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.

inate-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)

6-17). 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.

iran 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.

on 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 [see figures 1 and 2 in clinical studies (14.1, 14.2)] . cardiac electrophysiology at the recommended dose, oxlumo does not lead to clinically relevant qt interval prolongation. 12.3 pharmacokinetics the pharmacokinetic (pk) properties of oxlumo were evaluated following administration of single and multiple dosages in patients with ph1 as summarized in table 3. table 3. pharmacokinetic parameters of lumasiran lumasiran general information steady-state exposure c max [median (range)] 462 (38.5 to 1500) ng/ml auc 0-last [median (range)] 6810 (2890 to 10700) ng∙h/ml dose proportionality lumasiran exhibited an approximately dose proportional increase in plasma exposure following single subcutaneous doses ranging from 0.3 to 6 mg/kg. lumasiran exhibited time-independent pharmacokinetics with multiple doses of 1 and 3 mg/kg once monthly or 3 mg/kg quarterly. accumulation no accumulation of lumasiran was observed in plasma after repeated monthly or quarterly dosing. absorption t max [median (range)] 4 (0.5 to 12) hours distribution lumasiran distributes primarily to the liver after subcutaneous administration. c max = maximum plasma concentration; auc 0-last = area under the plasma concentration-time curve from time of administration (0) to the last measurable time point (last); t max = time to maximum concentration; vd/f = apparent volume of distribution; cv = coefficient of variation; cl/f = apparent clearance. estimated vd/f 4.9 l protein binding 85% elimination apparent half-life [mean (%cv)] 5.2 (47%) hours estimated cl/f 26.5 l/hour metabolism primary pathway lumasiran is metabolized by endo- and exonucleases to oligonucleotides of shorter lengths. excretion primary pathway less than 26% of the administered dose of lumasiran is excreted unchanged into the urine within 24 hours with the rest excreted as inactive metabolite. specific populations no clinically significant differences in the pharmacokinetics or pharmacodynamics of lumasiran were observed based on age (4 months to < 65 years old), sex, race/ethnicity, renal impairment, use of hemodialysis, or mild to moderate hepatic impairment (total bilirubin ≤ uln and ast > uln; or total bilirubin ≤ 3× uln). the effect of severe hepatic impairment on the pharmacokinetics of lumasiran is unknown. body weight in children < 20 kg, lumasiran c max was twice as high due to the higher 6 mg/kg dose and faster absorption rate. at the approved recommended dosage, lumasiran auc was similar across the 6.2 kg to 110 kg body weight range [see dosage and administration (2.1) ] . drug interaction studies clinical studies no clinical studies evaluating the drug interaction potential of lumasiran have been conducted. concomitant use of pyridoxine (vitamin b6) did not influence the pharmacodynamics or pharmacokinetics of lumasiran. in vitro studies in vitro studies indicate that lumasiran is not a substrate or an inhibitor of cytochrome p450 (cyp) enzymes. lumasiran is not expected to induce cyp enzymes or modulate the activities of drug transporters. 12.6 immunogenicity the observed incidence of anti-drug antibody (ada, including neutralizing antibody) is highly dependent on the sensitivity and specificity of the assay. differences in assay methods preclude meaningful comparisons of the incidence of ada in the studies described below with the incidence of ada in other studies, including those of oxlumo or of other sirna products. across all clinical studies in the lumasiran development program, including patients with ph1 and healthy volunteers dosed with oxlumo, 7 of 120 (6%) lumasiran-treated individuals with mean follow-up duration of 8.9 months, tested positive for ada, as early as from day 29. no clinically significant differences in the safety, pharmacokinetic, or pharmacodynamic profiles of lumasiran were observed in patients who tested positive for ada.

rea under the plasma concentration-time curve from time of administration (0) to the last measurable time point (last); t max = time to maximum concentration; vd/f = apparent volume of distribution; cv = coefficient of variation; cl/f = apparent clearance. estimated vd/f 4.9 l protein binding 85% elimination apparent half-life [mean (%cv)] 5.2 (47%) hours estimated cl/f 26.5 l/hour metabolism primary pathway lumasiran is metabolized by endo- and exonucleases to oligonucleotides of shorter lengths. excretion primary pathway less than 26% of the administered dose of lumasiran is excreted unchanged into the urine within 24 hours with the rest excreted as inactive metabolite. specific populations no clinically significant differences in the pharmacokinetics or pharmacodynamics of lumasiran were observed based on age (4 months to < 65 years old), sex, race/ethnicity, renal impairment, use of hemodialysis, or mild to moderate hepatic impairment (total bilirubin ≤ uln and ast > uln; or total bilirubin ≤ 3× uln). the effect of severe hepatic impairment on the pharmacokinetics of lumasiran is unknown. body weight in children < 20 kg, lumasiran c max was twice as high due to the higher 6 mg/kg dose and faster absorption rate. at the approved recommended dosage, lumasiran auc was similar across the 6.2 kg to 110 kg body weight range [see dosage and administration (2.1) ] . drug interaction studies clinical studies no clinical studies evaluating the drug interaction potential of lumasiran have been conducted. concomitant use of pyridoxine (vitamin b6) did not influence the pharmacodynamics or pharmacokinetics of lumasiran. in vitro studies in vitro studies indicate that lumasiran is not a substrate or an inhibitor of cytochrome p450 (cyp) enzymes. lumasiran is not expected to induce cyp enzymes or modulate the activities of drug transporters.

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) [figure 1]. abbreviation: ci ꞊ confidence interval. results are plotted as mean (95% ci) of percent change from baseline. figure 1. illuminate-a: percent change from baseline in 24-hour urinary oxalate by month 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 m 2 ) 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. figure 1 14.2 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 m 2 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 [see dosage and administration (2.1) ] . 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. abbreviation: ci ꞊ confidence interval. results are plotted as mean (95% ci) of percent change from baseline. figure 2. illuminate-b: percent change from baseline in spot urinary oxalate: creatinine ratio by month figure 2 14.3 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 m 2 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 [see dosage and administration (3.1)]. 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 is shown in figure 3. abbreviation: ci ꞊ confidence interval. results are plotted as mean (95% ci) of actual values. for cohort a, the baseline is defined as the mean of all plasma oxalate samples collected prior to the first dose of lumasiran; for cohort b, the baseline is defined as the last four pre-dialysis plasma oxalate samples collected prior to the first dose of lumasiran. in cohort b, only pre-dialysis samples are utilized. figure 3. illuminate-c: plasma oxalate levels (μmol/l) during the primary analysis period by month figure 3