Lumasiran
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alara Ece Dagsali, M.D.
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Overview
Lumasiran is an inhibits oxalate synthesis that is FDA approved for the treatment of of primary hyperoxaluria type 1 (PH1) to lower urinary and plasma oxalate levels in pediatric and adult patients. Common adverse reactions include *Injection site reaction
- Abdominal pain*.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
OXLUMO is indicated for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary and plasma oxalate levels in pediatric and adult patients
DOSING The recommended dosing regimen of OXLUMO consists of loading doses (monthly for 3 doses) followed by maintenance doses (beginning 1 month after the last loading dose) administered subcutaneously
Injection: 94.5 mg/0.5 mL clear, colorless-to-yellow solution in a single-dose vial.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lumasiran in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lumasiran in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Lumasiran FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lumasiran in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lumasiran in pediatric patients.
Contraindications
None
Warnings
There is limited information regarding Lumasiran Warnings' in the drug label.
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of OXLUMO has been evaluated in a placebo-controlled trial and two single-arm clinical trials. Across these trials, 98 patients with PH1 have been treated with OXLUMO, including 71 pediatric patients and 15 patients on hemodialysis. Overall, 92 patients were treated for at least 6 months, 78 patients for at least 12 months, and 29 patients for at least 24 months.
In the randomized, placebo-controlled, double-blind study ILLUMINATE-A in pediatric and adult patients with PH1 aged 6 to 61 years, 26 patients received OXLUMO, and 13 patients received placebo. Of these, 25 patients received ≥5 months of treatment.
In two single-arm studies in patients with PH1, ILLUMINATE-B (patients <6 years of age) and ILLUMINATE-C (pediatric and adult patients with moderately or severely reduced GFR [eGFR ≤45 mL/min/1.73 m2 or pediatric patients <12 months of age with serum creatinine above the upper limit of normal for age] and patients with kidney failure on hemodialysis), the OXLUMO safety profile was similar to that seen in ILLUMINATE-A
In placebo-controlled and open-label clinical studies the most common adverse reaction reported was injection site reaction. Injection site reactions included erythema, swelling, pain, hematoma, pruritus, and discoloration. These symptoms were generally mild and resolved within one day of the injection and did not lead to discontinuation of treatment.
Postmarketing Experience
The following additional adverse reaction has been reported during post-approval use. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency.
Immune system disorder: Hypersensitivity
Drug Interactions
There is limited information regarding Lumasiran Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Lumasiran in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lumasiran in women who are pregnant.
Labor and Delivery
There are no available data with the use of OXLUMO in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
No adverse effects on pregnancy or embryo-fetal development related to OXLUMO were observed in rats at 45 times and in rabbits at 90 times the maximum recommended human dose in women
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.
Nursing Mothers
There are no data on the presence of OXLUMO in human milk, the effects on the breastfed child, or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for OXLUMO and any potential adverse effects on the breastfed child from OXLUMO or from the underlying maternal condition.
Pediatric Use
The safety and effectiveness of OXLUMO have been established in pediatric patients aged birth and older. Use of OXLUMO in these age groups is supported by evidence from an adequate and well controlled study of OXLUMO in pediatric patients 6 years or older and adults with PH1 (ILLUMINATE-A), a single-arm clinical study in pediatric patients less than 6 years of age with PH1 (ILLUMINATE-B), and a single-arm clinical study in pediatric and adult patients with PH1 who had advanced chronic kidney disease including patients on hemodialysis (ILLUMINATE-C)
Geriatic Use
Clinical studies of OXLUMO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.
Gender
There is no FDA guidance on the use of Lumasiran with respect to specific gender populations.
Race
There is no FDA guidance on the use of Lumasiran with respect to specific racial populations.
Renal Impairment
No dose adjustment is necessary in patients with renal impairment including patients with kidney failure treated with hemodialysis. OXLUMO has not been studied in patients on peritoneal dialysis.
Hepatic Impairment
No dose adjustment is recommended for patients with mild [total bilirubin > upper limit of normal (ULN) to 1.5 × ULN or AST > ULN] or moderate hepatic impairment (total bilirubin > 1.5 to 3 × ULN with any AST). OXLUMO has not been studied in patients with severe hepatic impairment (total bilirubin > 3 × ULN with any AST)
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lumasiran in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Lumasiran in patients who are immunocompromised.
Administration and Monitoring
Administration
OXLUMO is intended for subcutaneous use and should be administered by a healthcare professional.
Visually inspect the drug product solution. Do not use if it contains particulate matter or if it is cloudy or discolored. OXLUMO is a sterile, preservative-free, clear, colorless-to-yellow solution. It is supplied in a single-dose vial, as a ready-to-use solution that does not require additional reconstitution or dilution prior to administration.
- Use aseptic technique.
- Divide injection volumes greater than 1.5 mL equally into multiple syringes.
- For volumes less than 0.3 mL, a sterile 0.3-mL syringe is recommended. If using a 0.3 mL (30 unit) insulin syringe, 1-unit markings indicate 0.01 mL.
- Administer subcutaneous injection into the abdomen, thigh, or the side or back of the upper arms. Rotate injection sites. Do not inject into scar tissue or areas that are reddened, inflamed, or swollen.
- If injecting into the abdomen, avoid the area around the navel.
- If more than one injection is needed for a single dose of OXLUMO, the injection sites should be at least 2 cm apart.
- Discard unused portion of the drug.
Monitoring
There is limited information regarding Lumasiran Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Lumasiran and IV administrations.
Overdosage
There is limited information regarding Lumasiran overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Lumasiran Pharmacology in the drug label.
Mechanism of Action
Lumasiran reduces levels of glycolate oxidase (GO) enzyme by targeting the hydroxyacid oxidase 1 (HAO1) messenger ribonucleic acid (mRNA) in hepatocytes through RNA interference. Decreased GO enzyme levels reduce the amount of available glyoxylate, a substrate for oxalate production. As the GO enzyme is upstream of the deficient alanine: glyoxylate aminotransferase (AGT) enzyme that causes PH1, the mechanism of action of lumasiran is independent of the underlying AGXT gene mutation. OXLUMO is not expected to be effective in primary hyperoxaluria type 2 (PH2) or type 3 (PH3) because its mechanism of action does not affect the metabolic pathways causing hyperoxaluria in PH2 and PH3.
Structure
There is limited information regarding Lumasiran Structure in the drug label.
Pharmacodynamics
The pharmacodynamic effects of OXLUMO have been evaluated in adult and pediatric patients with PH1 across a range of doses and dosing frequency. Dose-dependent reductions in urinary oxalate levels were observed, resulting in the selection of the recommended body weight-based loading and maintenance dosing regimens. With the recommended dosing regimens, onset of effect was observed within two weeks after the first dose and maximal reductions in urinary oxalate were observed by Month 2 and persisted with continued use of OXLUMO maintenance dosage
Cardiac Electrophysiology At the recommended dose, OXLUMO does not lead to clinically relevant QT interval prolongation.
Pharmacokinetics
The pharmacokinetic (PK) properties of OXLUMO were evaluated following administration of single and multiple dosages in patients with PH1
Nonclinical Toxicology
Carcinogenicity studies were conducted in Tg-rasH2 mice and Sprague Dawley rats.
Lumasiran was not carcinogenic in transgenic Tg-rasH2 mice following monthly subcutaneous administration of lumasiran for 26 weeks at doses of 150, 500, or 1500 mg/kg.
In a 2-year carcinogenicity study, lumasiran was not carcinogenic up to the highest dose tested. Sprague Dawley rats were administered subcutaneous doses of 20, 55, or 110 mg/kg lumasiran once every 4 weeks (3, 9, or 18 times the normalized maintenance MRHD, based on body surface area).
Lumasiran was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay, in the in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes, or the in vivo micronucleus assay in rats.
Administration of lumasiran by weekly subcutaneous doses of 0, 5, 15, and 50 mg/kg in male and female rats prior to and during mating and continuing in females once on Day 6 of presumed gestation resulted in no adverse effects upon the male or female fertility endpoints evaluated.
Clinical Studies
ILLUMINATE-A
ILLUMINATE-A was a randomized, double-blind trial comparing lumasiran and placebo in 39 patients 6 years of age and older with PH1 and an eGFR ≥30 mL/min/1.73 m2 (ILLUMINATE-A; NCT03681184). Patients received 3 loading doses of 3 mg/kg OXLUMO (N=26) or placebo (N=13) administered once monthly, followed by quarterly maintenance doses of 3 mg/kg OXLUMO or placebo. After six months, all patients received OXLUMO.
The median age of patients at first dose was 15 years (range 6 to 61 years), 67% were male, and 77% were White. At baseline, the median 24-hour urinary oxalate excretion corrected for body surface area (BSA) was 1.7 mmol/24 h/1.73 m2, the median plasma oxalate level was 13.1 µmol/L, 33% of patients had eGFR ≥90 mL/min/1.73 m2, 49% had eGFR of 60 to <90 mL/min/1.73 m2, and 18% had eGFR 30 to <60 mL/min/1.73 m2, 56% were on pyridoxine, and 85% reported a history of symptomatic kidney stone events.
The primary endpoint was the percent reduction from baseline in 24-hour urinary oxalate excretion corrected for BSA averaged over Months 3 through 6. The LS mean percent change from baseline in 24-hour urinary oxalate in the OXLUMO group was -65% (95% CI: -71, -59) compared with -12% (95% CI: -20, -4) in the placebo group, resulting in a between-group LS mean difference of 53% (95% CI: 45, 62; p<0.0001).
By Month 6, 52% (95% CI: 31, 72) of patients treated with OXLUMO achieved a normal 24-hour urinary oxalate corrected for BSA (≤0.514 mmol/24 hr/1.73 m2) compared to 0% (95% CI: 0, 25) placebo-treated patients (p=0.001). Reduced urinary oxalate levels were maintained through Month 24 in patients treated with OXLUMO.
ILLUMINATE-B ILLUMINATE-B was a single-arm study in 18 patients <6 years of age with PH1 and an eGFR >45 mL/min/1.73 m2 for patients ≥12 months of age or a normal serum creatinine for patients <12 months of age (ILLUMINATE-B; NCT03905694). Dosing was based on body weight
The median age of patients at first dose was 51 months (range 4 to 74 months), 56% were female, and 88% were White. Three patients were less than 10 kg, 12 were 10 kg to <20 kg, and 3 were ≥20 kg. The median spot urinary oxalate: creatinine ratio at baseline was 0.47 mmol/mmol.
The primary endpoint was the percent reduction from baseline in spot urinary oxalate: creatinine ratio averaged over Months 3 through 6. Patients treated with OXLUMO achieved a reduction in spot urinary oxalate: creatinine ratio from baseline of 72% (95% CI: 66, 78) (Figure 2). The reduction in urinary oxalate excretion was maintained with continued OXLUMO treatment through Month 12.
ILLUMINATE-C A total of 21 patients were enrolled and treated with OXLUMO in a multi-center, single-arm study in patients with PH1 and an eGFR ≤45 mL/min/1.73 m2 in patients 12 months of age and older or an elevated serum creatinine for age in patients less than 12 months of age, including patients on hemodialysis. ILLUMINATE-C included 2 cohorts. Cohort A included 6 patients who did not require dialysis at the time of study enrollment. Cohort B included 15 patients who were on a stable regimen of hemodialysis; the hemodialysis regimen was to remain stable in these patients for the first 6 months of the study. Patients received the recommended dosing regimen of OXLUMO based on body weight.
Patients requiring peritoneal dialysis were excluded.
The median age of patients at first dose was 9 years (range 0 to 59 years), 57% were male, and 76% were White. For Cohort A, the median plasma oxalate level was 58 µmol/L. For Cohort B, the median pre-dialysis plasma oxalate level was 104 µmol/L.
The primary endpoint was the percent change in plasma oxalate from baseline to Month 6 (average from Month 3 to Month 6) for Cohort A (N=6) and the percent change in pre-dialysis plasma oxalate from baseline to Month 6 (average from Month 3 to Month 6) for Cohort B (N=15). The percent change from baseline to Month 6 in plasma oxalate levels in Cohort A was an LS mean difference of -33% (95% CI: -82, 15) and in Cohort B was -42% (95% CI: -51, -34).
Mean plasma oxalate decreased from 65 µmol/L (95% CI: 21, 108) at baseline to 33 µmol/L (95% CI: 10, 56) at Month 6 in Cohort A, and from 108 µmol/L (95% CI: 92, 125) at baseline to 62 µmol/L (95% CI: 51, 72) at Month 6 in Cohort B. The time course for changes in plasma oxalate
How Supplied
OXLUMO is a clear, colorless-to-yellow solution available in single-dose vials of 94.5 mg/0.5 mL in cartons containing one vial (NDC 71336-1002-1).
Storage
Store at 2°C to 25°C [36°F to 77°F].
Store OXLUMO in its original container until ready for use.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
There is limited information regarding Lumasiran Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Lumasiran interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
OXLUMO
Look-Alike Drug Names
There is limited information regarding Lumasiran Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.