Dosing & Uses
Dosage Forms & Strengths
injectable SC solution
- 128mg/0.8mL (single-dose prefilled syringe)
- 160mg/mL (single-dose prefilled syringe)
Hyperoxaluria
Indicated to lower urinary oxalate levels in adults with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function (eg, eGFR ≥30 mL/min/1.73 m2)
Dosing based on actual body weight
<50 kg: 128 mg (prefilled syringe, 0.8 mL) SC once monthly
≥50 kg: 160 mg (prefilled syringe, 1 mL) SC once monthly
Dosage Modifications
Renal impairment
- Mild-to-moderate (eGFR ≥30 mL/min/1.73 m2): No dosage adjustment necessary
- Severe (eGFR <30 mL/min/1.73 m2): Not studied
Hepatic impairment
- Mild (total bilirubin ≤upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN or total bilirubin >1 to 1.5x ULN and any AST: No dose adjustment necessary
- Moderate or severe (total bilirubin >1.5x ULN with any AST): Not studied
Dosage Forms & Strengths
injectable SC solution
- 80mg/0.5mL (single-dose vial)
- 128mg/0.8mL (single-dose prefilled syringe)
- 160mg/mL (single-dose prefilled syringe)
Hyperoxaluria
Indicated to lower urinary oxalate levels in adults and children aged ≥9 years with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function (eg, eGFR ≥30 mL/min/1.73 m2)
Dosing based on actual body weight
<9 years: Safety and efficacy not established
9-11 years
- <50 kg: 3.3 mg/kg (vial dose) SC once monthly, not to exceed 128 mg
- ≥50 kg: 160 mg (prefilled syringe, 1 mL) SC once monthly
≥12 years
- <50 kg: 128 mg (prefilled syringe, 0.8 mL) SC once monthly
- ≥50 kg: 160 mg (prefilled syringe, 1 mL) SC once monthly
Dosage Modifications
Renal impairment
- Mild-to-moderate (eGFR ≥30 mL/min/1.73 m2): No dosage adjustment necessary
- Severe (eGFR <30 mL/min/1.73 m2): Not studied
Hepatic impairment
- Mild (total bilirubin ≤ULN and AST >ULN or total bilirubin >1 to 1.5x ULN and any AST: No dose adjustment necessary
- Moderate or severe (total bilirubin >1.5x ULN with any AST): Not studied
Adverse Effects
Frequency Not Defined
Injection site reactions including erythema, pain, bruising, and rash reported and were generally mild
Warnings
Contraindications
None
Pregnancy & Lactation
Pregnancy
Available data from reports of pregnancy are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes
Animal data
- No adverse developmental effects were observed when nedosiran was administered to pregnant mice at doses up to ~58x 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
- SC administration of nedosiran to pregnant rabbits during 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
Lactation
There are no data on the presence of nedosiran in human or animal milk, effects on breastfed children, or effects on milk production
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Double-stranded small interfering ribonucleic acid (siRNA), conjugated to GalNAc aminosugar residues; after SC administration, the GalNAc-conjugated sugars bind to asialoglycoprotein receptors (ASGPR) to deliver nedosiran to hepatocytes
Reduces hepatic lactate dehydrogenase (LDH) levels via degradation of LDHA messenger RNA (mRNA) in hepatocytes through RNA interference
Reduction of hepatic LDH by nedosiran reduces liver production of oxalate, thereby reducing subsequent oxalate burden
Absorption
Peak plasma concentration: 844 ng/mL
Peak plasma time: 6 hr
AUC: 13,600 ng⋅hr/mL
Distribution
Vd: 126 L
Protein bound: 85.6%
Metabolism
Metabolized by endo- and exonucleases to shorter oligonucleotides
Elimination
Clearance: 5.7 L/hr
Half-life: 15 hr
Excretion: ~27% (Urine, unchanged within 24 hr of dosing)
Administration
SC Administration
Visually inspect for particulate matter and discoloration before injection; should be colorless-to-yellow and particle free
Discard solution if cloudy or contains particulate matter
Administer by SC injection to abdomen (at least 2 inches from navel) or upper thigh
Do not inject into a vein or into scarred or bruised skin
Use leaflets enclosed with prefilled syringe and single-dose vial
Use prefilled syringe for
- Adults and adolescents aged >12 yr
- Children aged 9-11 weighing >50 kg
Vials
- Use for pediatric patients aged 9-11 yr who weigh <50 kg
- Vials are intended for use under the guidance and supervision of a healthcare professional
- May be administered by a caregiver to pediatric patients aged 9-11 yr who weigh <50 kg after proper training in preparing vials for administration, if a healthcare professional determines that it is appropriate, and with medical follow-up as necessary
Missed dose
- Missed dose within 7 days: Administer as soon as possible
- Missed dose by >7 days: Administer as soon as possible and resume monthly dosing from the most recently administered dose
Storage
Refrigerate at 2-8ºC (36-46ºF)
May be stored, if needed, at 15-30©C (59-86ºF) for maximum of 28 days (4 weeks); do not freeze
Store in original carton, away from direct heat and light
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Formulary
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