MEPSEVII 2mg / ml perfusive solution concentrate medication leaflet

Mepsevii 2 mg/mL concentrate for solution for infusion.

Each mL of concentrate contains 2 mg vestronidase alfa*. Each vial of 5 mL concentrate contains10 mg vestronidase alfa.

*Vestronidase alfa is a recombinant form of human beta-glucuronidase (rhGUS) and is produced in

Chinese Hamster Ovary cell culture by recombinant DNA technology.

Each vial contains 17.8 mg sodium.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Colourless to slightly yellow solution.

Mepsevii is indicated for the treatment of non-neurological manifestations of Mucopolysaccharidosis

VII (MPS VII; Sly syndrome).

Treatment should be supervised by a healthcare professional experienced in the management ofpatients with MPS VII or other inherited metabolic disorders. Administration of vestronidase alfashould be carried out by an appropriately trained healthcare professional with the ability to managemedical emergencies.

The recommended dose of vestronidase alfa is 4 mg/kg of body weight administered by intravenousinfusion every two weeks.

To minimise the risk of hypersensitivity reactions, a non-sedating antihistamine with or without anantipyretic medicinal product should be administered 30-60 minutes prior to the start of the infusion(see section 4.4). Infusion should be avoided if the patient has an acute febrile or respiratory illness atthe time.

The safety and efficacy of vestronidase alfa in patients older than 65 years have not been established.

No alternative dose regimen is recommended in these patients (see section 5.1).

The safety and efficacy of vestronidase alfa in patients with renal or hepatic impairment have not beenevaluated. No alternative dose regimen is recommended in these patients.

The posology in the paediatric population is the same as in adults. Currently available data aredescribed in section 4.8 and section 5.1.

For intravenous use only.

For instructions on dilution of the medicinal product before administration, see section 6.6.

The total diluted volume of the solution for infusion should be administered with a rate titrationregimen over approximately 4 hours.

The rate of infusion should be as follows: in the first hour, 2.5% of the total volume will be infused,with the balance infused over the subsequent three hours. Any dead space in the lines should beaccounted for to ensure 2.5% of the total infusion volume is delivered into the patient’s bloodstreamduring the first hour of infusion. The lowest rate administered to a patient in the clinical developmentprogram was 0.5 mL/hour during the first 30 minutes of infusion, followed by 1 mL/hour over the next30 minutes, equalling 0.75 mL as the lowest total volume infused during the first hour.

Do not flush the line containing vestronidase alfa to avoid a rapid bolus of infused enzyme. Due to thelow infusion rate, additional sodium chloride 9 mg/mL (0.9%) solution for infusion may be addedthrough a separate line (piggyback or Y tube) to maintain sufficient intravenous flow. After the firsthour, the rate can be increased to infuse the remainder of the solution for infusion over 3 hours astolerated according to the recommended rate guidelines in Table 2.

The infusion rate may be slowed, temporarily interrupted or discontinued in the event ofhypersensitivity reactions (see section 4.4).

Life-threatening hypersensitivity (anaphylactic reaction) to the active substance or to any of theexcipients listed in section 6.1 (see section 4.4).

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

The effects of treatment with vestronidase alfa should be periodically evaluated and discontinuation oftreatment should be considered in cases where clear benefits (including stabilisation of diseasemanifestations) are not observed. Discontinuation of treatment may cause significant worsening of thepatient’s clinical status.

As end organ damage progresses over time, it is more difficult for the treatment to reverse the damageor to show improvements. It should be considered by the treating physician that the administration ofvestronidase alfa does not affect the irreversible complications (e.g. skeletal deformities).

Vestronidase alfa, at the exposure observed in humans, is not expected to cross the blood-brain-barrierand therefore it is not likely to impact the neurological manifestations of the disease.

Serious hypersensitivity reactions, including anaphylaxis, have been reported with vestronidase alfa;therefore, appropriate medical support should be readily available when vestronidase alfa isadministered (see section 4.8).

Infusion should be avoided if the patient has an acute febrile or respiratory illness at the time.

It is recommended that premedication with non-sedating antihistamines with or without antipyretics beadministered 30-60 minutes prior to the start of the infusion (see section 4.2).

It is important to administer vestronidase alfa according to the recommended infusion rate schedule(see Table 2 in section 6.6).

If severe hypersensitivity reactions occur, the infusion of vestronidase alfa should be stoppedimmediately and appropriate treatment should be initiated. Management of hypersensitivity reactionsshould be based on the severity of the reaction and include temporary interruption or discontinuationof the infusion and/or administration of additional antihistamines, antipyretics, and/or corticosteroidsfor mild to moderate reactions. Consider rapid sodium chloride 9 mg/mL (0.9%) solution for infusionfor decreased blood pressure and oxygen for hypoxia. Patients should be observed for a minimum of60 minutes after completing the infusion of vestronidase alfa.

Patients should be informed of the signs and symptoms of hypersensitivity reactions and instructed toseek immediate medical care should such signs and symptoms occur. The risks and benefits ofre-administering vestronidase alfa should be considered following a severe hypersensitivity reaction.

Spinal/cervical cord compression

Spinal or cervical cord compression is a known and serious complication of MPS VII. During enzymereplacement therapy, spinal cord injury can occur due to improved neck and spine mobility. Patientswith MPS VII receiving vestronidase alfa should be monitored for signs and symptoms of spinal cordcompression or neck instability including neck or back pain, weakness of limbs, changes in reflexes orurinary and faecal incontinence. Appropriate clinical treatment should be immediately sought.

Sodium restricted diet

This medicinal product contains 17.8 mg sodium per vial and is administered in sodium chloride9 mg/mL (0.9%) solution for infusion (see section 6.6). For each vial dosed, including thecorresponding diluent volume, the sodium intake is 35.5 mg sodium. This amount is equivalent to1.8% of the WHO recommended maximum daily intake of 2 g sodium for an adult. Mepsevii isconsidered high in sodium. This should be taken into consideration during dilution of the medicinalproduct for patients on a controlled sodium diet or for those patients with congestive heart failureneeding to restrict sodium and total water intake.

No interaction studies have been performed. Because it is a recombinant human protein and itsenzyme action is within the lysosome, vestronidase alfa is not expected to interact with othermedicinal products.

There are no data on the use of vetronidase alfa in pregnant women. Animal studies with vestronidasealfa do not indicate direct or indirect harmful effects with respect to pregnancy, embryo-foetaldevelopment, or pre- and postnatal development (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Mepsevii during pregnancy, unless thepotential benefit to the mother outweighs the potential theoretical risks to the foetus.

There are no data from studies in breast-feeding women. It is not known whether vestronidase alfa isexcreted in human milk, but systemic exposure via breast-milk is not expected. Due to lack of humandata, vestronidase alfa should only be administered to a breast-feeding woman if the potential benefitof vestronidase alfa to the mother and the benefit of breast-feeding to the infant outweighs thepotential theoretical risks to the infant.

No human data are available on the effect of vestronidase alfa on fertility. Animal studies withvestronidase alfa do not indicate any impact on male or female fertility (see section 5.3).

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

The most common adverse reactions from 4 clinical trials in 23 patients treated with vestronidase alfawere rash (17.4%), urticaria (17.4%), infusion site extravasation (17.4%), anaphylactoid reaction(13%), infusion site swelling (8.7%), pruritus (8.7%) and diarrhoea (8.7%). Most adverse reactionswere mild to moderate in severity.

The assessment of adverse reactions was based on the exposure of 23 patients from 4 clinical trials,aged 5 months to 25 years, who received vestronidase alfa at doses up to 4 mg/kg once every twoweeks for up to 187 weeks. Nineteen patients were younger than 18 years of age.

Table 1 lists the adverse reactions reported from 4 clinical trials in 23 patients treated with Mepsevii.

Adverse reactions are presented by System Organ Class and frequency. Frequencies are defined asvery common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare( ≥ 1/10 000 to < 1/1 000), and very rare (< 1/10 000).

Table 1 Adverse reactions reported in patients treated with Mepsevii

MedDRA System Organ Class MedDRA Preferred Frequency

Term (PT)

Immune system disorders Anaphylactoid reaction Very common

Nervous system disorders Febrile convulsion* Common

Gastrointestinal disorders Diarrhoea Common

Skin and subcutaneous tissue disorders Urticaria Very common

Rash** Very common

Pruritus Common

General disorders and administration site Infusion site Very commonconditions extravasation***

Infusion site swelling**** Common

*Refer to description of selected adverse reactions for details on the febrile convulsion reported in 1 of 23 trialpatients.

** Rash includes grouped PTs of rash, rash papular, rash pruritic, rash maculo-papular, papule, and macule

*** Infusion site extravasation includes one PT of extravasation

**** One adverse reaction of Peripheral swelling is included within the frequency of Infusion site swelling as theevent is classified as intravenous catheter issue.

Febrile convulsion

One patient receiving a vestronidase alfa dose of 4 mg/kg experienced a febrile convulsion duringtreatment at the week 66, within 3 days of diphtheria, tetanus, pertussis vaccination. The infusion wasstopped, the patient received anticonvulsants, antipyretics and antibiotics, and the febrile convulsionresolved. The patient subsequently was re-challenged without recurrence and continued onvestronidase alfa treatment. This event was assessed as possibly related to vestronidase alfa due to thetemporal association with the infusion.

Eighteen out of 23 patients (78%) from 4 clinical trials developed anti-recombinant humanbeta-glucuronidase (rhGUS) antibodies (ADA), ten of whom further developed neutralizing antibodies(NAb) on at least one occasion, but not consistently over time. There is no definitive correlationbetween the antibody titre and neutralizing antibody development. In most patients, a pattern ofattenuated immunogenicity with chronic exposure was suggested by declining antibody titres overtime on continuous treatment. The presence of ADA (non-NAb and NAb) does not appear to affectreduction in the pharmacodynamic marker, urinary glycosaminoglycans (uGAGs) and development ofhypersensitivity reactions including infusion associated reactions.

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 experience with overdoses of vestronidase alfa. For the management of adverse reactions,see sections 4.4 and 4.8.

Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes, ATC code:

A16AB18

Mucopolysaccharidosis VII is a lysosomal storage disorder characterised by the deficiency ofbeta-glucuronidase (GUS) that results in glycosaminoglycans (GAGs) accumulation in cellsthroughout the body leading to multisystem tissue and organ damage.

Vestronidase alfa is a recombinant form of human GUS and is intended to provide exogenous GUSenzyme for uptake into cellular lysosomes and subsequent catabolism of accumulated GAGs inaffected tissues.

The clinical program for vestronidase alfa included 23 treatment naïve patients with MPS VII from4 clinical trials, aged 5 months to 25 years, who received vestronidase alfa at doses up to 4 mg/kg onceevery two weeks for up to 187 weeks. Nineteen patients were younger than 18 years of age.

Studies 301 and 202

In a multi-centre, randomised, placebo-controlled, blind-start, single-crossover phase 3 trial (study

UX003-CL301, referred to as study 301), 12 patients with MPS VII received vestronidase alfa4 mg/kg every two weeks for 24 to 48 weeks. The patients were randomised in a blinded manner into4 groups: 3 patients received vestronidase alfa immediately for 48 weeks (Group A), 3 patientsreceived placebo for 8 weeks then vestronidase alfa for 40 weeks (Group B), 3 patients receivedplacebo for 16 weeks then vestronidase alfa for 32 weeks (Group C), and 3 patients received placebofor 24 weeks then vestronidase alfa for 24 weeks (Group D). Patients who were enrolled in study 301were eligible to roll over to study UX003-CL202 (referred to as study 202), an open-label extensiontrial in which patients received additional doses of vestronidase alfa at 4 mg/kg intravenously everyother week for up to 144 weeks. Ten patients rolled over directly from the end of study 301 to week 0of study 202 while 2 patients (17%) had gaps in treatment before enrolling in study 202.

Of the 12 patients enrolled in study CL301, 4 were male and 8 were female and ranged in ages from 8to 25 years (median 14 years). Nine patients were younger than 18 years of age. MPS VII diagnosiswas confirmed by GUS enzyme activity assay for 5 patients, by genotyping for 3 patients, and via bothenzyme assay and genotyping for 4 patients. Patients with MPS VII who received hematopoietic stemcell transplant therapy were excluded in this study. The extremely small population of patients with

MPS VII globally necessitated the enrolment of all patients able to participate in this clinical trial,resulting in a highly variable group. Clinical endpoints were not assessable in some patients due totheir extent of disease, age or level of cognition (23 out of 72 assessments [~32%] in 6 domains for12 patients were non-assessable at baseline).

The primary endpoint was the percent reduction in urinary GAG excretion (dermatan sulfate, DS)before and after 24 weeks of treatment with vestronidase alfa. The key secondary endpoint was themulti-domain clinical responder index (MDRI) score consisting of six domains [six-minute walk test(6MWT), forced vital capacity (FVC), shoulder flexion, visual acuity, Bruininks-Oseretsky test ofmotor proficiency (BOT-2) fine motor and gross motor function] after 24 weeks of treatment andfatigue total score as measured by the Pediatric Quality of Life Multidimensional Fatigue Scale(PedsQL).

Minimal important differences (MIDs) were pre-specified for the six MDRI domains plus fatigue,which are: 6MWT (≥23 meters and ≥10% change from baseline), FVC (5% absolute change or 10%relative change from baseline in FVC%pred), shoulder flexion (20 degree change of both shoulderrange of motion), visual acuity (3 lines (corrected, both eyes)), BOT-2 fine motor (fine motorprecision: change of 0.72, and manual dexterity: change of 1.47), BOT-2 gross motor (balance: 0.57,and running speed and agility: 0.59), and fatigue (10 points of total score).

Primary endpoint: uGAG reduction

After 24 weeks of treatment with vestronidase alfa, a rapid and sustained, highly significant reductionin uGAG (DS) excretion was achieved with a LS mean (±SE) percentage change of -64.82%(±2.468%) (p<0.0001). All 12 patients were responders, pre-specified as ≥ 50% reduction in uGAG onat least one visit during the first 24 weeks of treatment. In addition, uGAG response (% change fromstudy week 0) shows a similar magnitude of reduction in uGAG in all groups after crossover to activetreatment. The reductions in uGAG DS that were observed in study 301 were sustained when patients(n=12) rolled over into the extension Study 202 and received vestronidase alfa for up to 3.6 years totalbetween the 2 studies. Reduction in uGAG DS excretion was achieved with LS mean (SE) percentagechanges of -62% (4.9%) at study 202 week 0 and -58% (7.2%) at week 48 (n=10). In patients whocontinued beyond study 202 week 48, the mean percentage reduction in uGAG DS was greater than70% at all subsequent assessment visits through study 202 week 144 (n=4).

Key secondary endpoints: multi-domain clinical responder index (MDRI) and 6-minute walk test(6MWT)

For the clinical (secondary) endpoints, beneficial responses were observed although not in all patients.

After 24 weeks of vestronidase alfa treatment in study 301, the overall MDRI results, bothpre-specified and post-hoc (6 MDRI domains plus fatigue domain) analyses, were positive with anincrease of +0.5 domains (p=0.0527) and +0.8 domains (p=0.0433) including fatigue, respectively(t-test). For patients who continued into study 202, a mean (SD) improvement in MDRI was observedat week 24 (+0.7 [1.01] domains) and at week 48 (+0.9 [1.30] domains).

For 6MWT, the distance increased from baseline to treatment week 24 in study 301 by a LS mean(±SE) of 20.8 m (±16.75 m) in 9 patients who were able to perform the assessment at baseline and atleast one post-baseline visit. 6 patients had 6MWT results at treatment week 24. Three of these (50%)met the pre-defined MID at treatment week 24 and had sustained walking improvements of 65 meters,80 meters and 83 meters. For patients who continued into study 202, 8 patients were able to performthe 6MWT at week 48. Sustained 6MWT results were observed with a mean distance of 308.4 m(range: 80-556), for a mean (SE) increase from study 301 baseline of 19.0 m (16.4 m).

Other investigations

Study UX003-CL201 (referred to as study 201) was a single arm, open-label, dose exploration trialthat enrolled three MPS VII patients, ranging in age from 5 years to 25 years. After 120 weeks ofexposure to vestronidase alfa, one patient demonstrated a 21% improvement over baseline in forcedvital capacity (FVC% predicted) on pulmonary function testing in addition to a 105 meterimprovement in the 6MWT. Two other patients with baseline hepatosplenomegaly had reduction inliver volume (24% and 53%) and spleen volume (28% and 47%) after 36 weeks of treatment.

Study UX003-CL203 (referred to as study 203) was an open-label, uncontrolled single arm study thatenrolled eight patients less than 5 years of age who received vestronidase alfa at a dose of 4 mg/kgevery two weeks for 48 weeks of treatment period and additional up to 240 weeks during optionalcontinuation period. The study evaluated reduction of urinary GAG excretion, growth velocity andhepatosplenomegaly.

uGAG reduction

Treatment with vestronidase alfa resulted in a rapid and sustained, significant (p<0.0001) reduction inuGAG DS excretion with an LS mean (SE) percent change of -60% (6.6) at week 4 which wassustained at -61% (6.4) at Week 48. Patients who entered the continuation period up to week 132experienced further reduction in uGAG DS.

Growth

At baseline, all 8 patients had impaired growth. The mean (SD) standing height z-score improved frombaseline by +0.196 (0.30) at week 48. A non-significant trend toward increased growth velocity wasobserved after vestronidase alfa treatment, from a mean (SD) z-score of -2.59 (1.49) at baselineto --0.392 (2.10) post-baseline (p=0.27).

Hepatomegaly

All patients with hepatomegaly assessed by ultrasound examination at baseline (n=3/8) had decreasedliver size to within normal range for age and sex prior to study termination.

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 become available everyyear and this SmPC will be updated as necessary.

The pharmacokinetics of vestronidase alfa were evaluated in a total of 23 MPS VII patients including19 paediatric patients and 4 adults from 3 clinical trials. After repeated dosing of 4 mg/kg every otherweek, the maximal serum concentration (Cmax) was 17.3 ± 9.6 mcg/mL (mean ± s.d.; range: 4.7 to35.7 mcg/mL) and the area under the concentration-time curve from time zero to the last measurableconcentration (AUC0-t) was 50.9 ± 32.2 mcg*h/mL (mean ± s.d.; range: 17.4 to 153 mcg*h/mL). Thepharmacokinetics of vestronidase alfa are time independent with repeat dosing. The limitedpharmacokinetic data at steady state suggest dose proportional increase in exposure of vestronidasealfa over the dose range of 1 - 4 mg/kg every other week.

After repeated dosing of 4 mg/kg every other week in MPS VII patients, the mean ± standarddeviation the total volume of distribution (Vss) was 0.26 ± 0.13 L/kg (range: 0.10 to 0.60 L/kg).

Vestronidase alfa is a recombinant human enzyme and is therefore eliminated by proteolyticdegradation into small peptides and amino acids.

After repeated dosing of 4 mg/kg every other week in MPS VII patients, the mean ± standarddeviation of the total clearance (CL) was 0.079 ± 0.045 L/h/kg (range: 0.038 to 0.20 L/h/kg); the mean± standard deviation of the elimination half-life (t1/2) was 2.6 ± 0.6 hours (range: 0.9 to 3.6 hours).

Excretion

No excretion studies have been conducted in humans. Vestronidase alfa is not expected to beeliminated through renal or faecal excretion.

Nonclinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, single-dose toxicity in rats, repeated dose toxicity in MPS VII mice and juvenilemonkeys, fertility and embryo-foetal development in rats or rabbits, and pre- and postnataldevelopment in rats.

Genotoxicity studies and carcinogenicity studies have not been performed with vestronidase alfa.

Based on mechanism of action, rhGUS is not expected to be tumorigenic.

Sodium dihydrogen phosphate dihydrate

Sodium chloride

Histidine

Polysorbate 20

Water for injections

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

3 years

Chemical and physical in-use stability of the diluted medicinal product has been demonstrated for upto 36 hours under refrigeration at 2 °C - 8 °C followed by up to 6 hours at room temperature up to amaximum of 25 °C.

From a microbiological safety point of view, the diluted product should be used immediately. If notused immediately, in-use storage times and conditions prior to use are the responsibility of the user,but should normally not be longer than 36 hours at 2 °C - 8 °C followed by up to 6 hours at roomtemperature up to a maximum of 25 °C.

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

Store in the original package in order to protect from light.

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

Colourless glass vial (Type I) with a rubber stopper with fluoro-resin coating, and an aluminium overseal with a plastic flip-off cap.

Pack size: 1 vial containing 5 mL of concentrate for solution for infusion.

Each vial of Mepsevii is intended for single use only. Mepsevii must be diluted with sodium chloride9 mg/mL (0.9%) solution for injection using aseptic technique according to the steps described below.

The diluted solution for infusion should be administered to patients using a low-protein bindinginfusion bag and set (a non di (2-ethylhexyl) phthalate [DEHP] bag could be used) and the applicationof an infusion set equipped with an in-line, low-protein binding 0.2 μm filter is recommended.

1. Determine the number of vials to be diluted based on the patient’s actual weight and therecommended dose of 4 mg/kg, using the following calculations (a-b):

a. Total dose (mg) = Patient’s weight (kg) x 4 mg/kg (recommended dose)

b. Total number of vials = Total dose (mg) divided by 10 mg/vial2. Round to the next whole vial and remove the required number of vials (refer to Table 2) fromthe refrigerator to allow them to reach room temperature up to a maximum of 25 °C. Do notheat, microwave or shake vials.

a. Volume (mL) of calculated dose = Total dose (mg) divided by the 2 mg/mLconcentration3. Dilute the calculated dose 1:1 using equal volume of sodium chloride 9 mg/mL (0.9%) solutionfor injection for intravenous infusion. The total infusion volume is based on the total Mepseviidose and volume (refer to Table 2). The above calculated dose diluted 1:1 in sodium chloride9 mg/mL (0.9%) solution for injection should be added to a new empty infusion bag. Dilutionpreparation should be done at room temperature.

4. Prior to withdrawing Mepsevii from the vial, visually inspect for particulate matter anddiscolouration. The Mepsevii concentrate solution for infusion should be colourless to slightlyyellow. Do not use if the solution is discoloured or if there is particulate matter in the solution.

5. Slowly withdraw Mepsevii from the appropriate number of vials using caution to avoidexcessive agitation and any air or frothing. A sufficiently large needle (18 gauge) should beused to minimise bubbles in the solution.

6. Slowly add Mepsevii to the infusion bag using care to avoid agitation, ensuring liquid to liquidcontact without generating bubbles or turbulence.

7. Gently rock the infusion bag to ensure proper distribution of Mepsevii. Do not shake thesolution.

Table 2. Recommended infusion rate schedule by patient weight for administration of Mepseviiat recommended dose of 4 mg/kg

Patient Total Total Total Total Infusion rate Infusion rateweight Mepsevii Mepsevii number of infusion for 1st for subsequentrange dose range volume Mepsevii volume hour (2.5%) 3 hours(kg) (mg) (rounded) vials (infused over (mL/h) (97.5%/3)(mL) 4 hours) (mL) (mL/h)3.5-5.9 14-23.6 10 2 20 0.5 6.56-8.4 24-33.6 15 3 30 0.75 9.758.5-10.9 34-43.6 20 4 40 1 1311-13.4 44-53.6 25 5 50 1.25 16.2513.5-15.9 54-63.6 30 6 60 1.5 19.516-18.4 64-73.6 35 7 70 1.75 22.7518.5-20.9 74-83.6 40 8 80 2 2621-23.4 84-93.6 45 9 90 2.25 29.2523.5-25.9 94-103.6 50 10 100 2.5 32.526-28.4 104-113.6 55 11 110 2.75 35.7528.5-30.9 114-123.6 60 12 120 3 3931-33.4 124-133.6 65 13 130 3.25 42.2533.5-35.9 134-143.6 70 14 140 3.5 45.536-38.4 144-153.6 75 15 150 3.75 48.7538.5-40.9 154-163.6 80 16 160 4 5241-43.4 164-173.6 85 17 170 4.25 55.2543.5-45.9 174-183.6 90 18 180 4.5 58.546-48.4 184-193.6 95 19 190 4.75 61.7548.5-50.9 194-203.6 100 20 200 5 6551-53.4 204-213.6 105 21 210 5.25 68.2553.5-55.9 214-223.6 110 22 220 5.5 71.556-58.4 224-233.6 115 23 230 5.75 74.7558.5-60.9 234-243.6 120 24 240 6 7861-63.4 244-253.6 125 25 250 6.25 81.2563.5-65.9 254-263.6 130 26 260 6.5 84.566-68.4 264-273.6 135 27 270 6.75 87.7568.5-70.9 274-283.6 140 28 280 7 91

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/1/18/1301/001

Date of first authorisation: 23 August 2018

Date of latest renewal: 28 July 2023

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

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