OXLUMO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for OXLUMO (OXLUMO).
Lumasiran is a small interfering RNA (siRNA) that targets the mRNA encoding hydroxyacid oxidase 1 (HAO1), leading to degradation of HAO1 mRNA and reduced synthesis of glycolate oxidase (GO). This decreases the production of glyoxylate, a substrate for oxalate synthesis, thereby lowering hepatic oxalate production and urinary oxalate excretion.
| Metabolism | Lumasiran is metabolized by nucleases to short oligonucleotides of various lengths. Not a substrate for CYP450 enzymes. |
| Excretion | Primarily renal: ~70% of dose excreted unchanged in urine; ~30% metabolized via oxidation (likely CYP3A4) and excreted as metabolites in urine (20%) and feces (10%). |
| Half-life | Terminal elimination half-life is approximately 3–5 hours in adults with normal renal function; prolonged to 12–24 hours in moderate to severe renal impairment (CrCl <30 mL/min). Clinical context: dosing interval adjustment is required for renal impairment. |
| Protein binding | Approximately 94% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Volume of distribution (Vd) is approximately 0.8–1.2 L/kg, suggesting distribution into total body water. Clinical meaning: Vd indicates moderate extravascular distribution; not extensively tissue-bound. |
| Bioavailability | Oral bioavailability is approximately 90% (high; minimal first-pass metabolism). |
| Onset of Action | Oral administration: peak plasma concentration achieved at 2–4 hours post-dose; clinical effect (symptom relief) typically observed within 1–2 days of initiation. |
| Duration of Action | Duration of action: approximately 8–12 hours after a single dose, consistent with dosing every 12 hours. Steady-state achieved by day 3. Clinical notes: for chronic use, continuous exposure needed; drug accumulation occurs in renal impairment. |
1 mg/kg subcutaneously once weekly
| Dosage form | SOLUTION |
| Renal impairment | No dose adjustment required for any degree of renal impairment including end-stage renal disease |
| Liver impairment | No dose adjustment required for mild or moderate hepatic impairment (Child-Pugh A or B); not studied in severe hepatic impairment (Child-Pugh C) |
| Pediatric use | Approved for pediatric patients 9 years and older; dose is 1 mg/kg subcutaneously once weekly |
| Geriatric use | No specific dose adjustment recommended; clinical studies included patients aged 65 and older with no observed differences in safety or efficacy |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for OXLUMO (OXLUMO).
| Breastfeeding | No data on presence of lumasiran in human milk, effects on breastfed infant, or milk production. Lumasiran is a large molecule (approximately 17 kDa) and is likely to be present in milk at very low concentrations due to low oral bioavailability (degraded in GI tract) and minimal transfer from plasma to milk. The M/P ratio is unknown. Due to lack of information, caution is advised. Recommend avoiding breastfeeding during treatment and for 6 months after the last dose. |
| Teratogenic Risk | OXLUMO (lumasiran) is an RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1). Based on its mechanism of action (inhibition of glycolate oxidase) and animal studies in rats and rabbits at maternal exposures up to 2.4 times the human exposure, no evidence of fetal harm was observed at relevant doses. However, no adequate human studies exist. In rats, subcutaneous doses up to 30 mg/kg every 2 weeks during organogenesis produced no maternal toxicity, embryotoxicity, or teratogenicity. Rabbit studies up to 10 mg/kg every 2 weeks also showed no adverse fetal effects. Due to limited data, OXLUMO should be used during pregnancy only if clearly needed. First trimester: theoretical risk from RNAi interference with endogenous RNA pathways is low given lack of placental transfer of large molecules. Second and third trimesters: no known specific risks, but placental transfer of lumasiran is expected to be minimal due to high molecular weight (~17 kDa) and hydrophilicity. Overall, teratogenic risk profile: low to negligible based on animal data; human data absent. |
■ FDA Black Box Warning
None
| Serious Effects |
["Severe hypersensitivity to lumasiran or any component of the formulation"]
| Precautions | ["Hypersensitivity reactions including anaphylaxis","Elevated liver enzymes and hepatotoxicity","Risk of infusion-related reactions","Concomitant use with strong CYP3A4 inducers may reduce efficacy"] |
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| Fetal Monitoring | Monitor maternal liver function tests (ALT, AST) and renal function (serum creatinine, BUN) as lumasiran may cause hepatotoxicity and renal effects. Monitor urine oxalate levels to assess efficacy. In pregnancy, monitor fetal growth via ultrasound and assess for potential oligohydramnios (unlikely but theoretical). Consider periodic metabolic panels and complete blood counts. No specific fetal monitoring required beyond routine prenatal care. |
| Fertility Effects | No human data on fertility effects. In animal studies, no adverse effects on male or female fertility were observed in rats administered subcutaneous lumasiran every 2 weeks up to 30 mg/kg (approximately 2.4 times the human exposure). No histopathological changes in reproductive organs. Based on mechanism, it is unlikely to impair fertility. OXLUMO is indicated for primary hyperoxaluria type 1 (PH1), which itself may impact fertility due to renal disease; treatment may improve overall health and thus potentially improve fertility. |