Leaflet EVKEEZA 150mg / ml concentrate for solution for infusion

Evkeeza 150 mg/ml concentrate for solution for infusion

Each ml of concentrate for solution for infusion contains 150 mg of evinacumab.

One vial of 2.3 ml of concentrate contains 345 mg of evinacumab.

One vial of 8 ml of concentrate contains 1 200 mg of evinacumab.

Evinacumab is produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate)

Clear to slightly opalescent, colourless to pale yellow sterile solution with a pH of 6.0 and anosmolality of approximately 500 mmol/kg.

Evkeeza is indicated as an adjunct to diet and other low-density lipoprotein-cholesterol (LDL-C)lowering therapies for the treatment of adult and paediatric patients aged 6 months and older withhomozygous familial hypercholesterolaemia (HoFH).

Before treatment initiation of evinacumab the patient should be on an optimal LDL-C loweringregimen.

Treatment with evinacumab should be initiated and monitored by a physician experienced in thetreatment of lipid disorders.

The recommended dose is 15 mg/kg body weight administered by intravenous infusion over60 minutes once monthly (every 4 weeks).

If a dose is missed, it should be administered as soon as possible. Thereafter, treatment withevinacumab should be scheduled monthly from the date of the last dose.

No dose adjustment is required for elderly patients (see sections 5.1 and 5.2).

No dose adjustment is required in patients with renal impairment (see section 5.2).

No dose adjustment is required in patients with hepatic impairment (see section 5.2).

No dose adjustment is required for paediatric patients aged 6 months to 17 years (see sections 4.8, 5.1and 5.2). The safety and efficacy of Evkeeza in children aged less than 6 months have not beenestablished. No data are available.

Evkeeza is for intravenous infusion use only.

Evkeeza can be administered without regard to lipoprotein apheresis.

* If refrigerated, the solution should be allowed to come to room temperature (up to 25 ºC) priorto administration.

* Evinacumab should be administered over 60 minutes by intravenous infusion through anintravenous line containing a sterile, in-line or add-on 0.2-micron to 5-micron filter.

Evinacumab should not be administered as an intravenous push or bolus.

* Other medicinal products should not be mixed with evinacumab or administered concomitantlyvia the same infusion line.

The rate of infusion may be slowed, interrupted, or discontinued if the patient develops any signs ofadverse reactions, including infusion-reactions (see sections 4.4 and 4.8).

Instructions on dilution of the medicinal product before administration are listed in section 6.6.

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

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Hypersensitivity and infusion reactions

Hypersensitivity reactions, including anaphylaxis, and infusion reactions have been reported withevinacumab (see section 4.8). If signs or symptoms of serious hypersensitivity or serious infusionreactions occur, discontinue treatment with evinacumab, treat according to the standard-of-care, andmonitor until signs and symptoms resolve.

This medicinal product contains 30 mg of proline in each ml. Proline may be harmful for patients withhyperprolinaemia type I or type II.

This medicinal product contains 1 mg of polysorbate 80 in each ml. Polysorbates may cause allergicreactions.

No interaction studies have been performed. No interacting mechanisms between evinacumab andother lipid-lowering medicinal products have been observed.

Women of childbearing potential have to use effective contraception during treatment withevinacumab and for at least 5 months after the last dose of evinacumab.

There is a limited amount of data from the use of evinacumab in pregnant women. Studies in animalshave shown reproductive toxicity (see section 5.3). Human IgG antibodies are known to cross theplacenta barrier; therefore, evinacumab has the potential to be transmitted from the mother to thedeveloping foetus. Evinacumab may cause foetal harm when administered to a pregnant woman and itis not recommended during pregnancy and in women of childbearing potential not using effectivecontraception unless the expected benefit to the patient outweighs the potential risk to the foetus.

It is unknown whether evinacumab is excreted in human milk. Human IgGs are known to be excretedin breast milk during the first few days after birth, which decrease to low concentrations soonafterwards; consequently, a risk to the breast-fed infant cannot be excluded during this short period.

Afterwards, Evkeeza could be used during breast-feeding if clinically needed.

No human data on the effect of evinacumab on fertility are available. Animal studies do not indicateharmful effects with respect to male and female fertility (see section 5.3).

Evkeeza may have a minor influence on the ability to cycle, drive and use machines. Dizziness,fatigue and asthenia may occur following administration of Evkeeza (see section 4.8).

The most frequently occurring adverse reactions are nasopharyngitis (13.7%), influenza-like illness(7.7%), dizziness (6.0%), back pain (5.1%) and nausea (5.1%). The most serious adverse reaction isanaphylaxis (0.9%).

Table 1 lists the incidence of adverse reactions in clinical trials of evinacumab therapy involving 137treated patients (117 adult and adolescent patients with HoFH and persistent hypercholesterolaemiafrom pooled controlled clinical trials and 20 paediatric patients aged >5 to 11 years with HoFH from

Study R1500-CL-17100). Adverse reactions are listed by MedDRA system organ class (SOC) and byfrequency. Frequencies are defined as: 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 available data). Within each frequency grouping, adverse reactions arepresented in the order of decreasing seriousness.

Table 1: Adverse reactions

System organ class Adverse reaction Frequency

Nasopharyngitis Very common

Infections and infestations Upper respiratorytract infection Common

Immune system disorders Anaphylaxis Uncommon

Nervous system disorders Dizziness Common

Respiratory, thoracic and mediastinal disorders Rhinorrhoea Common

Nausea Common

Gastrointestinal disorders Abdominal pain Common

Constipation Common

Back pain Common

Pain in extremity Common

Fatigue* Very common

Influenza like illness Common

General disorders and administration site conditions Asthenia Common

Infusion relatedreaction Common

Infusion site reactions Common

* See section Paediatric population, below.

Anaphylaxis was reported in 1 (0.9%) patient treated with evinacumab (see section 4.4).

Infusion reactions

Infusion reactions (e.g. infusion site pruritus) were reported in 9 (7.7%) patients treated withevinacumab and in 2 (3.7%) patients treated with placebo.

The safety profile observed in 14 adolescent patients with HoFH aged 12 to 17 years treated withevinacumab 15 mg/kg for intravenous use every 4 weeks was consistent with the safety profile of adultpatients with HoFH.

The safety of evinacumab was assessed in 20 paediatric patients aged ≥ 5 to 11 years. The safetyprofile of evinacumab observed in these patients was consistent with the safety profile observed inadult and adolescent patients aged 12 years and older, with the additional adverse reaction of fatigue.

Fatigue was reported in 3 (15%) patients (see section 5.1).

Data are available for 5 patients aged ≥1 to 5 years old treated with evinacumab via compassionateuse. The treatment duration was between 12 weeks and 90 weeks. Based on safety data received, nonew safety concern has been identified (see section 5.1).

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.

There is no specific treatment for evinacumab overdose. In the event of an overdose, the patient shouldbe treated symptomatically, and supportive measures instituted as required.

Pharmacotherapeutic group: Other lipid modifying agents, ATC code: C10AX17

Evinacumab is a recombinant human monoclonal antibody, which specifically binds to and inhibits

ANGPTL3. ANGPTL3 is a member of the angiopoietin-like protein family that is expressed primarilyin the liver and plays a role in the regulation of lipid metabolism by inhibiting lipoprotein lipase (LPL)and endothelial lipase (EL).

Evinacumab blockade of ANGPTL3 lowers TG and HDL-C by releasing LPL and EL activities from

ANGPTL3 inhibition, respectively. Evinacumab reduces LDL-C independent of the presence of LDLreceptor (LDLR) by promoting very low-density lipoprotein (VLDL) processing and VLDL remnantsclearance upstream of LDL formation through EL-dependent mechanism.

Homozygous familial hypercholesterolaemia (HoFH)

Study ELIPSE-HoFH

This was a multicentre, double-blind, randomised, placebo-controlled study evaluating the efficacyand safety of evinacumab compared to placebo in 65 patients with HoFH. The study consisted of a 24-week double-blind treatment period and a 24-week open-label treatment period. In the double-blindtreatment period, 43 patients were randomised to receive evinacumab 15 mg/kg administeredintravenously every 4 weeks and 22 patients to receive placebo. Patients were on a background ofother lipid-lowering therapies (e.g. statins, ezetimibe, PCSK9 inhibitor antibodies, lomitapide, andlipoprotein apheresis). The diagnosis of HoFH was determined by genetic testing or by the presence ofthe following clinical criteria: history of an untreated TC > 500 mg/dl (13 mmol/l) together with eitherxanthoma before 10 years of age or evidence of TC > 250 mg/dl (6.47 mmol/l) in both parents.

Patients regardless of mutation status were included in the trial. Patients were defined as havingnull/null or negative/negative variants if the variations resulted in little to no residual LDLR function;null/null variants were defined as having < 15% LDLR function based on in vitro assays andnegative/negative variants were defined as having premature termination codons, splice site variations,frame shifts, insertion/deletions or copy number variations. In this trial, 32.3% (21 of 65) of patientshad null/null variants and 18.5% (12 of 65) of patients had negative/negative variants.

The mean LDL-C at baseline was 255.1 mg/dl (6.61 mmol/l) and in the subset of patients withnull/null variants was 311.5 mg/dl (8.07 mmol/l) and with negative/negative variants was 289.4 mg/dl(7.50 mmol/l). At baseline, 93.8% of patients were on statins, 75.4% on ezetimibe, 76.9% on a PCSK9inhibitor antibodies, 21.5% on lomitapide, and 33.8% were receiving lipoprotein apheresis. The meanage at baseline was 42 years (range 12 to 75) with 12.3% ≥65 years old; 53.8% women, 73.8% White,15.4% Asian, 3.1% Black and 7.7% Other or not reported.

The primary efficacy endpoint was percent change in LDL-C from baseline to week 24. At week 24,the LS mean treatment difference between evinacumab and placebo in mean percent change in LDL-Cfrom baseline, was -49.0% (95% CI: -65.0% to -33.1%; p < 0.0001). For efficacy results see Table 2.

Table 2: Effect of evinacumab on lipid parameters in patients with HoFH in study

ELIPSE-HoFH

Baseline LS mean percent change or(mean), change from baseline at Differencemmol/l week 24 from placebo P-value(N = 65) evinacumab placebo (95% CI)(N = 43) (N = 22)

LDL-C(percent 6.6 -47.1% +1.9% -49%(-65.0 to -33.1) < 0.0001change)

LDL-C(absolutechange) 6.6 -3.5 -0.1 -3.4(-4.5 to -2.3) < 0.0001(mmol/l)

ApoB (g/l) 1.7 -41.4% -4.5% -36.9%(-48.6 to -25.2) < 0.0001

Non-HDL-C 7.2 -49.7% +2.0% -51.7%(-64.8 to -38.5) < 0.0001

TC 8.3 -47.4% +1.0% -48.4%(-58.7 to -38.1) < 0.0001

TG 1.4 -55.0% -4.6% -50.4%(-65.6 to -35.2) < 0.0001a

HDL-Cb 1.2 -29.6% +0.8% - -anominal p-value since TG is not a key secondary endpointbMean percent change at week 24 results are presented based on the actual treatment received in safetypopulation (evinacumab, n=44; placebo, n=20); there is no formal statistical testing in safetypopulation

After the double-blind treatment period, 64 of the 65 randomised patients who entered the open-labeltreatment period received evinacumab. The mean percent change in LDL-C from baseline to week 48ranged from -42.7% to -55.8%. Figure 1 shows the LDL-C mean percent change from baseline for thedouble-blind and observed mean percent change for the open-label treatment periods across patientswho were on evinacumab or placebo during the double-blind treatment period.

Figure 1: Calculated LDL-C LS mean percent change from baseline over time throughweek 24, and observed mean percent change from week 28 through week 48 instudy ELIPSE-HoFH

At week 24, the observed reduction in LDL-C with evinacumab was similar across predefinedsubgroups, including age, gender, null/null or negative/negative variants, concomitant treatment withlipoprotein apheresis, and concomitant background lipid-lowering medicinal products (statins,ezetimibe, PCSK9 inhibitor antibodies, and lomitapide). The effect of evinacumab on cardiovascularmorbidity and mortality has not been determined.

Study ELIPSE-OLE

This was a multicentre, open-label extension study in 116 patients with HoFH. Data available from 86patients at 24 weeks showed a 43.6% decrease in LDL-C following evinacumab treatment 15 mg/kgfor intravenous use every 4 weeks on top of other lipid-lowering therapies (e.g. statins, ezetimibe,

PCSK9 inhibitor antibodies, lomitapide, and lipoprotein apheresis). Reductions from baseline in LDL-

C were consistent at 48 and 96 weeks; the mean percent change from baseline in calculated LDL-C at48 weeks (n=95) was -43.9% and at 96 weeks (n=63) was -37.2%. Patients regardless of mutationstatus were included in the trial, including patients with null/null or negative/negative variants.

ELIPSE-HoFH

In ELIPSE-HoFH, 1 adolescent patient received 15 mg/kg of evinacumab for intravenous use every4 weeks and 1 adolescent patient received placebo, as an adjunct to other lipid-lowering therapies (e.g.statins, ezetimibe, PCSK9 inhibitor antibodies and lipoprotein apheresis). Both adolescent patients hadnull/null variants in the LDLR. At week 24, the percent change in LDL-C with evinacumab was

- 73.3% and with placebo +60%.

ELIPSE-OLE

In ELIPSE-OLE, 14 adolescent patients received 15 mg/kg of evinacumab intravenously every4 weeks as an adjunct to other lipid-lowering therapies (e.g. statins, ezetimibe, PCSK9 inhibitorantibodies and lipoprotein apheresis). Two patients entered after completing the ELIPSE-HoFH studyand 12 patients were evinacumab-naïve. The mean baseline LDL-C in these adolescent patients was300.4 mg/dl (7.88 mmol). The mean age was 14.4 years (range: 12 to 17 years), with 64.3% males and35.7% females. At baseline, all patients were on a statin, 71.4% on ezetimibe, 42.9% on PCSK9inhibitor, and 64.3% were receiving lipoprotein apheresis. Four (28.6%) patients had null/null variantsand 4 (28.6%) patients had negative/negative variants for LDLR mutations. At week 24, the percentchange in LDL-C with evinacumab was -55.4% (n=12).

Study R1500-CL-17100

This was a multicenter, three-part, single-arm, open-label study evaluating the efficacy, safety, andtolerability of evinacumab in paediatric patients aged ≥ 5 to 11 years with HoFH. The study includedthree parts: Part A, Part B, and Part C. Part A was a single-dose, open-label study to assess the safety,

PK, and PD of evinacumab 15 mg/kg administered intravenously in 6 patients with HoFH followed bya 16-week observational period to determine the dose for the rest of the study. Part B was a single-arm, 24-week, open-label treatment period evaluating the efficacy and safety of evinacumab 15 mg/kgadministered intravenously every 4 weeks in 14 patients with HoFH. Part C was an extension studyfrom Part A and Part B evaluating the long-term safety of evinacumab 15 mg/kg administeredintravenously every 4 weeks in 20 patients with HoFH. It consists of a 48-week treatment period and a24-week follow-up period (ongoing). Patients in Part C entered directly from Part A or Part B.

Patients were on any combination of lipid-lowering therapies, including maximally tolerated statins,ezetimibe, lomitapide, and lipoprotein apheresis.

The diagnosis of HoFH was determined by genetic testing or by the presence of the following clinicalcriteria: history of untreated total cholesterol (TC) > 13 mmol/l (> 500 mg/dl) and TG < 7.8 mmol/l(< 690 mg/dl) AND either tendinous xanthoma before 10 years of age or evidence of TC> 6.47 mmol/l (> 250 mg/dl) in both parents; LDL-C > 3.36 mmol/l (> 130 mg/dl); body weight≥ 15 kg.

Overall, for patients in Part A and Part B, the mean LDL-C at baseline was 7.8 mmol/l (301.9 mg/dl).

At baseline, 90% of patients were on statins, 95% were on ezetimibe, and 60% were receivinglipoprotein apheresis.

The mean age at baseline was 9.0 years (range ≥ 5 to < 12); 40% males and 60% females; 70% White,5% Black, 10% Asian, 5% American Indian or Alaska Native, and 10% Other. Mean body weight was37.9 kg, and body mass index (BMI) was 18.8 kg/m2.

In Part B, the primary efficacy endpoint was percent change in calculated LDL-C from baseline toweek 24. At week 24, the mean percent change in calculated LDL-C from baseline was −48.3% (95%confidence interval: −68.8% to −27.8%). For efficacy results, see Table 3.

Table 3: Lipid parameters in paediatric patients (≥ 5 to 11 years) with HoFH on otherlipid-lowering therapies at week 24

LDL-C ApoB Non-HDL-C TC Lp(a)

Baseline(mean) 6.8 mmol/l 168.2 mg/dl 7.3 mmol/l 8.1 mmol/l(N = 14) (263.7 mg/dl) (1.682 g/l) (282.2 mg/dl) (315.5 mg/dl) 158.6 nmol/L

Percentchange from -48.3 -41.3 -48.9 -49.1 -37.3baseline (-68.8 to (-58.9 to (-68.1 to (-64.9 to (-42.2 to(95% CI) -27.8) -23.8) -29.7) -33.2) -32.3)

At week 24, the reduction in LDL-C with evinacumab was similar across baseline characteristics,including age, gender, limited LDL-R activity, concomitant treatment with lipoprotein apheresis, andconcomitant background lipid-lowering medicinal products (statins, ezetimibe, and lomitapide).

Other investigations

The efficacy of evinacumab for paediatric patients aged 6 months to less than 5 years has beenpredicted based on integrated PK/PD modelling and simulations (see section 5.2). Paediatric patientsaged 6 months to less than 5 years receiving evinacumab 15 mg/kg every 4 weeks are predicted toexperience a similar or higher magnitude of percent change in LDL-C at week 24 compared to adultswhile plateauing at higher absolute LDL-C concentrations at week 24.

In addition, data are available for 5 patients aged ≥1 to 5 years old with HoFH who receivedevinacumab via compassionate use. The prescribed dose was 15 mg/kg evinacumab every 4 weeks, thesame as that used in older children and adults. Administration of evinacumab showed a clinicallymeaningful reduction of LDL-C consistent with that observed in patients ≥ 5 years old in clinicalstudies. The benefits included a reduction in LDL-C of 37.1% at week 90 in one of the patients inwhom plasmapheresis frequency was reduced during the treatment period, and reductions of 43.1% atweek 72, 66.3% at week 62, 77.3% at week 16, and 75.0% at week 12 respectively in the otherpatients. Xanthomas completely resolved in the patient in whom plasmapheresis frequency wasreduced, after approximately 1 year of treatment with evinacumab.

This medicinal product has been authorised under ‘exceptional circumstances’. This means that due tothe rarity of the disease it has not been possible to obtain complete information on this medicinalproduct. The European Medicines Agency will review any new information which may becomeavailable every year and this SmPC will be updated as necessary.

Evinacumab is administered intravenously to patients with HoFH. Based on population PK modelling,at the end of infusion at steady-state, mean ± SD Cmax is 681 ± 185 mg/l in adult patients following adose of 15 mg/kg every 4 weeks. The accumulation ratio is approximately 2. The mean ± SD steady-state trough concentration is 230 ± 81.3 mg/l in adult patients.

The steady-state volume of distribution estimated by population PK analysis in a typical individualweighing 72 kg was approximately 4.9 L in adult patients, indicating that evinacumab is distributedprimarily in the vascular system.

Specific metabolism studies were not conducted because evinacumab is a protein. As a humanmonoclonal IgG4 antibody, evinacumab is expected to be degraded into small peptides and aminoacids via catabolic pathways in the same manner as endogenous IgG.

Evinacumab elimination is mediated by parallel linear and nonlinear pathways. At higherconcentrations, evinacumab elimination is primarily through a non-saturable proteolytic pathway,while at lower concentrations, the non-linear saturable ANGPTL3 target-mediated eliminationpredominates. Elimination half-life is a function of evinacumab concentrations in serum and is not aconstant.

After the last steady-state dose of 15 mg/kg administered intravenously every 4 weeks, the mediantime for evinacumab concentrations to decrease below the lower limit of detection (78 ng/ml) isapproximately 21 weeks.

Due to nonlinear clearance, a slightly greater than dose proportional increase was observed, with a4.3- fold increase in area under the concentration-time curve at steady-state (AUCtau.ss) for a 3-foldincrease in dose from 5 mg/kg to 15 mg/kgadministered intravenously every 4 weeks.

The pharmacodynamic effect of evinacumab in lowering LDL-C is indirect and mediated through thebinding to ANGPTL3. Concentration of total ANGPTL3 increases from baseline upon administrationof evinacumab and the increases plateau when target saturation is approached. When target issaturated, further increase in evinacumab concentrations is not expected to result in a further LDL-Creduction.

A population PK analysis conducted on data from 183 healthy adult participants and 139 patients with

HoFH, suggests that the following factors have no clinically significant effect on the exposure ofevinacumab: age (5 to 75 years), gender, body weight (19.7 to 152 kg), race. Apheresis did not appearto substantially influence the pharmacokinetics of evinacumab.

There were 14 patients aged 12 to 17 years with HoFH receiving evinacumab at 15 mg/kgadministered intravenously every 4 weeks, steady-state trough and maximum concentrations weregenerally within the range of those in adult patients. The mean steady-state Cmax was 566 ± 206 mg/l inpatients aged 12 to < 18 years with HoFH.

For the 20 patients aged 5 to 11 years with HoFH receiving evinacumab at 15 mg/kg administeredintravenously every 4 weeks, the mean (SD) steady-state trough evinacumab concentration based onpopulation PK analyses was 160 ± 57.6 mg/l and the mean (SD) steady-state Cmax was 419 ± 99.4 mg/lin patients aged 5 to 11 years with HoFH.

The pharmacokinetics of evinacumab in paediatric patients less than 5 years of age with HoFH werepredicted from a model-based extrapolation analysis. This analysis used population PK modelling andsimulations based on previously observed data in older children, adolescents, and adults, together withassumptions on the biological development and pathophysiological circumstances in younger childrenwith HoFH. The predicted mean steady-state trough concentrations and mean accumulation ratios inpatients 6 months to less than 5 years were lower but within the ranges predicted for patients aged5 years and older. The predicted mean steady-state maximum concentration was 499±185 mg/L forpatients aged 6 months to less than 2 years and 513±179 mg/L for patients aged 2 to less than 5 years.

Evinacumab is not expected to undergo significant renal elimination. Observed trough concentrationsat steady-state were comparable between patients with mild or moderate renal impairment and patientswith normal renal function. No data are available in patients with severe renal impairment.

Evinacumab is not expected to undergo significant hepatic elimination. No data are available inpatients with hepatic impairment.

Non-clinical data including juvenile toxicity studies reveal no special hazard for humans based onconventional studies of safety pharmacology and repeated dose toxicity.

Carcinogenicity and genotoxicity studies have not been conducted with evinacumab. Monoclonalantibodies are not expected to alter DNA or chromosomes.

No effects on surrogate markers of fertility in male and female reproductive organs were observed in a6-month chronic toxicology study with sexually mature cynomolgus monkeys. In animal reproductionstudies, evinacumab was administered subcutaneously to pregnant rabbits every 3 days from gestationday 7 until gestation day 19 during organogenesis. Maternal toxicity (premature neonatal death, foetalloss and/or premature delivery) was observed at all doses and foetal findings (soft tissues and skeletalmalformations) were observed at all but the lowest dose (1 mg/kg). Mean systemic exposure measuredduring the gestation period in rabbits was below that measured at maximum recommended humandose (MRHD) of 15 mg/kg every 4 weeks. Because the lipid profile of rabbits differs significantlyfrom that of humans, particularly during pregnancy, the clinical relevance of these results is uncertain.

There were no effects on embryo-foetal development when rats were subcutaneously administeredevinacumab every 3 days from gestation day 6 to gestation day 18 during organogenesis. Meansystemic exposure measured during the gestation period in rats was below that measured at MRHD of15 mg/kg every 4 weeks.

Proline

Arginine hydrochloride

Histidine hydrochloride monohydrate

Polysorbate 80

Histidine

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vial4 years

From a microbiological point of view, the product should be used immediately. If not usedimmediately, it is the responsibility of the user to follow the in-use storage times and conditions priorto use.

If the diluted solution is not administered immediately, it may be stored temporarily either:

* under refrigeration at 2 ºC to 8 ºC for no more than 24 hours from the time of infusionpreparation to the end of the infusionor

* at room temperature up to 25 ºC for no more than 6 hours from the time of infusion preparationto the end of the infusion.

Store in a refrigerator (2 ºC - 8 ºC).

Store in the original carton to protect from light.

Do not freeze.

Do not shake.

For storage conditions after dilution of the medicinal product, see section 6.3.

2.3 ml of concentrate in a 3 ml clear Type 1 glass vial with a grey chlorobutyl stopper with coatingand a seal cap with a flip-off button containing 345 mg of evinacumab.

Pack size of 1 vial.

8 ml of concentrate in a 20 ml clear Type 1 glass vial, with a grey chlorobutyl stopper with coatingand a seal cap with a flip-off button containing 1 200 mg of evinacumab.

Pack size of 1 vial.

Not all pack sizes may be marketed.

Preparation of solution

Evkeeza is supplied as a single use vial only. During preparation and reconstitution a strictly aseptictechnique should be used.

* Visually inspect the medicinal product for cloudiness, discolouration or particulate matter priorto administration.

* Discard the vial if the solution is cloudy or discoloured or contains particulate matter.

* Do not shake the vial.

* Withdraw the required volume of evinacumab from the vial(s) based on patient’s body weightand transfer into an intravenous infusion bag containing sodium chloride 9 mg/ml (0.9%) ordextrose 50 mg/ml (5%) for infusion. Mix the diluted solution by gentle inversion.

* For patients weighing 45 kg and above, the intravenous infusion bag should contain amaximum volume of 250 ml of 9 mg/ml (0.9%) sodium chloride, or 50 mg/ml (5%)dextrose.

* For patients weighing between 26 kg and 44 kg, the intravenous infusion bag shouldcontain a maximum volume of 150 ml of 9 mg/ml (0.9%) sodium chloride, or50 mg/ml (5%) dextrose.

* For patients weighing between 3 kg and 25 kg, the intravenous infusion bag shouldcontain a maximum volume of 5 ml/kg. The corresponding volume for patientsweighing between 3 kg and 25 kg should range from 15 ml to 125 ml of 9 mg/ml(0.9%) sodium chloride, or 50 mg/ml (5%) dextrose administered at a maximum rateof 5 ml/kg/hour.

* Do not freeze or shake the solution.

* Discard any unused portion left in the vial.

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

Ultragenyx Germany GmbH

Rahel-Hirsch-Str. 1010557 Berlin

Germany

EU/1/21/1551/001

EU/1/21/1551/002

Date of first authorisation: 17 June 2021

Date of latest renewal:

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

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