OXLUMO 94.5mg / 0.5ml injectible solution medication leaflet

Oxlumo 94.5 mg/0.5 mL solution for injection.

Each mL of solution contains lumasiran sodium equivalent to 189 mg lumasiran.

Each vial contains 94.5 mg lumasiran in 0.5 mL.

For the full list of excipients, see section 6.1.

Solution for injection.

Clear, colourless to yellow solution (pH of approximately 7; osmolality 240 to 360 mOsm/kg).

Oxlumo is indicated for the treatment of primary hyperoxaluria type 1 (PH1) in all age groups.

Therapy should be initiated and supervised by a physician experienced in the management ofhyperoxaluria.

Oxlumo is administered by subcutaneous injection. The recommended dose of Oxlumo consists ofloading doses given once a month for 3 doses, followed by maintenance doses beginning one monthafter the last loading dose, as shown in Table 1. Dosing is based on body weight.

The patient dose (in mg) and volume (in mL) should be calculated as follows:

Patient body weight (kg) × dose (mg/kg) = total amount (mg) of medicinal product to be administered.

Total amount (mg) divided by concentration (189 mg/mL) = total volume of medicinal product (mL)to be injected.

Table 1: Oxlumo weight-based dosing regimen

Body weight Loading dose (beginning one month after the lastloading dose)less than 10 kg 6 mg/kg once monthly for 3 mg/kg once monthly, beginning3 doses one month after the last loading dose10 kg to less than 20 kg 6 mg/kg once monthly for 6 mg/kg once every 3 months3 doses (quarterly), beginning one month afterthe last loading dose20 kg and above 3 mg/kg once monthly for 3 mg/kg once every 3 months3 doses (quarterly), beginning one month afterthe last loading dose

Patients on haemodialysis

Administer Oxlumo following haemodialysis if administered on dialysis days.

If a dose is delayed or missed, treatment should be administered as soon as possible. Prescribedmonthly or quarterly dosing should be resumed from the most recently administered dose.

No dose adjustment is necessary in patients ≥ 65 years of age (see section 5.2).

Oxlumo has not been studied in patients with hepatic impairment. No dose adjustment is necessary inpatients with transient elevation in total bilirubin (total bilirubin > 1.0 to 1.5×ULN). Caution isrequired when treating patients with moderate or severe hepatic impairment (see sections 4.4 and 5.2).

No dose adjustment is necessary in patients with renal impairment (eGFR < 90 mL/min/1.73 m2)including end-stage renal disease (ESRD), or those on dialysis. Limited data are available in patientswith ESRD and on dialysis, and these patients should be treated with caution (see sections 4.4 and5.2).

In patients under 1 year of age, limited data are available. Caution should be used when treating thesepatients (see section 5.2).

For subcutaneous use only.

This medicinal product is provided as a ready-to-use solution in a single use vial.

* The required volume of Oxlumo should be calculated based on the recommended weight-baseddose as shown in Table 1.

* If the dose is more than 0.5 mL (94.5 mg), more than one vial will be needed.

* The maximum acceptable single injection volume is 1.5 mL. Doses requiring more than 1.5 mLshould be administered as multiple injections (the total dose divided equally between syringeswith each injection containing approximately the same volume) to minimise potential injectionsite discomfort due to injection volume.

* Having the medicinal product on the needle tip before the needle is in the subcutaneous spaceshould be avoided.

* This medicinal product should be injected subcutaneously into the abdomen, upper arms, orthighs.

* For subsequent injections or doses, rotating the injection site is recommended.

* This medicinal product should not be administered into scar tissue or areas that are reddened,inflamed, or swollen.

Oxlumo should be administered by a healthcare professional. For instructions on the medicinalproduct before administration see section 6.6.

Severe hypersensitivity to the active substance or any of the excipients listed in section 6.1.

Severe or end-stage renal impairment

Treatment with lumasiran increases plasma glycolate levels, which may increase the risk of metabolicacidosis or worsening of pre-existing metabolic acidosis in patients with severe or end-stage renaldisease. These patients should therefore be monitored for signs and symptoms of metabolic acidosis.

Moderate or severe hepatic impairment

In patients with moderate or severe hepatic impairment there is a potential for decreased efficacy.

Therefore, efficacy should be monitored in these patients (see section 5.2).

Excipient (sodium content)

This medicinal product contains less than 1 mmol sodium (23 mg) per mL, that is to say essentially‘sodium-free’.

No clinical drug interaction studies have been performed (see section 5.2).

Concomitant use with pyridoxine

Concomitant use of pyridoxine did not meaningfully influence the pharmacodynamics orpharmacokinetics of lumasiran.

There are no data from the use of lumasiran in pregnant women. Animal studies do not indicate director indirect harmful effects with respect to reproductive toxicity (see section 5.3). The use of thismedicinal product could be considered during pregnancy taking into account the expected healthbenefit for the woman and potential risks to the foetus.

It is unknown whether lumasiran is excreted in human milk. A risk to the newborns/infants cannot beexcluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstainfrom Oxlumo therapy, taking into account the benefit of breast-feeding for the child and the benefit oftherapy for the woman.

There are no data on the effects of lumasiran on human fertility. No impact on male or female fertilitywas detected in animal studies (see section 5.3).

Oxlumo has no or negligible influence on the ability to drive and use machines.

The most common adverse reaction reported was injection site reaction (35%).

Adverse reactions associated with lumasiran obtained from clinical studies and spontaneous reportingare tabulated below. The adverse reactions are coded to preferred terms (PTs) under the MedDRAsystem organ class (SOC) and are presented by frequency. The frequency of the adverse reactions isexpressed according to the following categories: Very common (≥ 1/10); common (≥ 1/100 to < 1/10);uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known(cannot be estimated from the available data).

Table 2: Adverse reactions

System organ class Adverse reaction Frequency

Immune system disorders Hypersensitivitya Not known

Gastrointestinal disorders Abdominal painb Very common

General disorders and administration Injection site reactionc Very commonsite conditionsa Adverse reaction reported during post-marketing use.b Includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, and abdominal tenderness.c Includes injection site reaction, injection site erythema, injection site pain, injection site pruritus, injection site swelling,injection site discomfort, injection site discolouration, injection site mass, injection site induration, injection site rash,injection site bruising, injection site haematoma and injection site exfoliation.

In placebo-controlled and open-label clinical studies, injection site reactions were reported in 34 out of98 patients (34.7%). The most commonly reported symptoms were erythema, swelling, pain,haematoma, pruritus, and discolouration. The majority of injection site reactions started on the day ofadministration, with < 2% of injection site reactions occurring 5 or more days after administration.

Injection site reactions were generally mild, resolved within two days, and did not result ininterruption or discontinuation of treatment.

Abdominal pain

In the placebo-controlled study, abdominal pain was reported in 1 of 13 (7.7%) placebo-treatedpatients and 4 of 26 (15.4%) lumasiran-treated patients. In the placebo-controlled and open-labelclinical studies, 16 of 98 patients (16.3%) reported abdominal pain, including upper or lowerabdominal pain, abdominal discomfort, or abdominal tenderness. Most of the events have been mild,transient, and resolved without treatment. None have resulted in discontinuation of treatment.

In patients with PH1 and healthy volunteers dosed with Oxlumo in clinical studies, 7 of 120 (5.8%)individuals tested positive for anti-drug-antibodies (ADA). ADA titres were low and generallytransient, with no impact on the efficacy, safety, pharmacokinetic, or pharmacodynamic profiles of themedicinal product.

ILLUMINATE-A (trial description see below)

The safety profile in the open-label extension period (median treatment duration of 55.0 months) wasconsistent with the known safety profile of lumasiran from the placebo-controlled double-blind periodof the study.

The safety profile of lumasiran was similar in paediatric (aged 4 months to 17 years) and adult patientswith PH1.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In case of overdose, it is recommended that the patient be monitored as medically indicated for anysigns or symptoms of adverse reactions and appropriate symptomatic treatment be instituted.

Pharmacotherapeutic group: Various alimentary tract and metabolism products, ATC code: A16AX18.

Lumasiran is a double-stranded small interfering ribonucleic acid (siRNA) that reduces levels ofglycolate oxidase (GO) enzyme by targeting the hydroxyacid oxidase 1 (HAO1) gene messengerribonucleic acid (mRNA) in hepatocytes through RNA interference. Decreased GO enzyme levelsreduce the amount of available glyoxylate, a substrate for oxalate production. This results in reductionof urinary and plasma oxalate levels, the underlying cause of disease manifestations in patients with

PH1. 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.

The efficacy of lumasiran was studied in a randomised, double-blind, placebo-controlled clinical studyin patients 6 years and older with PH1 (ILLUMINATE-A), in a single-arm clinical study in patientsless than 6 years of age with PH1 (ILLUMINATE-B), and in a single-arm clinical study in paediatricand adult patients with PH1 who have advanced renal disease, including patients on haemodialysis(ILLUMINATE-C).

ILLUMINATE-A

A total of 39 patients with PH1 were randomised 2:1 to receive subcutaneous doses of lumasiran orplacebo during the 6-month double-blind, placebo-controlled period. Patients 6 years and older withan estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 were enrolled and received3 loading doses of 3 mg/kg lumasiran or placebo administered once monthly, followed by quarterlymaintenance doses of 3 mg/kg lumasiran or placebo (see section 4.2). After the 6-month double-blindtreatment period, patients, including those originally assigned to placebo, entered an extension periodwith administration of lumasiran for up to 54 months. The overall lumasiran exposure was 165.7patient years.

During the 6-month double-blind, placebo-controlled period, 26 patients received lumasiran, and13 received placebo. The median age of patients at first dose was 14.9 years (range 6.1 to 61.0 years),66.7% were male, and 76.9% were white. The median 24-hour urinary oxalate excretion corrected forbody surface area (BSA) at baseline was 1.72 mmol/24h/1.73 m2, the median spot urinaryoxalate: creatinine ratio at baseline was 0.21 mmol/mmol, and the median plasma oxalate level atbaseline was 13.1 µmol/L. Overall, 33.3% of patients had normal renal function (eGFR≥ 90 mL/min/1.73 m2), 48.7% had mild renal impairment (eGFR of 60 to < 90 mL/min/1.73 m2), and18% had moderate renal impairment (eGFR of 30 to < 60 mL/min/1.73 m2). Of the patients enrolled inthe study, 84.6% reported a history of symptomatic renal stone events and 53.8% reported a history ofnephrocalcinosis at baseline. The treatment arms were balanced at baseline with respect to age, urinaryoxalate level, and eGFR.

The primary endpoint was the percent reduction from baseline in 24-hour urinary oxalate excretioncorrected for BSA averaged over months 3 through 6. Lumasiran was associated with a statisticallysignificant reduction of 65.4% in 24-hour urinary oxalate corrected for BSA, as compared to 11.8% inthe placebo group, representing a difference of 53.5% (95% CI: 44.8, 62.3; p<0.0001). Consistent withthe primary endpoint, a reduction of 60.5% was observed at month 6 in spot urinary oxalate: creatinineratio in the lumasiran arm compared to an 8.5% increase in the placebo arm. Furthermore, patientstreated with lumasiran had a rapid and sustained decrease in 24-hour urinary oxalate corrected for

BSA, as shown in Figure 1.

Figure 1: ILLUMINATE-A: Percent change from baseline in 24-hour urinary oxalatecorrected for BSA by month (6-month double-blind, placebo-controlled period)

Abbreviations: BL = baseline; BSA = body surface area; M = month; SEM = standard error of mean.

Results are plotted as mean (±SEM) of percent change from baseline.

At month 6, a higher proportion of lumasiran-treated patients achieved normal or near-normal levelsof 24-hour urinary oxalate corrected for BSA (≤ 1.5×ULN) compared to placebo-treated patients, asshown in Table 3.

Table 3: ILLUMINATE-A: Secondary endpoint results over the 6-month double-blind,placebo-controlled period

Endpoints Lumasiran Placebo Treatment difference p-value(N=26) (N=13) (95% CI)

Proportion of patients with24-hour urinary oxalate 0.52 (0.31, 0.72)§ 0 (0, 0.25)§ 0.52 (0.23, 0.70)¶ 0.001#levels at or below ULN‡

Proportion of patients with24-hour urinary oxalatelevels at or below 0.84 (0.64, 0.95)§ 0 (0, 0.25)§ 0.84 (0.55, 0.94)¶ <0.0001#1.5×ULN‡

Percent reduction in plasma 39.8 (2.9)† 0.3 (4.3)† 39.5 (28.9, 50.1) <0.0001oxalate from baseline*Þ

Abbreviations: ULN = upper limit of normal; SEM = standard error of mean

Results are based on liquid chromatography tandem mass spectrometry (LC-MS/MS) assay.

* The estimate based on the average of the least square mean of percent reduction at Months 3, 4, 5, and 6 using a mixedmodel for repeated measures.† LS Mean (SEM).‡ ULN=0.514 mmol/24hr/1.73 m2 for 24-hour urinary oxalate corrected for BSA.§ 95% CI based on Clopper Pearson Exact confidence interval.¶ Calculated using the Newcombe Method based on the Wilson Score.# p-value is based on Cochran-Mantel-Haenszel test stratified by baseline 24-hour urinary oxalate corrected for BSA (≤1.70vs >1.70 mmol/24hr/1.73 m2).

Þ Analysed in 23 lumasiran and 10 placebo patients who had baseline levels that allowed for reduction to occur.

Reduction in 24-hour urinary oxalate corrected for BSA from baseline in patients with PH1 receivinglumasiran compared to placebo was similar across all pre-specified subgroups, including age, sex,race, renal impairment, baseline pyridoxine (vitamin B6) use, and history of symptomatic renal stoneevents (Figure 2).

Figure 2: ILLUMINATE-A: Percent change from baseline in 24-hour urinary oxalate correctedfor BSA, subgroup analysis

Reduced oxalate levels observed in the double-blind period were maintained with continued lumasirantreatment up to 60 months during the extension period of the study. eGFR, renal stone events (reportedby events per person-year) and medullary nephrocalcinosis were assessed through the 6-monthdouble-blind and extension periods for a total of up to 60 months.

eGFR remained stable in patients administered lumasiran. The mean annual rate of change frombaseline during treatment with lumasiran up to 60 months was -0.63 ml/min/1.73 m2/year.

The rate of renal stone events per person-year reported in patients randomised to lumasiran andplacebo in ILLUMINATE-A are presented in Table 4.

Table 4: Rate of renal stone events per person-year reported in the lumasiran and placebogroup

Time Period Lumasiran Placebo

Rate (95% CI) Rate (95% CI)12 months prior to 3.19 (2.57, 3.96) 0.54 (0.26, 1.13)consent6-month double-blind 1.09 (0.63, 1.88) 0.66 (0.25, 1.76)period

During extended open-label treatment with lumasiran up to 60 months, the rate of renal stone eventswas 0.49 per person-year, and 53.8% of the patients had no renal stone events.

Medullary nephrocalcinosis results, assessed by renal ultrasound, from month 6 relative to baseline arepresented in Table 5.

Table 5: ILLUMINATE-A: Patients with medullary nephrocalcinosis at month 6double-blind, placebo-controlled period relative to baseline*

Timepoint Treatment Improvement No Change Worsening(n)

Lumasiran 3 19 0

Month 6 (n=22)

Placebo(n=12) 0 11 1

* Patients with renal ultrasounds at baseline and the relevant timepoint were assessed.

The evaluation of medullary nephrocalcinosis was performed only in a part of the study population(17/26 lumasiran/lumasiran patients and 6/13 placebo/lumasiran patients were evaluated at bothbaseline and at the end of the 54-month extension period). In this subpopulation a general trend forimprovement over time was demonstrated.

ILLUMINATE-B

A total of 18 patients were enrolled and treated with lumasiran in an ongoing multi-centre, single-armstudy in patients with PH1 (ILLUMINATE-B). The study enrolled patients less than 6 years of agewith an eGFR > 45 mL/min/1.73 m2 in patients 12 months of age and older, and normal serumcreatinine in patients less than 12 months of age. In the 6-month primary analysis, at first dose,3 patients were less than 10 kg, 12 were 10 kg to less than 20 kg, and 3 were 20 kg and above. Themedian age of patients at first dose was 51.4 months (range 4.0 to 74.0 months), 55.6% were female,and 88.9% were white. The median spot urinary oxalate: creatinine ratio at baseline was0.47 mmol/mmol.

At month 6, patients treated with lumasiran achieved a reduction of 72.0% (95% CI: 66.4, 77.5) inspot urinary oxalate: creatinine ratio from baseline (averaged over months 3 through month 6), theprimary endpoint. Lumasiran was associated with rapid, and sustained reductions in spot urinaryoxalate: creatinine ratio (Figure 3), which were similar across all weight strata. The percent reductionin urinary oxalate excretion was maintained with continued lumasiran treatment through month 12 andconsistent with data from ILLUMINATE-A.

Figure 3: ILLUMINATE-B: Percent change in spot urinary oxalate: creatinine ratio frombaseline by month

At month 6, nine of 18 patients achieved near normalisation (≤ 1.5×ULN), including 1 patient whoachieved normalisation (≤ ULN), in spot urinary oxalate: creatinine ratio. At month 12, ten of 18patients achieved near normalization (≤ 1.5×ULN), including 2 patients who achieved normalization(≤ ULN), in spot urinary oxalate: creatinine ratio.

Furthermore, from baseline to month 6 (average of month 3 to month 6), a mean plasma oxalatereduction of 31.7% (95% CI: 23.9, 39.5) was observed. Reduced plasma oxalate levels observed in theprimary analysis period were maintained with continued lumasiran treatment. The eGFR remainedstable in all patients with continued dosing.

The rate of renal stone events per person-year reported in the 12-month period prior to consent andduring the 6-month primary analysis period was 0.24 (95% CI: 0.09, 0.63) and 0.24 (95% CI: 0.06,0.96), respectively. The rate of events from month 6 to month 12 was 0.12 (95% CI: 0.02, 0.84).

Medullary nephrocalcinosis results, assessed by renal ultrasound, at month 6 and month 12 relative tobaseline are presented in Table 6.

Table 6: ILLUMINATE-B: Patients with medullary nephrocalcinosis at month 6and month 12 relative to baseline*

Timepoint Improvement (n) No Change Worsening

Month 6(n=18) 8 10 0

Month 12(n=17) 11 6 0

*Patients with renal ultrasounds at baseline and the relevant timepoint were assessed.

ILLUMINATE-C

A total of 21 patients were enrolled and treated with lumasiran in an on-going multi-centre, single-armstudy in patients with PH1 and advanced renal disease (eGFR ≤ 45 mL/min/1.73 m2 in patients 12months of age and older and elevated serum creatinine in patients less than 12 months of age),including patients on haemodialysis. ILLUMINATE-C includes 2 cohorts: Cohort A consists of 6patients who did not require dialysis at the time of study enrolment and Cohort B consists of 15patients who were on stable regimen of haemodialysis. Patients received the recommended dosingregimen of lumasiran based on body weight (see section 4.2).

The median age of patients at first dose was 8.9 years (range 0 to 59 years), 57.1% were male, and76.2% were white. For Cohort A patients, the median plasma oxalate level was 57.94 µmol/L. For

Cohort B patients, the median plasma oxalate level was 103.65 µmol/L.

The primary endpoint of the study 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 plasmaoxalate from baseline to month 6 (average from month 3 to month 6) for Cohort B (N=15).

During the 6-month primary analysis period, patients in both cohorts had a reduction in plasma oxalateas early as month 1. The percent change from baseline to month 6 (average from month 3 to month 6)in plasma oxalate levels for Cohort A was an LS mean difference of -33.3% (95% CI: -81.82, 15.16)and for Cohort B the LS mean difference was -42.4% (95% CI: -50.71, -34.15).

Figure 4: ILLUMINATE-C: Percent change from baseline in plasma oxalate (µmol/L) at eachvisit during the primary analysis period

Results are plotted as mean (±SEM) of percent change from baseline.

Abbreviations: BL = baseline; M = month; SEM = standard error of mean.

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 oflumasiran. In Cohort B, only pre-dialysis samples are utilized.

In Cohort A the mean (SD) eGFR was 19.85 (9.6) mL/min/1.73 m2 at baseline and 16.43 (9.8)mL/min/1.73 m2 at month 6.

The rate of renal stone events per person-year reported 12 months prior to consent for Cohort A andduring the 6-month primary analysis period was 3.20 (95% CI: 1.96, pct. 5.22) and 1.48 (95% CI: 0.55,3.92), respectively.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Oxlumo in one or more subsets of the paediatric population in hyperoxaluria (see section 4.2 forinformation on paediatric use).

Following subcutaneous administration, lumasiran is rapidly absorbed with a median (range) time toreach maximum plasma concentration (tmax) of 4.0 (0.5 to 12.0) hours. In children and adults with PH1≥ 20 kg, the peak plasma concentration of lumasiran (Cmax) and area under the concentration curvefrom time zero to the last measurable concentration after dosing (AUC0-last) following therecommended lumasiran dose of 3 mg/kg were 529 (205 to 1130) ng/mL and7400 (2890 to 10700) ng·h/mL, respectively. In children less than 20 kg, Cmax and AUC0-last oflumasiran following the recommended lumasiran dose of 6 mg/kg were 912 (523 to 1760) and7960 (5920 to 13300). Lumasiran concentrations were measurable, up to 24 to 48 hours post-dose.

In healthy adult plasma samples, the protein binding of lumasiran is moderate to high (77 to 85%) atclinically relevant concentrations. For an adult patient with PH1, the population estimate for theapparent central volume of distribution (Vd/F) for lumasiran is 4.9 L. Lumasiran primarily distributes tothe liver after subcutaneous dosing.

Lumasiran is metabolised by endo- and exonucleases to oligonucleotides of shorter lengths. In vitrostudies indicate that lumasiran does not undergo metabolism by CYP450 enzymes.

Lumasiran is primarily eliminated from plasma by hepatic uptake, with only 7 to 26% of theadministered dose recovered in urine as lumasiran in the pooled data from healthy adult subjects andpatients with PH1 > 6 years of age. The mean (%CV) terminal plasma half-life of lumasiran is5.2 (47.0%) hours. The population estimate for apparent plasma clearance was 26.5 L/h for a typical70-kg adult. The mean renal clearance of lumasiran was minor and ranged from 2.0 to 3.4 L/h inpaediatric and adult patients with PH1.

Lumasiran exhibited linear to slightly nonlinear, time-independent pharmacokinetics in plasmafollowing single subcutaneous doses ranging from 0.3 to 6 mg/kg and multiple doses of 1 and 3 mg/kgonce monthly or 3 mg/kg quarterly. There was no accumulation of lumasiran in plasma after repeatedonce monthly or quarterly dosing.

Plasma concentrations of lumasiran do not reflect the extent or duration of the pharmacodynamicactivity of lumasiran. Rapid and targeted uptake of lumasiran by the liver results in rapid decline inplasma concentrations. In the liver, lumasiran exhibits a long half-life leading to maintenance ofpharmacodynamic effect over the monthly or quarterly dosing interval.

In vitro studies indicate that lumasiran is not a substrate or an inhibitor of cytochrome P450 (CYP)enzymes. Lumasiran is not expected to inhibit or induce CYP enzymes or modulate the activities ofdrug transporters.

No studies have been conducted in patients ≥ 65 years of age. Age was not a significant covariate inthe pharmacokinetics of lumasiran.

In clinical studies, there was no difference in the plasma exposure or pharmacodynamics of lumasiranbased on gender or race.

No studies have been conducted in patients with hepatic impairment (see section 4.2). Limitedpharmacokinetic data in patients with mild and transient elevations in total bilirubin (totalbilirubin > 1.0 to 1.5×ULN) showed comparable plasma exposure of lumasiran and similarpharmacodynamics as patients with normal hepatic function. Published literature show lowerexpression of the asialoglycoprotein receptors in the liver, i.e. the receptors responsible for lumasiranuptake, in patients with hepatic impairment. Nonclinical data suggest that this may not influence liveruptake or pharmacodynamics at therapeutic doses. The clinical relevance of these data is unknown.

Patients with mild renal impairment (eGFR 60 to < 90 mL/min/1.73 m2) had comparable plasmaexposure of lumasiran as patients with normal renal function (eGFR ≥ 90 mL/min/1.73 m2). In patientswith moderate renal impairment (eGFR 30 to < 60 mL/min/1.73 m2) Cmax was similar to that inpatients with normal renal function; AUC was 25% higher based on limited data. In patients withsevere renal impairment (eGFR 15 to < 30 mL/min/1.73 m2), ESRD (eGFR < 15 mL/min/1.73 m2), orwho are on dialysis (see section 4.2), within the same body weight category, a transient 1.8 to 3.6 foldhigher Cmax and 1.6 to 3.1 fold higher AUC0-last was observed (see section 5.2). These increases weretransient as plasma concentrations decline below the level of detection within 24 to 48 hours, similarto patients without renal impairment (see section 5.2 Pharmacokinetic/pharmacodynamicrelationship(s)). The pharmacodynamics in patients with renal impairment(eGFR < 90 mL/min/1.73 m2), including ESRD (eGFR< 15 mL/min/1.73 m2) or those on dialysis weresimilar to patients with normal renal function (eGFR ≥ 90 mL/min/1.73 m2) (see section 4.2).

Data in children younger than 1 year of age are limited. In children < 20 kg, lumasiran Cmax was 2-foldhigher due to the nominally higher 6-mg/kg dose and faster absorption rate. The pharmacodynamics oflumasiran were comparable in paediatric patients (aged 4 months to 17 years) and in adults, despite thetransiently higher plasma concentrations in children < 20 kg, due to the rapid and predominantdistribution of lumasiran to the liver.

The recommended dosing regimens yielded up to 2-fold higher Cmax in children < 20 kg while AUCwas similar across the body weights studied (6.2 to 110 kg).

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, genotoxicity, and carcinogenicity.

In rats, but not in monkeys, microscopic changes in the liver (e.g. hepatocellular vacuolation, mitosisand karyomegaly) were observed, accompanied by decrease in plasma fibrinogen levels and otherlaboratory changes. The reason for the apparent rodent-specificity is not understood and the relevancefor humans is unclear.

Lumasiran did not show any adverse effects on male and female fertility and pre- and post-nataldevelopment in rats. In embryo-foetal development studies in rats and rabbits, skeletal abnormalitieswere observed, but at high exposure multiples relative to human therapeutic exposures. The NOAELswere approximately 20- to 70-times higher (based on monthly exposures).

A dose-range finding toxicity study in neonate rats did not show increased sensitivity of thedeveloping rat to either the toxicology or pharmacology of lumasiran at exposure multiples of 2compared to human therapeutic exposures (based on monthly exposures).

Sodium hydroxide (pH adjustment)

Phosphoric acid (pH adjustment)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years.

Once the vial is opened, the medicinal product should be used immediately.

Do not store above 30°C.

Keep vial in the outer carton to protect from light.

Glass vial with a fluoropolymer-coated rubber stopper and an aluminium overseal with a flip-offbutton. Each vial contains 0.5 mL solution for injection.

Pack size of one vial.

This medicinal product is ready-to-use and for single use only.

For subcutaneous use only

* Before administration, materials not included in the pack that are needed for administration shouldbe collected, which will include a sterile syringe (0.3 mL, 1 mL, or 3 mL), an 18-gauge (G)needle, and a 25 G to 31 G needle.

* The required volume of Oxlumo should be calculated based on the recommended weight-baseddose (see section 4.2).

* An 18-gauge needle should be used to withdraw Oxlumo from the vial. The vial should be heldupright or tilted at a slight angle, and the flat edge of the needle should be pointed downwards.

* For volumes less than 0.3 mL, a sterile 0.3 mL syringe is recommended.

* The medicinal product should be administered with a sterile 25- to 31-G needle with a 13 mm or16 mm needle length for subcutaneous injection.

* Note: This medicinal product should not be pushed into the 25 G to 31 G needle.

* Syringes, transfer needles, and injection needles should only be used once.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Alnylam Netherlands B.V.

Antonio Vivaldistraat 1501083 HP Amsterdam

Netherlands

EU/1/20/1496/001

Date of first authorisation: 19 November 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu