Oxlumo (lumasiran): Uses, Dosage, Side Effects & Warnings

Uses

1 INDICATIONS AND USAGE OXLUMO is indicated for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary and plasma oxalate levels in pediatric and adult patients [see Clinical Pharmacology (12.1) , Clinical Studies (14.1 , 14.2 , 14.3) ] . OXLUMO is a HAO1 -directed small interfering ribonucleic acid (siRNA) indicated for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary and plasma oxalate levels in pediatric and adult patients. ( 1 )

Dosage and administration

The recommended dose of OXLUMO by subcutaneous injection is based on body weight. ( 2.1 ) Body Weight Loading Dose Maintenance Dose less than 10 kg 6 mg/kg once monthly for 3 doses 3 mg/kg once monthly, beginning 1 month after the last loading dose 10 kg to less than 20 kg 6 mg/kg once monthly for 3 doses 6 mg/kg once every 3 months (quarterly), beginning 1 month after the last loading dose 20 kg and above 3 mg/kg once monthly for 3 doses 3 mg/kg once every 3 months (quarterly), beginning 1 month after the last loading dose See Full Prescribing Information for important preparation and administration instructions. ( 2.2 ) 2.1 Recommended Dosage 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 as shown in Table 1. Dosing is based on actual body weight. Table 1. OXLUMO Weight-Based Dosing Regimen Body Weight Loading Dose Maintenance Dose Less than 10 kg 6 mg/kg once monthly for 3 doses 3 mg/kg once monthly, beginning 1 month after the last loading dose 10 kg to less than 20 kg 6 mg/kg once monthly for 3 doses 6 mg/kg once every 3 months (quarterly), beginning 1 month after the last loading dose 20 kg and above 3 mg/kg once monthly for 3 doses 3 mg/kg once every 3 months (quarterly), beginning 1 month after the last loading dose For Patients on Hemodialysis Administer OXLUMO after hemodialysis if administered on dialysis days. Missed Dose If a dose is delayed or missed, administer OXLUMO as soon as possible. Resume prescribed monthly or quarterly dosing, from the most recently administered dose. 2.2 Administration Instructions 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.

Dosage forms and strengths

Injection: 94.5 mg/0.5 mL clear, colorless-to-yellow solution in a single-dose vial. Injection: 94.5 mg/0.5 mL in a single-dose vial. ( 3 )

Contraindications

None. None. ( 4 )

Side effects

The most common adverse reaction (reported in ≥20% of patients) is injection site reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alnylam Pharmaceuticals at 1-877-256-9526 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 m 2 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 [see Clinical Studies (14) ] . 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. Table 2. Adverse Reactions Reported in at Least 10% of Patients Treated with OXLUMO and that Occurred at Least 5% More Frequently than in Patients Treated with Placebo in ILLUMINATE-A during the 6-Month Double-Blind Period Adverse Reaction OXLUMO N=26 N (%) Placebo N=13 N (%) Injection site reaction 10 (38) 0 (0) Abdominal pain Grouped term includes abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort. 4 (15) 1 (8) 6.2 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

Use in specific populations

8.1 Pregnancy Risk Summary 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 (see Data ). 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. Data Animal Data In an embryo-fetal development study in pregnant rats, lumasiran was administered subcutaneously at doses of 3, 10, and 30 mg/kg/day during organogenesis (gestational days 6-17). Administration of lumasiran resulted in no effects on embryo-fetal survival or fetal body weights and no lumasiran-related fetal malformations were observed. The 30 mg/kg/day dose in rats is 45 times the maximum recommended human dose (MRHD) for women of 3 mg/kg/month normalized to 0.1 mg/kg/day, based on body surface area. In an embryo-fetal development study in female rabbits, lumasiran was administered subcutaneously at doses of 3, 10, and 30 mg/kg/day during organogenesis (gestational days 7-19). There were decreases in maternal food consumption and decreases in maternal body weight gains at doses ≥3 mg/kg/day. There were no lumasiran-related fetal findings identified at doses up to 30 mg/kg/day (90 times the normalized MRHD based on body surface area). In a postnatal development study, lumasiran administered subcutaneously to pregnant female rats on gestational days 7, 13, 19 and on lactation days 6, 12, and 18 through weaning at doses up to 50 mg/kg did not produce maternal toxicity or developmental effects in the offspring. 8.2 Lactation Risk Summary 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. 8.4 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) [see Adverse Reactions (6.1) , Clinical Studies (14) ] . 8.5 Geriatric 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. 8.6 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) [see Clinical Pharmacology (12.3) ] . 8.7 Renal Impairment No dose adjustment is necessary in patients with renal impairment including patients with kidney failure treated with hemodialysis [see Clinical Pharmacology (12.3) ] . OXLUMO has not been studied in patients on peritoneal dialysis.

Pregnancy

8.1 Pregnancy Risk Summary 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 (see Data ). 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. Data Animal Data In an embryo-fetal development study in pregnant rats, lumasiran was administered subcutaneously at doses of 3, 10, and 30 mg/kg/day during organogenesis (gestational days 6-17). Administration of lumasiran resulted in no effects on embryo-fetal survival or fetal body weights and no lumasiran-related fetal malformations were observed. The 30 mg/kg/day dose in rats is 45 times the maximum recommended human dose (MRHD) for women of 3 mg/kg/month normalized to 0.1 mg/kg/day, based on body surface area. In an embryo-fetal development study in female rabbits, lumasiran was administered subcutaneously at doses of 3, 10, and 30 mg/kg/day during organogenesis (gestational days 7-19). There were decreases in maternal food consumption and decreases in maternal body weight gains at doses ≥3 mg/kg/day. There were no lumasiran-related fetal findings identified at doses up to 30 mg/kg/day (90 times the normalized MRHD based on body surface area). In a postnatal development study, lumasiran administered subcutaneously to pregnant female rats on gestational days 7, 13, 19 and on lactation days 6, 12, and 18 through weaning at doses up to 50 mg/kg did not produce maternal toxicity or developmental effects in the offspring.

Pediatric use

8.4 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) [see Adverse Reactions (6.1) , Clinical Studies (14) ] .

Geriatric use

8.5 Geriatric 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.

Description

11 DESCRIPTION OXLUMO injection contains lumasiran, a HAO1 -directed double-stranded small interfering ribonucleic acid (siRNA), covalently linked to a ligand containing N- acetylgalactosamine (GalNAc). The structural formula of lumasiran sodium is presented below: The molecular formula of lumasiran sodium is C 530 H 669 F 10 N 173 O 320 P 43 S 6 Na 43 and the molecular weight is 17,286 Da. OXLUMO is supplied as a sterile, preservative-free, clear, colorless-to-yellow solution for subcutaneous administration containing the equivalent of 94.5 mg of lumasiran (provided as lumasiran sodium) in 0.5 mL of water for injection and sodium hydroxide and/or phosphoric acid to adjust the pH to ~ 7.0. Chemical Structure

Mechanism of action

12.1 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.

How supplied

16.1 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). 16.2 Storage and Handling Store at 2°C to 25°C [36°F to 77°F]. Store OXLUMO in its original container until ready for use.

Storage

16.2 Storage and Handling Store at 2°C to 25°C [36°F to 77°F]. Store OXLUMO in its original container until ready for use.

Active ingredients

Lumasiran Sodium in 1 product

Oxlumo NDC products (1)

NDC	Strength & form	Labeler	Type
71336-1002	Lumasiran Sodium 94.5 mg/.5mL Injection, Solution	Alnylam Pharmaceuticals, Inc.	NDA

Frequently asked questions

What is Oxlumo used for?

1 INDICATIONS AND USAGE OXLUMO is indicated for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary and plasma oxalate levels in pediatric and adult patients [see Clinical Pharmacology (12.1) , Clinical Studies (14.1 , 14.2 , 14.3) ] . OXLUMO is a HAO1 -directed small interfering ribonucleic acid (siRNA) indicated for the treatment of primary hyperoxaluria type 1 (PH1) to lower…

What are the side effects of Oxlumo?

The most common adverse reaction (reported in ≥20% of patients) is injection site reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alnylam Pharmaceuticals at 1-877-256-9526 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of… See the full label for the complete list.

Who makes Oxlumo?

Oxlumo is listed by 1 labeler in the FDA NDC directory, including Alnylam Pharmaceuticals, Inc..