute Organ Dysfunction Working Group criteria (total bilirubin of the upper limit of normal (ULN) or less and alanine aminotransferase (ALT) more than the upper limit of normal or total bilirubin more than 1 to 1.5 times the ULN and any AST).
Renal Impairment
No clinically significant differences in the pharmacokinetics or pharmacodynamics of nedosiran were observed based on mild to moderate renal impairment (eGFR 30 to 89 mL/minute/1.73 m2).
Pediatrics
No clinically significant differences in the pharmacokinetics or pharmacodynamics of nedosiran were observed based on age. Pharmacokinetic exposure of nedosiran at the recommended clinical dose is similar in adult and pediatric persons 9 years and older.
Geriatric
No clinically significant differences in the pharmacokinetics or pharmacodynamics of nedosiran were observed based on age (up to 73 years). Clinical trials of nedosiran did not include persons 65 years and older to determine whether they respond differently from younger persons. No dosage adjustment is recommended in persons 65 years and older.
Gender Differences
No clinically significant differences in the pharmacokinetics or pharmacodynamics of nedosiran were observed based on gender.
Ethnic Differences
No clinically significant differences in the pharmacokinetics or pharmacodynamics of nedosiran were observed based on race/ethnicity.