ELFABRIO 2mg / ml concentrate for solution for infusion medication leaflet

Elfabrio 2 mg/mL concentrate for solution for infusion

Each vial contains 20 mg of pegunigalsidase alfa in a volume of 10 mL or 5 mg of pegunigalsidasealfa in a volume of 2.5 mL, at a concentration of 2 mg/mL.

The strength indicates the quantity of the pegunigalsidase alfa with consideration of the pegylation.

Pegunigalsidase alfa is produced in tobacco cells (Nicotiana tabacum BY2 cells) using recombinant

DNA technology.

The active substance, pegunigalsidase alfa, is a covalent conjugate of prh-alpha-GAL-A withpolyethylene glycol (PEG).

The potency of this medicinal product should not be compared to the one of another pegylated or non-pegylated protein of the same therapeutic class. For more information, see section 5.1.

Each 10 mL vial contains 46 mg sodium.

Each 2.5 mL vial contains 11.5 mg sodium.

For a full list of excipients, see section 6.1.

Concentrate for solution for infusion

Clear, colourless, solution.

Elfabrio is indicated for long-term enzyme replacement therapy in adult patients with a confirmeddiagnosis of Fabry disease (deficiency of alpha-galactosidase).

Pegunigalsidase alfa treatment must be managed by a physician experienced in the treatment ofpatients with Fabry disease.

Appropriate medical support measures should be readily available when pegunigalsidase alfa isadministered to patients who have not had treatment before, or who have experienced severehypersensitivity reactions to pegunigalsidase alfa in the past.

Pre-treatment with antihistamines and/or corticosteroids may be advisable for patients who hadpreviously experienced hypersensitivity reactions to pegunigalsidase alfa or to another enzymereplacement therapies (ERT) treatment (see section 4.4).

The recommended dose of pegunigalsidase alfa is 1 mg/kg of body weight administered once everytwo weeks.

The treatment can be also administered at the dose of 2 mg/kg of body weight once every four weeksin patients stable with an ERT treatment (see section 4.4 Treatment monitoring).

For instructions on reconstitution, see section 6.6.

Patients switching treatment from agalsidase alfa or beta

For the initial 3 months of treatment with pegunigalsidase alfa, pre-treatment regimen should bepreserved with stepwise discontinuation of pre-treatment based on appropriate tolerability of thepatients.

No dose adjustment is needed in patients with hepatic impairment.

No dose adjustment is needed in patients with renal impairment.

Renal function should be evaluated regularly during pegunigalsidase alfa treatment (see section 4.4).

Elderly (≥ 65 years old)

Safety and efficacy of pegunigalsidase alfa in patients older than 65 years have not been evaluated andno alternative dose regimens can be recommended for these patients. Elderly patients may be treatedwith the same dose as other adult patients, see section 5.1.

The safety and efficacy of pegunigalsidase alfa in children and adolescents aged 0-17 years have notyet been established. No data are available.

For intravenous infusion use only.

Pegunigalsidase alfa must not be infused in the same intravenous line with other products.

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

After preparation, the dilution should be administered via intravenous infusion and filtered through anin-line low protein-binding 0.2 μm filter.

The patient should be observed for infusion-related reactions (IRRs) for two hours after the infusion;see section 4.4.

Further details on how to handle pegunigalsidase alfa before administration, see section 6.6.

Home administration

Infusion of pegunigalsidase alfa at home may be considered if the patient is tolerating infusions welland has no history of moderate or severe IRRs for a few months.

The decision to move to home infusion should be made after evaluation and recommendation by thetreating physician. The patient should be medically stable. Home infusion infrastructure, resources,and procedures, including training, must be established and available to the healthcare professional incharge of home infusion.

The healthcare professional should be available at all times during the home infusion and for aspecified time after infusion.

Appropriate training should be given by the treating physician and/or nurse to the patient and/orcaregiver prior to initiation of home infusion. The dose and infusion rate used in the home settingshould remain the same as was used in the hospital setting; they should be changed only under thesupervision of the treating physician.

Infusion rate and duration of infusion

Table 1: Recommended dose and infusion time for intravenous administration of 1 mg/kg ofbody weight of pegunigalsidase alfa every 2 weeks

Initial infusion 1 mg/kg of body weight every 2 weeks

Body weight (Kg) Total volume (ml) Infusion time Infusion rate*<70 150 ml ≥ 3 hours 0.83 ml/min (50 ml/hr)70-100 250 ml ≥ 3 hours 1.39 ml/min (83.33 ml/hr)> 100 500 ml ≥ 3 hours 2.78 ml/min (166.67 ml/hr)

Maintenance infusion

The target infusion duration can be achieved pending patient’s tolerability. The increase in theinfusion rate should be achieved gradually starting from the rate given at the first infusion.1 mg/kg of body weight every 2 weeks

Body weight (Kg) Total volume (ml) Infusion time Infusion rate*<70 150 ml ≥ 1.5 hours 1.68 ml/min (100 ml/hr)70-100 250 ml ≥ 1.5 hours 2.78 ml/min (166.67 ml/hr)> 100 500 ml ≥ 1.5 hours 5.56 ml/min (333.33 ml/hr)

*infusion rate may be adjusted in case of infusion reaction (see section 4.4)

Table 2: Recommended dose and infusion time for intravenous administration of 2 mg/kg ofbody weight of pegunigalsidase alfa every 4 weeks

Initial infusion 2 mg/kg of body weight every 4 weeks

Body weight (Kg) Total volume (ml) Infusion time Infusion rate*< 70 150 ml ≥ 4.5 hours 0.56 ml/min (33.33 ml/hr)70-100 250 ml ≥ 4.5 hours 0.93 ml/min (55.56 ml/hr)> 100 500 ml ≥ 6 hours 1.39 ml/min (83.33 ml/hr)

Maintenance infusion

The target infusion duration can be achieved pending patient’s tolerability. The increase in theinfusion rate should be achieved gradually starting from the rate given at the first infusion.2 mg/kg of body weight every 4 weeks

Body weight (Kg) Total volume (ml) Infusion time Infusion rate*< 70 150 ml ≥ 2 hours 1.25 ml/min (75 ml/hr)70-100 250 ml ≥ 2 hours 2.08 ml/min (125 ml/hr)> 100 500 ml ≥ 3 hours 2.78 ml/min (166.67 ml/hr)

*infusion rate may be adjusted in case of infusion reaction (see section 4.4)

If patients experience infusion-related reactions, including hypersensitivity reactions or anaphylacticreactions during the infusion, the infusion must be immediately stopped and appropriate medicaltreatment should be initiated (see section 4.4).

Any patients experiencing adverse events during the home infusion need to immediately stop theinfusion process and seek the attention of a healthcare professional. Subsequent infusions may need tooccur in a clinical setting.

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.

For patients switched to pegunigalsidase alfa 2 mg/kg body weight once every 4 weeks, regularmonitoring (e.g.: after 3, 6, 12, 18 and 24 months) should be performed. Monitoring should include atleast the evaluation of lyso-Gb3, renal (eGFR, proteinuria), cardiac (LVMi, NT-proBNP, troponin or

ECG), and biochemical parameters. A change in any individual parameter should be interpreted in thecontext of the patient's overall clinical status, and clinically relevant deterioration should prompt re-evaluation of the treatment regimen.

Infusion-related reactions (IRRs), defined as any related adverse events with onset after start ofinfusion and up to 2 hours after end of infusion have been reported (see section 4.8). The mostcommonly observed symptoms of IRRs were hypersensitivity, itching, nausea, dizziness, chills andmuscular pain.

The management of IRRs must be based on the severity of the reaction, and include slowing theinfusion rate and treatment with medicinal products such as antihistamines, antipyretics and/orcorticosteroids, for mild to moderate reactions. Pre-treatment with antihistamines and/orcorticosteroids may prevent subsequent reactions in those cases where symptomatic treatment wasrequired, although IRRs occurred in some patients after receiving pre-treatment (see section 4.2).

Hypersensitivity reactions have been reported in patients in clinical studies (see section 4.8). As withany intravenous protein product, allergic-type hypersensitivity reactions may manifest and can includelocalised angioedema (including swelling of the face, mouth, and throat), bronchospasm, hypotension,generalised urticaria, dysphagia, rash, dyspnoea, flushing, chest discomfort, pruritus, nausea, chillsand nasal congestion. If a severe allergic or anaphylactic-type reactions occur, immediatediscontinuation of pegunigalsidase alfa is recommended and current medical standards for emergencytreatment are to be followed.

In patients who have experienced severe hypersensitivity reactions during pegunigalsidase alfainfusion, caution should be exercised upon re-challenge and appropriate medical support should bereadily available. Moreover, for patients who experienced severe hypersensitivity reactions with ERTinfusion including pegunigalsidase alfa, appropriate medical support should be readily available.

In clinical studies, treatment-induced anti-drug antibodies (ADA) development has been observed (seesection 4.8).

The presence of ADAs to pegunigalsidase alfa may be associated with a higher risk of infusion-relatedreactions, and severe IRRs are more likely to occur in ADA positive patients. Patients who developinfusion or immune reactions with pegunigalsidase alfa treatment should be monitored.

Additionally, patients who are ADA positive to other enzyme replacement therapies, who haveexperienced hypersensitivity reactions to pegunigalsidase alfa and patients who are switching topegunigalsidase alfa should be monitored.

Membranoproliferative glomerulonephritis

Depositions of immune complexes can potentially occur during treatment with ERTs, as amanifestation of immunological response to the product. A single case of membranoproliferativeglomerulonephritis was reported during the clinical development of pegunigalsidase alfa, due toimmune depositions in the kidney (see section 4.8). This event led to a temporary decline in renalfunction, which improved upon discontinuation of the medicinal product.

The presence of extensive renal damage (eGFR < 60 ml/min) may limit the renal response to enzymereplacement therapy, possibly due to underlying irreversible pathological changes. In such cases, theloss of renal function remains within the expected range of the natural progression of disease. Regularevaluation of changes in the estimated glomerular filtration rate (eGFR) during pegunigalsidase alfatreatment is recommended.

Excipients of known effect

This medicinal product contains 46 mg sodium per 10 mL vial, equivalent to 2% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

This medicinal product contains 11.5 mg sodium per 2.5 mL vial, equivalent to 1% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

No interaction studies and no in vitro metabolism studies have been performed. Based on itsmetabolism, pegunigalsidase alfa is an unlikely candidate for cytochrome P450 mediated drug-druginteractions.

Pegunigalsidase alfa is a protein and is expected to be metabolically degraded through peptidehydrolysis.

There are no or limited amount of data from the use of pegunigalsidase alfa in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity(see section 5.3). As a precautionary measure, it is preferable to avoid the use of pegunigalsidase alfaduring pregnancy unless clearly necessary.

It is unknown whether pegunigalsidase alfa/metabolites are excreted in human milk. Availablepharmacodynamic/toxicological data in animals have shown excretion of pegunigalsidase alfa in milk(for details see section 5.3). A risk to the newborns/infants cannot be excluded. A decision must bemade whether to discontinue breast-feeding or to discontinue/abstain from pegunigalsidase alfatherapy taking into account the benefit of breast feeding for the child and the benefit of therapy for thewoman.

There are no studies assessing the potential effect of pegunigalsidase alfa on fertility in humans.

Animal studies show no evidence of impaired fertility (see section 5.3).

Dizziness, syncope or vertigo were observed in some patients following pegunigalsidase alfaadministration. These patients should refrain from driving or the use of machines until symptoms havesubsided.

The most common adverse reactions were infusion-related reactions reported in 7.8% of patients,followed by nausea and asthenia, both reported in 5.6% of patients and headache, reported in 4.2% ofpatients.

In clinical studies, 5 patients (3.5%) experienced a serious reaction that was considered related topegunigalsidase alfa. Four of these reactions were confirmed IgE-mediated hypersensitivity(bronchospasm, hypersensitivity) that occurred at the first infusion of pegunigalsidase alfa andresolved within the day after occurrence.

The data described below reflects data from 141 patients with Fabry disease who receivedpegunigalsidase alfa in 8 clinical studies, following the posology of 1 mg/kg every two weeks or2 mg/kg every four weeks for a minimum of 1 infusion up to 7 years.

Adverse reactions are listed in Table 3. Information is presented by system organ class. Frequenciesare 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); frequency not known (cannot beestimated from available data).

Table 3: Adverse reactions reported during treatment with pegunigalsidase alfa

System organ class Frequency

Common Uncommon

Immune system disorders hypersensitivity*type I hypersensitivity*

Psychiatric disorders agitation* insomnia

Nervous system disorders paraesthesia* restless legs syndromedizziness* peripheral neuropathyheadache* neuralgiaburning sensationtremor*syncope*

Ear and labyrinth disorders vertigo

Vascular disorders flushinghypotension*hypertension*lymphoedema

System organ class Frequency

Common Uncommon

Respiratory, thoracic and bronchospasm*mediastinal disorders sneezing*nasal congestion*dyspnoea*throat irritation*throat tightness

Gastrointestinal disorders nausea* gastrooesophageal reflux diseaseabdominal pain* gastritisdiarrhoea dyspepsiavomiting* flatulence

Skin and subcutaneous issue rash* hypohidrosisdisorders erythema*pruritus*

Musculoskeletal and arthralgiaconnective tissue disorders musculoskeletal pain*

Renal and urinary disorders membranoproliferative glomerulonephritischronic kidney diseaseproteinuria

Reproductive system and nipple painbreast disorders

General disorders and asthenia* influenza-like illnessadministration site conditions chills* infusion site extravasationchest pain* infusion site painpain* oedema

Investigations body temperature increased*urine protein/creatinine ratio increasedwhite blood cells urine positiveblood uric acid increasedweight increased

Injury, poisoning and infusion related reaction*procedural complications

Cardiac disorders supraventricularextrasystoles

The following preferred terms have been grouped in Table 3:

* hypersensitivity includes: drug hypersensitivity

* agitation includes: nervousness

* abdominal pain includes: abdominal discomfort

* rash includes: rash maculo-papular and rash pruritic

* musculoskeletal stiffness recorded as musculoskeletal pain includes: myalgia

* asthenia includes: malaise and fatigue

* chest pain includes: chest discomfort and non-cardiac chest pain

* pain includes: pain in extremity

* oedema peripheral recorded as oedema

* Preferred terms considered as IRR as described in the section below.

Infusion related reactions (adverse reactions within 2 hours of infusion)

IRRs were reported in a total of 36 patients (25%): 26 patients (23%) treated with 1 mg/kg every twoweeks and 10 patients (34%) treated with 2 mg/kg every four weeks. The most commonly reportedsymptoms associated with IRRs reported for 1 mg/kg dosage were: hypersensitivity, chills, dizziness,rash and itching. For the 2 mg/kg dose the most commonly reported symptoms were pain, headacheand nausea. IRRs were mostly mild or moderate in intensity and resolved with continuous treatment;however, 5 patients (all male, 1 mg/kg dose) experienced 5 severe IRRs. These 5 IRRs were alsoserious. Four of these events were confirmed type I hypersensitivity reactions and 3 led to thediscontinuation from the study. Another patient was later withdrawn from the study, after theoccurrence of another moderate IRR. All 5 patients however recovered within the day after ofoccurrence with appropriate treatment. IRRs predominantly occurred within the first year of treatmentwith pegunigalsidase alfa and no serious IRR was observed during the second year and beyond.

In clinical studies, 17 out of 111 of patients (16%) treated with 1 mg/kg pegunigalsidase alfa everytwo weeks and 1 out of 30 patients (3.4%) treated with 2 mg/kg pegunigalsidase alfa every four weeksdeveloped treatment-induced anti-drug antibodies (ADAs).

Membranoproliferative glomerulonephritis

During the clinical development of pegunigalsidase alfa, one patient out of 141 reported a severe eventof membranoproliferative glomerulonephritis after receiving treatment for more than 2 years. Thepatient was ADA positive at the start of the infusions. The event led to a transitory reduction in theeGFR and an increase on the level of proteinuria, with no additional signs or symptoms. A biopsyrevealed the immune-complex mediated nature of this event. Upon discontinuation of the treatment,the eGFR values stabilised and the glomerulonephritis was reported as resolving.

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 are no reports of overdose of pegunigalsidase alfa during clinical studies. The maximum dose ofpegunigalsidase alfa studied was 2 mg/kg body weight every two weeks and no specific signs andsymptoms were identified following the higher doses. The most common adverse reactions reportedwere infusion related reaction and pain in extremity. If overdose is suspected, seek emergency medicalattention.

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

A16AB20.

The active substance of Elfabrio is pegunigalsidase alfa. Pegunigalsidase alfa is a pegylatedrecombinant form of human α-galactosidase-A. The amino acid sequence of the recombinant form issimilar to the naturally occurring human enzyme.

Pegunigalsidase alfa supplements or replaces α-galactosidase-A, the enzyme that catalyses thehydrolysis of the terminal α-galactosyl moieties of oligosaccharides and polysaccharides in thelysosome, reducing the amount of accumulation of globotriaosylceramide (Gb3) andglobotriaosylsphingosine (Lyso-Gb3).

The efficacy and safety of pegunigalsidase alfa were evaluated in 141 patients. Among these patients,the efficacy was evaluated in 111 receiving pegunigalsidase alfa 1 mg/kg once every two weeks(E2W), and in 29 receiving pegunigalsidase alfa 2 mg/kg body weight once every four weeks (E4W).

Disease substrate

Analyses of kidney biopsies from naïve patients treated with pegunigalsidase alfa at a dosage of 1mg/kg body weight E2W in a phase 1/2 study exhibited a reduction of the globotriaosylceramide(Gb3) substrate from the renal peritubular capillaries, measured with BLISS (Barisoni Lipid Inclusion

Scoring System) of 68% in the overall population (including females, classic males and non-classicmales exposed to different tested doses; n=13) after 6 months of treatment. Additionally, 11 out of 13subjects with available biopsies had substantial reduction (≥50%) in their BLISS score following 6months of treatment. Plasma Lyso-Gb3 decreased by 49% after 12 months of treatment (n=16) and by83% after 60 months of treatment (n=10). In a phase 3 study, where patients were switching fromagalsidase beta to pegunigalsidase alfa at a dosage of 1 mg/kg body weight E2W, plasma lyso-Gb3values stayed stable after 24 months of treatment (+3.3 nM mean value, n=48).

In an open-label Phase 3 study in 29 patients with stable Fabry disease on ERT (agalsidase alfa oragalsidase beta), lyso-Gb3 values were evaluated prior to and after treatment conversion intopegunigalsidase alfa at a dosage of 2 mg/kg body weight E4W. The observed median (Q1, Q3) plasmalyso-Gb3 levels at baseline were 17.2 (12.1, 32.8) nmol/l for male study patients (n= 23) and 4.4 (2.9,5.9) nmol/l for female study patients (n=6). In men, the median (Q1, Q3) changes in lyso-Gb3 levelsafter 1, 2, and 4 years compared to baseline were respectively +5.1 (0.3, 7.8), +4.5 (-0.1, 9.4), and +2.7(-2.0, 7.4) nmol/l. In women, the median (Q1, Q3) changes in lyso-Gb3 levels after 1, 2, and 4 yearscompared to baseline were respectively -0.1 (-0.4, 0.2), +0.2 (-0.2, 0.7), and -0.3 (-1.0, 1.2) nmol/l.

The renal function was evaluated through the estimated glomerular filtration rate (eGFR - CKD-EPIequation) and its annualised measurement slope was the primary endpoint for efficacy in severalphase 3 studies.

Two phase 3 studies evaluated pegunigalsidase alfa 1 mg/kg E2W in previously ERT-treated adult

Fabry patients: BALANCE (main study), a randomized, double blinded, head-to-head comparisonwith agalsidase beta, after switch from agalsidase beta at month 12 (primary analysis) and month 24,and an open label single arm study, after switch from agalsidase alfa, both followed by a long-termextension study.

No final conclusion on non-inferiority over agalsidase beta as measured by the annualised eGFR canbe retrieved from the main study given that the data for the primary endpoint comparison at month 12was not on its own sufficiently informative due to the design and size of the trial. Nevertheless, themedian eGFR slopes from baseline to month 24 of pegunigalsidase and the comparator agalsidase betaappeared close. At month 12, the mean slopes for eGFR were -2.5 ml/min/1.73 m²/year for thepegunigalsidase alfa arm and -1.7 for the agalsidase beta arm (difference -0.8 [-3.0, 1.5]. At month 24,the median slopes for eGFR were -2.5 [-3. 8; -1.2] ml/min/1.73 m²/year for the pegunigalsidase alfaarm and -2.2 [-3.8; -0.5] for the agalsidase beta arm (difference -0.36 [-2.4; 1.7]).

The renal function was also evaluated through the annualised eGFR slope in a phase 3 study thatinvestigated pegunigalsidase alfa 2 mg/kg E4W in previously ERT-treated adult Fabry patients: thisstudy was an open label single arm study, after switch from agalsidase beta or agalsidase alfa,followed by a long-term extension study.

The mean (SD) annualized eGFR slope in the efficacy population was -1.8 (3.7) and -2.0(2.1) ml/min/1.73 m2/year respectively at pre-treatment baseline and during treatment over ≥4 years oftreatment with pegunigalsidase alfa 2 mg/kg E4W.

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

Elfabrio in one or more subsets of the paediatric population in the treatment of Fabry disease (seesection 4.2 for information on paediatric use).

Plasma pharmacokinetic (PK) profiles of pegunigalsidase alfa were characterized during the course ofthe clinical development at 0.2, 1, and 2 mg/kg administered every two weeks and 2 mg/kg every fourweeks in adult patients with Fabry disease. The pharmacokinetic results (non-compartmental PKanalysis) for all dose levels demonstrated that the enzyme was available throughout the whole dosingintervals with a plasma half-life (t1/2) ranging from 53-134 hours across dose groups and visit day.

In adult ERT-naïve patients, on Day 1, the mean values for dose-normalized AUCs were similar for alldose levels, indicating linear dose-proportionality in the range of tested doses (0.2, 1 and 2 mg/kg

E2W). At 3, 6 and 12 Months, the mean values for AUCs and Clast increased more than as per dose-proportionality with relatively high inter-subject variability in 0.2 mg/kg group and at some visits in 1and 2 mg/kg dose groups. For patients who received 1 and 2 mg/kg pegunigalsidase alfa, there wereincreases in mean t1/2 and AUC0-2wk with increasing duration of treatment and corresponding decreasesin CL and Vz, suggesting a saturated clearance.

In adult ERT-experienced patients, for 1 mg/kg E2W dosing regimen, mean Cmax ranged from 21.2 to23.3 mcg/mL, while mean AUClast ranged from 972 to 1156 mcg·h/mL. All the observations on the

PK parameters indicate a consistent PK profile of pegunigalsidase alfa throughout the 2-years studytreatment duration.

For 2 mg/kg E4W dosing regimen, mean Cmax ranged from 36 to 47 mcg/mL, while mean AUClastranged from 1648 to 2179 mcg·h/mL. There appears to be no time effect on the PK.

Population PK modelling indicates that steady state is effectively achieved within the first month oftreatment, with negligible accumulation, in both ERT-experienced and ERT-naïve patients irrespectiveof the dosing regimen.

Pegunigalsidase alfa is a protein and is expected to be metabolically degraded through peptidehydrolysis. Consequently, impaired liver function is not expected to affect the pharmacokinetics ofpegunigalsidase alfa in a clinically significant way. The molecular weight of pegunigalsidase alfa is~116 KDa, which is twice the cut-off value for glomerular filtration, thus excluding filtration and/orproteolytic degradation in kidneys.

The population PK model showed that over a 4-week interval AUC and Cavg are simulated to besimilar following 1 mg/kg E2W or 2 mg/kg E4W, whereas Cmax is simulated to be 2-fold higher and

Cmin is simulated to be 0.4-fold lower in the 2 mg/kg E4W regimen. The PK/PD analysis indicatedthat no clear relationship between pegunigalsidase alfa exposure and Lyso-Gb3 change from baselineat 12 months of treatment or with eGFR annualized slope can be quantified. Despite the fact that thedata do not support the quantification of an exposure-response relationship, an overlap in the median[Q1, Q3] lyso-Gb3 concentrations at baseline, 24 months, and 48 months after switching from ERT to2 mg/kg E4W was observed (see section 5.1).

There are no animal studies to assess the carcinogenic or mutagenic potential of pegunigalsidase alfa.

In the 6-month chronic toxicity study in mice, an increased incidence and/or mean severity ofmultifocal nephropathy and interstitial lymphocytic infiltration in the kidneys, hepatocytic vacuolationand hepatocyte necrosis in the liver, were confined to males and females administered the high-dose of40 mg/kg/injection (3.2-fold human exposure, in terms of AUC, following a dose of 1 mg/kg); inmonkeys, an increased incidence of Kupffer cell hypertrophy was noted in the liver (7.6-fold above

AUC reached in humans following a dose of 1 mg/kg); all findings resolved during the recoveryperiod.

Animal studies demonstrated low systemic exposure in foetus (between 0.005 and 0.025% of dams’systemic exposure) and suckling pups (maximum 0.014% compared to mother’s systemic exposure)following repeated treatment of the dams or mothers with pegunigalsidase alfa. Fertility andembryofoetal developmental toxicity studies did not show evidence of impaired fertility,embryotoxicity or teratogenicity. However, prenatal and postnatal developmental toxicity studies werenot performed with pegunigalsidase alfa and the risks for foetus and pups during the late pregnancyand lactation are unknown.

Sodium citrate tribasic dihydrate

Citric acid

Sodium chloride

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

4 years.

Chemical and physical in use stability has been demonstrated for 72 hours both at 2 °C-8 °C andbelow 25 °C.

From a microbiological point of view, the product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours in the refrigerator (2 °C-8 °C) or 8 hours if stored below25 °C, unless dilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2 °C-8 °C).

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

10 mL vial (15R clear glass) closed with coated rubber stopper and sealed with aluminium flip off cap.2.5 mL vial (6R clear glass) closed with coated rubber stopper and sealed with aluminium flip off cap.

Pack sizes of 1, 5 or 10 vials.

Not all pack sizes may be marketed.

Pegunigalsidase alfa is for intravenous infusion only. Aseptic technique to be used.

Vials are for single use only.

If contamination is suspected, the vial has not to be used. Shaking or agitating this medicinal productmust be avoided.

Filter needles do not have to be used during the preparation of the infusion.

The number of vials to be diluted should be determined based on the individual patient’s weight andthe required vials should be removed from the refrigerator in order to allow them to reach roomtemperature (in approximately 30 minutes).

Dilution1) Determine the total number of vials required for the infusion.

The number of vials required is based on the total dose required for each individual patient andrequires calculation for weight-based dosing.

An example calculation for total dose in an 80 kg patient prescribed 1 mg/kg is as follows:

- Patient weight (in kg) ÷ 2 = Volume of dose (in mL)

- Example: 80 kg patient ÷ 2 = 40 mL (volume to be withdrawn).

- In this example, 4 vials of the 10 mL vial (or 16 vials of the 2.5 mL vial) are needed.

An example calculation for total dose in an 80 kg patient prescribed 2 mg/kg is as follows:

- Patient weight (in kg) = Volume of dose (in mL)

- Example: 80 kg patient = 80 mL (volume to be withdrawn).

- In this example, 8 vials of the 10 mL vial (or 32 vials of the 2.5 mL vial) are needed.

2) Allow the required number of vials to reach room temperature prior to dilution (approximately30 minutes).

Visually inspect the vials. Do not use if cap is missing or broken. Do not use if there isparticulate matter or if it is discoloured.

Avoid shaking or agitating the vials.

3) Remove and discard the same volume as calculated in step 1 of sodium chloride 9 mg/mL(0.9%) solution for infusion from the infusion bag.

4) Withdraw the required volume of pegunigalsidase alfa solution from the vials, and dilute withsodium chloride 9 mg/mL (0.9%) solution for infusion, to a total volume based on patientweight specified in Table 4 below.

Table 4: Minimum total infusion volume for patients by body weight

Patient weight Minimum total infusion volume< 70 kg 150 mL70-100 kg 250 mL> 100 kg 500 mL

Inject the pegunigalsidase alfa solution directly into the infusion bag.

Do NOT inject in the airspace within the infusion bag.

Gently invert the infusion bag to mix the solution, avoiding vigorous shaking and agitation.

The diluted solution should be administered using an inline low protein binding 0.2 μm filter.

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

Chiesi Farmaceutici S.p.A.

Via Palermo 26/A43122 Parma

Italy

EU/1/23/1724/001

EU/1/23/1724/002

EU/1/23/1724/003

EU/1/23/1724/004

EU/1/23/1724/005

EU/1/23/1724/006

Date of first authorisation: 4 May 2023

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

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