CERDELGA 84mg capsules medication leaflet

Cerdelga 21 mg hard capsules

Cerdelga 84 mg hard capsules

Cerdelga 21 mg hard capsule

Each capsule contains 21 mg of eliglustat (as tartrate).

Each capsule contains 27 mg of lactose (as monohydrate).

Cerdelga 84 mg hard capsule

Each capsule contains 84.4 mg of eliglustat (as tartrate).

Each capsule contains 106 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Hard capsule

Cerdelga 21 mg hard capsule

Capsule with a pearl white opaque cap and pearl white opaque body with 'GZ04' printed in black onthe capsule. The size of the capsule is ‘size 4’ (dimensions 14 x 5 mm).

Cerdelga 84 mg hard capsule

Capsule with pearl blue-green opaque cap and pearl white opaque body with “GZ02” printed in blackon the body of the capsule. The size of the capsule is ‘size 2’ (dimensions 18 x 6.4 mm).

Cerdelga is indicated for the long-term treatment of adult patients with Gaucher disease type 1 (GD1),who are CYP2D6 poor metabolisers (PMs), intermediate metabolisers (IMs) or extensive metabolisers(EMs).

Paediatric population (from 6 to < 18 years of age) weighing ≥ 15 kg

Cerdelga is indicated for paediatric patients with GD1 who are 6 years and older with a minimumbody weight of 15 kg, who are stable on enzyme replacement therapy (ERT), and who are CYP2D6

PMs, IMs or EMs.

Therapy with Cerdelga should be initiated and supervised by a physician knowledgeable in themanagement of Gaucher disease.

Patient selection

Before initiation of treatment with Cerdelga, patients must be genotyped for CYP2D6 to determine the

CYP2D6 metaboliser status.

Eliglustat should not be used in patients who are CYP2D6 ultra-rapid metabolisers (URMs) orindeterminate metabolisers (see section 4.4).

The recommended dose is 84 mg eliglustat twice daily in CYP2D6 IMs and EMs.

The recommended dose is 84 mg eliglustat once daily in CYP2D6 PMs.

Paediatric population (from 6 to <18 years of age) weighing ≥ 15 kg

Table 1: Paediatric population (from 6 to <18 years of age) weighing ≥ 15 kg

Weight CYP2D6 EMs and IMs CYP2D6 PMs≥ 50 kg 84 mg twice daily 84 mg once daily25 to < 50 kg 84 mg twice daily 42 mg once daily15 to < 25 kg 42 mg twice daily 21 mg once daily

Cerdelga is to be taken orally in children who can swallow intact capsule.

If a dose is missed, the prescribed dose should be taken at the next scheduled time; the next doseshould not be doubled.

There is limited experience in the treatment of elderly with eliglustat. Data indicates that no doseadjustment is considered necessary (see sections 5.1 and 5.2).

Table 2: Patients with hepatic impairment

CYP2D6 Hepatic Impairment Inhibitors Dose adjustmentmetaboliser type

EM Mild (Child-Pugh Eliglustat alone No dose adjustmentclass A) required

Moderate (Child-Pugh Eliglustat alone Not recommendedclass B) (see section 5.2)

Eliglustat alone Contraindicated

Severe (Child-Pugh

Eliglustat + Any CYP (see sections 4.3class C)inhibitor and 5.2)

CYP2D6 Hepatic Impairment Inhibitors Dose adjustmentmetaboliser type

Mild (Child-Pugh Eliglustat + strong or Contraindicatedclass A) or moderate moderate inhibitor of (see sections 4.3(Child-Pugh class B) CYP2D6 and 5.2)

Mild (Child-Pugh Eliglustat + weak Once daily dose shouldclass A) inhibitor of CYP2D6; be consideredor strong, moderate or (see sections 4.4weak inhibitor CYP3A and 5.2)

IM or PM Any N/A Not recommended(see section 5.2)

Table 3: Patients with renal impairment

CYP2D6 Renal impairment Dose adjustmentmetaboliser type

EM Mild, moderate or No dose adjustment requiredsevere (see sections 4.4 and 5.2)

End stage renal disease Not recommended(ESRD) (see sections 4.4 and 5.2)

IM or PM Mild, moderate or Not recommendedsevere, or ESRD (see sections 4.4 and 5.2)

Paediatric population (<6 years of age) weighing <15 kg

Safety and efficacy data of eliglustat are limited in paediatric patients below the age of 6 years. Thereare no data to support the use of eliglustat in children weighing less than 15 kg. Currently availabledata are described in section 5.1.

Cerdelga is to be taken orally. The capsules should be swallowed whole, preferably with water, andmust not be crushed or dissolved.

The capsules may be taken with or without food. Consumption of grapefruit or its juice should beavoided (see section 4.5).

Mixing the content of the capsule (eliglustat powder) into food or drinks has not been studied.

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

Cerdelga is contraindicated in patients who are CYP2D6 IMs or EMs taking a strong or moderate

CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor, and patients who are

CYP2D6 PMs taking a strong CYP3A inhibitor (see section 4.5).

Cerdelga is contraindicated in CYP2D6 EMs with severe hepatic impairment and in CYP2D6 EMswith mild or moderate hepatic impairment taking a strong or moderate CYP2D6 inhibitor (seesections 4.2 and 5.2).

Patients with pre-existing cardiac conditions

Use of eliglustat in patients with pre-existing cardiac conditions has not been studied during clinicaltrials. Because eliglustat is predicted to cause mild increases in ECG intervals at substantially elevatedplasma concentrations, use of eliglustat should be avoided in patients with cardiac disease (congestiveheart failure, recent acute myocardial infarction, bradycardia, heart block, ventricular arrhythmia),long QT syndrome, and in combination with Class IA (e.g. quinidine) and Class III (e.g. amiodarone,sotalol) antiarrhythmic medicinal products.

Patients with hepatic impairment and concomitant use with other medicinal products

Concomitant use of eliglustat with CYP2D6 or CYP3A4 inhibitors in CYP2D6 EMs with mild hepaticimpairment can result in further elevation of eliglustat plasma concentrations, with the magnitude ofthe effect depending on the enzyme inhibited and the potency of the inhibitor. In CYP2D6 EMs withmild hepatic impairment taking a weak CYP2D6 inhibitor or strong, moderate or weak CYP3Ainhibitor, a once daily dose is recommended (e.g. if a dose of 84 mg eliglustat is taken twice daily, itshould be adjusted to 84 mg eliglustat once daily) (see sections 4.2 and 5.2).

Limited or no data are available in CYP2D6 EMs, IMs or PMs with ESRD and in CYP2D6 IMs or

PMs with mild, moderate, or severe renal impairment; use of eliglustat in these patients is notrecommended (see sections 4.2 and 5.2).

Monitoring of clinical response

Some treatment-naïve patients showed less than 20% spleen volume reduction (sub-optimal results)after 9 months of treatment (see section 5.1). For these patients, monitoring for further improvement oran alternative treatment modality should be considered.

For patients with stable disease who switch from enzyme replacement therapy to eliglustat, monitoringfor disease progression (e.g. after 6 months with regular monitoring thereafter) should be performedfor all disease domains to evaluate disease stability. Reinstitution of enzyme replacement therapy or analternative treatment modality should be considered in individual patients who have a sub-optimalresponse.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency orglucose-galactose malabsorption should not take this medicine.

Eliglustat is metabolised primarily by CYP2D6 and to a lesser extent by CYP3A4. Concomitantadministration of substances affecting CYP2D6 or CYP3A4 activity may alter eliglustat plasmaconcentrations. Eliglustat is an inhibitor of P-gp and CYP2D6 in vitro; concomitant administration ofeliglustat with P-gp or CYP2D6 substrate substances may increase the plasma concentration of thosesubstances.

The list of substances in section 4.5 is not an inclusive list and the prescriber is advised to consult the

SmPC of all other prescribed medicinal products for potential drug-drug interactions with eliglustat.

Agents that may increase eliglustat exposure

Cerdelga is contraindicated in patients who are CYP2D6 IMs or EMs taking a strong or moderate

CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor, and in patients who are

CYP2D6 PMs taking a strong CYP3A inhibitor (see section 4.3). Use of eliglustat under theseconditions results in substantially elevated eliglustat plasma concentrations.

CYP2D6 inhibitors in IMs and EMs

After repeated 84 mg twice daily doses of eliglustat in non-PMs, concomitant administration withrepeated 30 mg once daily doses of paroxetine, a strong inhibitor of CYP2D6, resulted in a 7.3- and8.9-fold increase in eliglustat Cmax and AUC0-12, respectively. Once a day dosing of eliglustat for EMsand IMs is recommended when a strong CYP2D6 inhibitor (e.g. paroxetine, fluoxetine, quinidine,bupropion) is used concomitantly in IMs and EMs.

At 84 mg twice daily dosing with eliglustat in non-PMs, it is predicted that concomitant use ofmoderate CYP2D6 inhibitors (e.g., duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet,dronedarone) would increase eliglustat exposure approximately up to 4-fold. Caution should be usedwith moderate CYP2D6 inhibitors in IMs and EMs.

CYP2D6 inhibitors in EMs with mild or moderate hepatic impairment

See sections 4.2, pct. 4.3 and 4.4.

CYP2D6 inhibitors in EMs with severe hepatic impairment

See sections 4.2 and 4.3.

CYP3A inhibitors in IMs and EMs

After repeated 84 mg twice daily doses of eliglustat in non-PMs, concomitant administration withrepeated 400 mg once daily doses of ketoconazole, a strong inhibitor of CYP3A, resulted in a 3.8 and4.3-fold increase in eliglustat Cmax and AUC0-12, respectively; similar effects would be expected forother strong inhibitors of CYP3A (e.g. clarithromycin, ketoconazole, itraconazole, cobicistat,indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole,telithromycin, conivaptan, boceprevir). Caution should be used with strong CYP3A inhibitors in IMsand EMs.

At 84 mg twice daily dosing with eliglustat in non-PMs, it is predicted that concomitant use ofmoderate CYP3A inhibitors (e.g., erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil,aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine) would increase eliglustatexposure approximately up to 3-fold. Caution should be used with moderate CYP3A inhibitors in IMsand EMs.

CYP3A inhibitors in EMs with mild hepatic impairment

See sections 4.2 and 4.4.

CYP3A inhibitors in EMs with moderate or severe hepatic impairment

See sections 4.2 and 4.3.

CYP3A inhibitors in PMs

At 84 mg once daily dosing with eliglustat in PMs, it is predicted that concomitant use of strong

CYP3A inhibitors (e.g., ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir,ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan,boceprevir) would increase the Cmax and AUC0-24 of eliglustat 4.3- and 6.2-fold. The use of strong

CYP3A inhibitors is contraindicated in PMs.

At 84 mg once daily dosing with eliglustat in PMs, it is predicted that concomitant use of moderate

CYP3A inhibitors (e.g., erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant,atazanavir, darunavir, fosamprenavir, imatinib, cimetidine) would increase the Cmax and AUC0-24 ofeliglustat 2.4- and 3.0-fold, respectively. Use of a moderate CYP3A inhibitor with eliglustat is notrecommended in PMs.

Caution should be used with weak CYP3A inhibitors (e.g., amlodipine, cilostazol, fluvoxamine,goldenseal, isoniazid, ranitidine, ranolazine) in PMs.

CYP2D6 inhibitors used simultaneously with CYP3A inhibitors

In IMs and EMs

At 84 mg twice daily dosing with eliglustat in non-PMs, it is predicted that the concomitant use ofstrong or moderate CYP2D6 inhibitors and strong or moderate CYP3A inhibitors would increase Cmaxand AUC0-12 up to 17- and 25-fold, respectively. The use of a strong or moderate CYP2D6 inhibitorconcomitantly with a strong or moderate CYP3A inhibitor is contraindicated in IMs and EMs.

Grapefruit products contain one or more components that inhibit CYP3A and can increase plasmaconcentrations of eliglustat. Consumption of grapefruit or its juice should be avoided.

Agents that may decrease eliglustat exposure

Strong CYP3A inducers

After repeated 127 mg twice daily doses of eliglustat in non-PMs, concomitant administration ofrepeated 600 mg once daily doses of rifampicin (a strong inducer of CYP3A as well as the effluxtransporter P-gp) resulted in an approximately 85% decrease in eliglustat exposure. After repeated84 mg twice daily doses of eliglustat in PMs, concomitant administration of repeated 600 mg oncedaily doses of rifampicin resulted in an approximately 95% decrease in eliglustat exposure. Use of astrong CYP3A inducer (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin, rifabutin and St.

John’s wort) with eliglustat is not recommended in IMs, EMs and PMs.

Agents whose exposure may be increased by eliglustat

After a single 0.25 mg dose of digoxin, a P-gp substrate, concomitant administration of 127 mg twicedaily doses of eliglustat resulted in a 1.7- and 1.5-fold increase in digoxin Cmax and AUClast,respectively. Lower doses of substances which are P-gp substrates (e.g., digoxin, colchicine,dabigatran, phenytoin, pravastatin) may be required.

After a single 50 mg dose of metoprolol, a CYP2D6 substrate, concomitant administration of repeated127 mg twice daily doses of eliglustat resulted in a 1.5- and 2.1-fold increase in metoprolol Cmax and

AUC, respectively. Lower doses of medicinal products that are CYP2D6 substrates may be required.

These include certain antidepressants (tricyclic antidepressants, e.g. nortriptyline, amitriptyline,imipramine, and desipramine), phenothiazines, dextromethorphan and atomoxetine).

There are no or limited amount of data from the use of eliglustat in pregnant women. Animal studiesdo not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

As a precautionary measure, it is recommended to avoid the use of Cerdelga during pregnancy.

It is unknown whether eliglustat/metabolites are excreted in human milk. Availablepharmacodynamic/toxicological data in animals have shown excretion of eliglustat in milk (seesection 5.3). A risk to the newborns/infants cannot be excluded. A decision must be made whether todiscontinue breast-feeding or to discontinue/abstain from Cerdelga therapy taking into account thebenefit of breast-feeding for the child and the benefit of therapy for the woman.

Effects on testes and reversible inhibition of spermatogenesis were observed in rats (see section 5.3).

The relevance of these findings for humans is not known.

Cerdelga may affect the ability to drive and use machines in patients who experience dizziness after itsadministration.

The most frequently reported adverse reaction with eliglustat is dyspepsia, reported in approximately6% of the pooled adult clinical trial patients, and in 10.5% (for both cohorts) of paediatric patientsfrom the ELIKIDS study. Overall, the safety profile of eliglustat in paediatric patients observed inclinical development setting was consistent with the established safety profile in adults.

Adverse reactions are ranked by system organ class and frequency ([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)]). Adverse reactions from long term clinical trial data reported in at least 4 patients arepresented in Table 4. Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness.

Table 4: Tabulated list of adverse reactions

System organ class Common

Nervous system disorders Headache*, dizziness*, dysgeusia

Cardiac disorders Palpitations

Respiratory, thoracic and Throat irritation, coughmediastinal disorders

Dyspepsia, abdominal pain upper*, diarrhoea*, nausea, constipation,

Gastrointestinal disorders abdominal pain*, gastroesophageal reflux disease, abdominaldistension*, gastritis, dysphagia, vomiting*, dry mouth, flatulence

Skin and subcutaneous tissue

Dry skin, urticaria*disorders

Musculoskeletal and

Arthralgia, pain in extremity*, back pain*connective tissue disorders

General disorders and

Fatigueadministration site conditions

* The incidence of the adverse reaction was the same or higher with placebo than with eliglustat in theplacebo-controlled pivotal study.

In the ELIKIDS paediatric study Cohort 1 (eliglustat monotherapy), the most common adversereactions were dyspepsia (9.8%) and dry skin (3.6%). In Cohort 2 (eliglustat/imiglucerase combinationtherapy), the most common adverse reactions were headache, dyspepsia, gastritis, and fatigue (eachexperienced by 16.7% (1/6) of the patients). Of 57 enrolled patients, 53 (93%, 48/51 in Cohort 1)experienced at least one treatment-emergent adverse event (TEAE) with no meaningful difference byage group, gender, or GD type. No patients permanently discontinued treatment due to TEAE.

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.

The highest eliglustat plasma concentration observed to date occurred in a Phase 1 single-dose doseescalation study in healthy subjects, in a subject taking a dose equivalent to approximately 21 timesthe recommended dose for GD1 patients. At the time of the highest plasma concentration (59-foldhigher than normal therapeutic conditions), the subject experienced dizziness marked bydisequilibrium, hypotension, bradycardia, nausea, and vomiting.

In the event of acute overdose, the patient should be carefully observed and given symptomatictreatment and supportive care.

Pharmacotherapeutic group: Other alimentary tract and metabolism products, various alimentary tractand metabolism products, ATC code: A16AX10

Eliglustat is a potent and specific inhibitor of glucosylceramide synthase and acts as a substratereduction therapy (SRT) for GD1. SRT aims to reduce the rate of synthesis of the major substrateglucosylceramide (GL-1) to match its impaired rate of catabolism in patients with GD1, therebypreventing glucosylceramide accumulation and alleviating clinical manifestations.

In clinical trials in treatment-naïve GD1 patients, plasma GL-1 levels were elevated in the majority ofthese patients and decreased upon eliglustat treatment. Additionally, in a clinical trial in GD1 patientsstabilised on enzyme replacement therapy (ERT) (i.e. having already achieved therapeutic goals on

ERT prior to initiating eliglustat treatment), plasma GL-1 levels were normal in most patients anddecreased upon eliglustat treatment.

The recommended dosing regimens (see section 4.2) are based on modelling, either of PK/PD datafrom the dose-titration regimens applied in the clinical studies for IMs and EMs, or physiologically-based PK data for PMs.

Pivotal study of eliglustat in treatment-naïve GD1 patients - Study 02507(ENGAGE)

Study 02507 was a randomized, double-blind, placebo-controlled, multicentre clinical study in40 patients with GD1. In the eliglustat group 3 (15%) patients received a starting dose of 42 mgeliglustat twice daily during the 9-month primary analysis period and 17 (85%) patients received adose escalation to 84 mg twice daily based on plasma trough concentration.

Table 5: Change from baseline to month 9 (primary analysis period) in treatment-naïve patientswith GD1 receiving treatment with eliglustat in study 02507

Difference

Placebo* Eliglustat (Eliglustat -p valueb(n=20) a (n=20) a Placebo)[95% CI]

Percentage change in spleen volume MN (%) -30.02.26 -27.77 < 0.0001(primary endpoint) [-36.8, -23.2]1.22(g/dL) -0.54 0.69

Absolute change in haemoglobin [0.57, 1.88]0.0006level (secondary endpoint) 0.76(mmol/L) -0.34 0.43[0.35,1.17]

Percentage change in liver volume MN (%) -6.641.44 -5.20 0.0072(secondary endpoint) [-11.37, -1.91]

Percentage change in platelet count (%) 41.06

- 9.06 32.00 < 0.0001(secondary endpoint) [23.95, 58.17]

MN = Multiples of Normal, CI = confidence intervala At baseline, mean spleen volumes were 12.5 and 13.9 MN in the placebo and eliglustat groups,respectively, and mean liver volumes were 1.4 MN for both groups. Mean haemoglobin levelswere 12.8 g/dL (7.954 mmol/L) and 12.1 g/dL (7.51 mmol/L), and platelet counts were 78.5 and75.1 x 109/L, respectively.b Estimates and p-values are based on an ANCOVA model.

* All patients transitioned to eliglustat treatment after Month 9.

During the open-label long term treatment period with eliglustat (extension phase), all patients withcomplete data who continued to receive eliglustat showed further improvements throughout theextension phase. Results (change from baseline) after 18 months, 30 months and 4.5 years of exposureto eliglustat on the following endpoints were: absolute change in haemoglobin level 1.1 g/dL (1.03)[0.68 mmol/L (0.64); n=39], 1.4 g/dL (0.93) [0.87 mmol/L (0.58); n=35], and 1.4 g/dL (1.31)[0.87 mmol/L (0.81); n=12]; mean increase in platelet count (mm3) 58.5% (40.57%) [n=39], 74.6%(49.57%) [n=35], and 86.8% (54.20%) [n=12]; mean reduction in spleen volume (MN) 46.5% (9.75%)[n=38], 54.2% (9.51%) [n=32], and 65.6% (7.43%) [n=13]; and mean reduction in liver volume (MN)13.7% (10.65%) [n=38], 18.5% (11.22%) [n=32], and 23.4% (10.59%) [n=13].

Long-term clinical outcomes in treatment-naïve GD1 patients - Study 304

Study 304 was a single-arm, open-label, multicentre study of eliglustat in 26 patients of which 19completed 4 years of treatment. Of these patients, 15 (79%) received a dose escalation to 84 mgeliglustat twice daily; 4 (21%) patients continued to receive 42 mg twice daily.

In the study, 18 patients completed 8 years of treatment. Of these 18 patients, one (6%) received afurther dose escalation to 127 mg twice daily; 14 (78%) continued on 84 mg eliglustat twice daily; 3(17%) patients continued to receive 42 mg twice daily. At year 8, 16 patients had an efficacy endpointassessment.

Eliglustat showed sustained improvements in organ volume and haematological parameters over the8 year treatment period (see Table 6).

Table 6: Change from baseline to year 8 in study 304

N Baseline Change from Standardvalue baseline (Mean) deviation(Mean)

Spleen volume (MN) 15 17.34 -67.9% 17.11

Haemoglobin level (g/dL) 16 11.33 2.08 1.75(mmol/L) 7.04 1.29 1.09

Liver volume (MN) 15 1.60 -31.0% 13.51

Platelet count (x109/L) 16 67.53 109.8% 114.73

MN = Multiples of Normal

Pivotal study of eliglustat in GD1 patients switching from ERT - Study 02607 (ENCORE)

Study 02607 was a randomized, open-label, active-controlled, non-inferiority, multicentre clinicalstudy in 159 patients previously stabilised with ERT. In the eliglustat group 34 (32%) patientsreceived a dose escalation to 84 mg eliglustat twice daily and 51 (48%) to 127 mg twice daily duringthe 12-month primary analysis period, and 21 (20%) patients continued to receive 42 mg twice daily.

Based on the aggregate data from all doses tested in this study, eliglustat met the criteria set in thisstudy to be declared non-inferior to imiglucerase in maintaining patient stability. After 12 months oftreatment, the percentage of patients meeting the primary composite endpoint (composed of all fourcomponents mentioned in Table 7) was 84.8% [95% confidence interval 76.2% - 91.3%] for theeliglustat group compared to 93.6% [95% confidence interval 82.5% - 98.7 %] for the imiglucerasegroup. Of the patients who did not meet stability criteria for the individual components, 12 of 15eligslustat patients and 3 of 3 imiglucerase patients remained within therapeutic goals for GD1.

There were no clinically meaningful differences between groups for any of the four individual diseaseparameters (see Table 7).

Table 7: Changes from baseline to Month 12 (primary analysis period) in patients with GD1switching to eliglustat in study 02607

Imiglucerase Eliglustat(N=47)** (N=99)

Mean [95% CI] Mean [95% CI]

Spleen volume

Percentage of patients with stable100% 95.8%spleen volume*a

Percentage change in spleen volume

- 3.01 [-6.41, 0.40] -6.17 [-9.54, -2.79]

MN (%)*

Haemoglobin level

Percentage of patients with stable100% 94.9%haemoglobin levela

Absolute change in (g/dL) 0.038 [-0.16, 0.23] -0.21 [-0.35, -0.07]haemoglobin level(mmol/L) 0.024 [-0.099,0.14] -0.13 [-0.22, -0.043]

Liver volume

Percentage of patients with stablea 93.6% 96.0%liver volume

Percentage change in liver volume3.57 [0.57, 6.58] 1.78 [-0.15, 3.71]

MN (%)

Platelet count

Percentage of patients with stable100% 92.9%platelet counta

Percentage change in platelet count2.93 [-0.56, 6.42] 3.79 [0.01, 7.57](%)

MN = Multiples of Normal, CI = confidence interval

* Excludes patients with a total splenectomy.

** All patients transitioned to eliglustat treatment after 52 weeks.

a The stability criteria based on changes between baseline and 12 months: haemoglobin level≤ 1.5 g/dL (0.93 mmol/L) decrease, platelet count ≤ 25% decrease, liver volume ≤ 20% increase,and spleen volume ≤ 25% increase.

All patient number (N)= Per Protocol Population

During the open-label long term treatment period with eliglustat (extension phase) the percentage ofpatients with complete data meeting the composite stability endpoint was maintained at 84.6%(n=136) after 2 years, 84.4% (n=109) after 3 years and 91.1% (n=45) after 4 years. The majority ofextension phase discontinuations were due to transition to commercial product from year 3 onwards.

Individual disease parameters of spleen volume, liver volume, haemoglobin levels and platelet countremained stable through 4 years (see Table 8).

Table 8: Changes from month 12 (primary analysis period) to month 48 in patients with GD1 inthe long term treatment period on eliglustat in study 02607

Year 2 Year 3 Year 4

Imiglucerase Eliglustatb Imiglucerase Eliglustatb Imiglucerase Eliglustatb/Eliglustata Mean [95% /Eliglustata Mean [95% /Eliglustata Mean [95%

Mean [95% CI] CI]) Mean [95% CI] CI] Mean [95% CI] CI]

Patients at start of 51 101 46 98 42 96year (N)

Patients at end of 46 98 42 96 21 44year (N)

Patients with 39 97 16 93 3 42available data (N)

Spleen volume

Patients with stable 31/33 (93.9) 69/72 (95.8) 12/12 (100.0) 65/68 (95.6) 2/2 (100.0) 28/30 (93.3)spleen volume (%)* [0.798, 0.993] [0.883, 0.991] [0.735, 1.000] [0.876, [0.158, 1.000] [0.779, 0.992]0.991]

Change in spleen -3.946[-8.80, -6.814[-10.61, - -10.267[-20.12, - -7.126[- -27.530[-89.28, -13.945[-volume MN (%)* 0.91] 3.02] 0.42] 11.70, -2.55] 34.22] 20.61, -7.28]

Haemoglobin level

Patients with stable 38/39 (97.4) 95/97 (97.9) 16/16 (100.0) 90/93 (96.8) 3/3 (100.0) 42/42 (100.0)haemoglobin level [0.865, 0.999] [0.927, 0.997] [0.794, 1.000] [0.909, (0.292, 1.000] [0.916, 1.000](%) 0.993]

Change (g/dL) 0.034[-0.31, -0.112[-0.26, 0.363[-0.01, 0.74] -0.103[-0.27, 0.383[-1.62, 2.39] 0.290[0.06,from 0.38] 0.04] 0.07] 0.53]baseline in (mmol 0.021[-0.19, -0.077[-0.16, 0.23[-0.006, 0.46] -0.064[-0.17, 0.24 [-1.01, 1.48] 0.18 [0.0374,

Haemoglo /L) 0.24] 0.025] 0.043] 0.33]bin Level

Liver volume

Patients with stable 38/39 (97.4) 94/97 (96.9) 15/16 (93.8) 87/93 (93.5) 3/3 (100.0) 40/42 (95.2)liver volume (%) (0.865, 0.999) (0.912, 0.994) [0.698, 0.998] (0.865, [0.292, 1.000] [0.838, 0.994]0.976)

Change from 0.080[-3.02, 2.486[0.50, -4.908[-11.53, 1.71] 3.018[0.52, -14.410[-61.25, -1.503[-5.27,baseline in liver 3.18] 4.47] 5.52] 32.43] 2.26]volume MN (%)

Platelet count

Patients with stable 33/39 (84.6) 92/97 (94.8) 13/16 (81.3) 87/93 (93.5) 3/3 (100.0) 40/42 (95.2)platelet count (%) [0.695, 0.941] [0.884, 0.983] [0.544, 0.960] [0.865, [0.292, 1.000] [0.838, 0.994]0.976]

Change in platelet -0.363[-6.60, 2.216[-1.31, 0.719[-8.20, 9.63] 5.403[1.28, -0.163[-35.97, 35.64] 7.501[1.01,count (%) 5.88] 5.74] 9.52] 13.99]

Composite stability endpoint

Patients who are 30/39 (76.9) 85/97 (87.6) 12/16 (75.0) 80/93 (86.0) 3/3 (100.0) 38/42 (90.5)stable on eliglustat [0.607, 0.889] [0.794, 0.934] [0.476, 0.927] [0.773, 0.923] [0.292, 1.000] [0.774, 0.973](%)

MN = Multiples of Normal, CI = confidence interval

* Excludes patients with a total splenectomy.

a Imiglucerase/Eliglustat - Originally randomized to imigluceraseb Eliglustat - Originally randomized to eliglustat

Clinical experience in CYP2D6 PMs and URMs

There is limited experience with eliglustat treatment of patients who are PMs or URMs. In the primaryanalysis periods of the three clinical studies, a total of 5 PMs and 5 URMs were treated with eliglustat.

All PMs received 42 mg eliglustat twice daily, and four of these (80%) had an adequate clinicalresponse. The majority of URMs (80%) received a dose escalation to 127 mg eliglustat twice daily, allof which had adequate clinical responses. The one URM who received 84 mg twice daily did not havean adequate response.

The predicted exposures with 84 mg eliglustat once daily in patients who are PMs are expected to besimilar to exposures observed with 84 mg eliglustat twice daily in CYP2D6 IMs. Patients who are

URMs may not achieve adequate concentrations to achieve a therapeutic effect. No dosingrecommendation for URMs can be given.

Effects on skeletal pathology

After 9 months of treatment, in Study 02507, bone marrow infiltration by Gaucher cells, as determinedby the total Bone Marrow Burden (BMB) score (assessed by MRI in lumbar spine and femur)decreased by a mean of 1.1 points in eliglustat treated patients (n=19) compared to no change inpatients receiving placebo (n=20). Five eliglustat-treated patients (26%) achieved a reduction of atleast 2 points in the BMB score.

After 18 and 30 months of treatment, BMB score had decreased by a mean 2.2 points (n=18) and2.7 (n=15), respectively for the patients originally randomised to eliglustat, compared to a meandecrease of 1 point (n=20) and 0.8 (n=16) in those originally randomised to placebo.

After 18 months of eliglustat treatment in the open-label extension phase, the mean (SD) lumbar spine

Bone Mineral Density T-score increased from -1.14 (1.0118) at Baseline (n=34) to -0.918(1.1601) (n=33) in the normal range. After 30 months and 4.5 years of treatment, the T-score furtherincreased to -0.722 (1.1250) (n=27) and -0.533 (0.8031) (n=9), respectively.

Results of study 304 indicate that skeletal improvements are maintained or continue to improve duringat least 8 years of treatment with eliglustat.

In study 02607, lumbar spine and femur BMD T- and Z-scores were maintained within the normalrange in patients treated with eliglustat for up to 4 years.

Electrocardiographic evaluation

No clinically significant QTc prolonging effect of eliglustat was observed for single doses up to675 mg.

Heart-rate corrected QT interval using Fridericia's correction (QTcF) was evaluated in a randomized,placebo and active (moxifloxacin 400 mg) controlled cross-over, single-dose study in 47 healthysubjects. In this trial with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo-adjusted, baseline-corrected QTcF was below10 msec, the threshold for regulatory concern. While there was no apparent effect on heart rate,concentration-related increases were observed for the placebo corrected change from baseline in the

PR, QRS, and QTc intervals. Based on PK/PD modelling, eliglustat plasma concentrations 11-fold thepredicted human Cmax are expected to cause mean (upper bound of the 95% confidence interval)increases in the PR, QRS, and QTcF intervals of 18.8 (20.4), 6.2 (7.1), and 12.3 (14.2) msec,respectively.

A limited number of patients aged 65 years (n=10) and over were enrolled in clinical trials. Nosignificant differences were found in the efficacy and safety profiles of elderly patients and youngerpatients.

Paediatric patients (2 to < 18 years of age)

Study EFC13738 (ELIKIDS) is an ongoing Phase 3, open-label, two-cohort, multicentre study toevaluate the safety and pharmacokinetics (PK) of eliglustat alone (Cohort 1) or in combination withimiglucerase (Cohort 2) in paediatric patients aged 2 to less than 18 years old with GD1 and GD3.

Cohort 1 enrolled GD1 and GD3 patients who were receiving ERT for at least 24 months and reachedprespecified therapeutic goals with respect to their haemoglobin level (ages 2 to < 12 years:

≥ 11.0 g/dL (6.827 mmol/L); for ages 12 to <18 years: ≥ 11.0 g/dL (6.827 mmol/L) for females and≥ 12.0 g/dL (7.452 mmol/L) for males), platelet count (≥ 100 000/mm3), and spleen volume (< 10.0

MN) and liver volume (< 1.5 MN), and had absence of Gaucher-related pulmonary disease, severebone disease, or persistent thrombocytopenia. Cohort 2 enrolled GD1 and GD3 patients who, despiteongoing treatment with ERT for ≥ 36 months, were having at least one severe clinical manifestation of

GD (e.g., pulmonary disease, symptomatic bone disease, or persistent thrombocytopenia).

There were 51 patients in Cohort 1 (n=46 GD1 and n=5 GD3) and 6 in Cohort 2 (n=3 GD1 andn=3 GD3). Patients were dosed according to their CPY2D6 predicted phenotype (EM, IM, PM) andweight category with potential dose increase due to increased body weight and lower PK exposure(based on the results of individual and subgroup PK analyses). No patient below 15 kg at baseline wasenrolled into the study. During the 52week period, 28 patients (49.2%) had at least one dose increase.

The safety profile of eliglustat seen in this study is consistent with the safety profile of eliglustat inadults and no new adverse reactions were identified (see section 4.8).

The main efficacy endpoints for Cohort 1 included change from baseline to 52-weeks (primaryanalysis period) for haemoglobin (g/dL), platelets (%), spleen volume (%), and liver volume (%). Themajority of study patients (96%) on eliglustat monotherapy maintained their Gaucher-related clinicalparameters (Table 9) within the prespecified therapeutic goals for study entry. Of the three patientsbelow the age of 6 years on eliglustat monotherapy, two switched to imiglucerase. Out of 51 patients,47 in Cohort 1 were maintained on eliglustat monotherapy through 52 weeks.

Four patients (n=2 GD1, n=2 GD3) required a switch to imiglucerase due to decline in Gaucher-related clinical parameters. Of the 4 patients, one (GD3) discontinued the study and 3 initiated rescuetherapy treatment. Further, one (GD1) of the 3 patients who initiated rescue therapy withdrew from thestudy during the primary analysis period.

Of the five patients with GD3 on eliglustat monotherapy, one discontinued the study due to COVID-19 and 2 patients qualified for rescue therapy; of the two who qualified for rescue therapy, one patientdiscontinued the study and one completed the PAP on rescue therapy as stated above. The efficacydata of eliglustat as monotherapy in paediatric patients below the age of 6 years (n=3) and with GD3(n=5) are limited; no clinically meaningful conclusion can be drawn.

The main efficacy endpoint for patients in Cohort 2 was the percentage of patients with improvementin the severe manifestation(s) that made the patient eligible for inclusion in Cohort 2 after 52 weeks oftreatment. For efficacy of combination therapy, 4 out of 6 patients did not meet the main endpoint; noconclusion can be drawn as to the use of combination therapy in the paediatric population.

Table 9: Changes from baseline to 52 weeks (primary analysis period) in patients with GD oneliglustat monotherapy (Cohort 1) in study EFC13738

Gaucher-related Mean (SD) at Mean (SD) at

Age (years) [n] Mean change (SD)clinical parameters baseline week 522 to < 6 [n = 3] Haemoglobin level (g/dL) 12.25 (0.76) 11.93 (0.60) -0.32 g/dL (0.20)(mmol/L) 7.61 (0.47) 7.41 (0.37) -0.25 mmol/L (0.01)

GD1: n = 2 Platelet count (x109/L) 261.50 (59.33) 229.33 (90.97) -12.19% (26.05)

GD3: n = 1 Spleen volume (MN) 3.84 (1.37) 5.61 (2.56) 42.12% (16.64)

Liver volume (MN) 1.22 (0.27) 1.43 (0.02) 21.23% (26.97)6 to < 12 [n = 15] Haemoglobin level (g/dL) 13.70 (1.17) 13.21 (1.22) -0.49 g/dL (1.17)(mmol/L) 8.51 (0.73) 8.2 (0.76) -0.3 mmol/L (0.73)

GD1: n = 14 Platelet count (x109/L) 216.40 (51.80) 231.73 (71.62) 7.25% (20.50)

GD3: n = 1 Spleen volume (MN) 3.01 (0.86) 2.93 (0.82) 0.11% (19.52)

Liver volume (MN) 1.02 (0.20) 1.03 (0.16) 2.22% (13.86)12 to < 18 [n = 33] Haemoglobin level (g/dL) 13.75 (0.97) 13.37 (1.20) -0.38 g/dL (1.01)(mmol/L) 8.54 (0.60) 8.3 (0.75) -0.24 mmol/L (0.63)

Gaucher-related Mean (SD) at Mean (SD) at

Age (years) [n] Mean change (SD)clinical parameters baseline week 52

GD1: n = 30 Platelet count (x109/L) 210.64 (49.73) 177.11 (50.92) -14.36% (20.67)

GD3: n = 3 Spleen volume (MN) 3.48 (1.78) 3.41 (1.65) 1.79% (26.11)

Liver volume (MN) 0.93 (0.16) 0.92 (0.18) -1.47% (10.39)

The European Medicines Agency has waived the obligation to submit the results of studies witheliglustat in all subsets of the paediatric population in Gaucher disease type 2 (see section 4.2 forinformation on paediatric use).

Median time to reach maximum plasma concentrations occurs between 1.5 to 6 hours after dosing,with low oral bioavailability (< 5%) due to significant first-pass metabolism. Eliglustat is a substrateof the efflux transporter P-gp. Food does not have a clinically relevant effect on eliglustatpharmacokinetics. Following repeated dosing of eliglustat 84 mg twice daily in non-PMs and oncedaily in PMs, steady state was reached by 4 days, with an accumulation ratio of 3-fold or less.

Eliglustat is moderately bound to human plasma proteins (76 to 83%) and is mainly distributed inplasma. After intravenous administration, the volume of distribution was 816 L, suggesting widedistribution to tissues in humans. Nonclinical studies demonstrated a wide distribution of eliglustat totissues, including bone marrow.

Eliglustat is extensively metabolized with high clearance, mainly by CYP2D6 and to a lesser extent

CYP3A4. Primary metabolic pathways of eliglustat involve sequential oxidation of the octanoylmoiety followed by oxidation of the 2,3-dihydro-1,4-benzodioxane moiety, or a combination of thetwo pathways, resulting in multiple oxidative metabolites.

After oral administration, the majority of the administered dose is excreted in urine (41.8%) andfaeces (51.4%), mainly as metabolites. After intravenous administration, eliglustat total bodyclearance was 86 L/h. After repeated oral doses of 84 mg eliglustat twice daily, eliglustat eliminationhalf-life is approximately 4-7 hours in non-PMs and 9 hours in PMs.

CYP2D6 phenotype

Population pharmacokinetic analysis shows that the CYP2D6 predicted phenotype based on genotypeis the most important factor affecting pharmacokinetic variability. Individuals with a CYP2D6 poormetaboliser predicted phenotype (approximately 5 to 10% of the population) exhibit higher eliglustatconcentrations than intermediate or extensive CYP2D6 metabolisers.

Gender, body weight, age, and race

Based on the population pharmacokinetic analysis, gender, body weight, age, and race had limited orno impact on the pharmacokinetics of eliglustat.

In paediatric patients treated with body-weight tiered dosing regimens (see section 4.2), steady stateexposures (Cmax and AUC) were comparable and within the observed range in adult patients.

Effects of mild and moderate hepatic impairment were evaluated in a single dose phase 1 study. Aftera single 84 mg dose, eliglustat Cmax and AUC were 1.2- and 1.2-fold higher in CYP2D6 extensivemetabolisers (EMs) with mild hepatic impairment, and 2.8- and 5.2-fold higher in CYP2D6 EMs withmoderate hepatic impairment compared to healthy CYP2D6 EMs.

After repeated 84 mg twice daily doses of eliglustat, Cmax and AUC0-12 are predicted to be 2.4- and2.9-fold higher in CYP2D6 EMs with mild hepatic impairment and 6.4- and 8.9-fold higher in

CYP2D6 EMs with moderate hepatic impairment compared to healthy CYP2D6 EMs.

After repeated 84 mg once daily doses of eliglustat, Cmax and AUC0-24 are predicted to be 3.1- and3.2-fold higher in CYP2D6 EMs with moderate hepatic impairment compared to healthy CYP2D6

EMs receiving eliglustat 84 mg twice daily (see sections 4.2 and 4.4).

Steady state PK exposure could not be predicted in CYP2D6 IMs and PMs with mild and moderatehepatic impairment due to limited or no single-dose data. The effect of severe hepatic impairment wasnot studied in subjects with any CYP2D6 phenotype (see sections 4.2, pct. 4.3 and 4.4).

Effect of severe renal impairment was evaluated in a single dose phase 1 study. After a single 84 mgdose, eliglustat Cmax and AUC were similar in CYP2D6 EMs with severe renal impairment and healthy

CYP2D6 EMs.

Limited or no data were available in patients with ESRD and in CYP2D6 IMs or PMs with severerenal impairment (see sections 4.2).

The principal target organs for eliglustat in toxicology studies are the GI tract, lymphoid organs, theliver in rat only and, in the male rat only, the reproductive system. Effects of eliglustat in toxicologystudies were reversible and exhibited no evidence of delayed or recurring toxicity. Safety margins forthe chronic rat and dog studies ranged between 8-fold and 15-fold using total plasma exposure and 1-to 2-fold using unbound (free fraction) plasma exposures.

Eliglustat did not have effects on central nervous system (CNS) or respiratory functions.

Concentration-dependent cardiac effects were observed in non-clinical studies: inhibition of humancardiac ion channels, including potassium, sodium, and calcium, at concentrations ≥ 7-fold ofpredicted human Cmax; sodium ion channel-mediated effects in an ex-vivo electrophysiology study indog Purkinje fibres (2-fold of predicted human unbound plasma Cmax); and increases in QRS and PRintervals in dog telemetry and cardiac conduction studies in anaesthetised dogs, with effects seen atconcentrations 14-fold of predicted human total plasma Cmax, or 2-fold of predicted human unboundplasma Cmax.

Eliglustat was not mutagenic in a standard battery of genotoxicity tests and did not show anycarcinogenic potential in standard lifetime bioassays in mice and rats. Exposures in the carcinogenicitystudies were approximately 4-fold and 3-fold greater in mice and rats, respectively, than the meanpredicted human eliglustat total plasma exposure, or less than 1-fold using unbound plasma exposure.

In mature male rats, no effects on sperm parameters were observed at systemically non-toxic doses.

Reversible inhibition of spermatogenesis was observed in the rat at 10-fold of predicted humanexposure based on AUC, a systemically toxic dose. In rat repeated dose toxicity studies, seminiferousepithelial degeneration and segmental hypoplasia of the testes was seen at 10-fold of predicted humanexposure based on AUC.

Placental transfer of eliglustat and its metabolites was shown in the rat. At 2 and 24 hours post-dose,0.034 % and 0.013 % of labelled dose was detected in foetal tissue, respectively.

At maternal toxic doses in rats, foetuses showed a higher incidence of dilated cerebral ventricles,abnormal number of ribs or lumbar vertebrae, and many bones showed poor ossification.

Embryofoetal development in rats and rabbits was not affected up to clinically relevant exposure(based on AUC).

A lactation study in the rat showed that 0.23% of labelled dose was transferred to pups during24-hours post--dose, indicating milk excretion of eliglustat and/or its related materials.

Cellulose, microcrystalline (E460)

Lactose monohydrate

Hypromellose15 mPa.S, 2910

Glycerol dibehenate

Capsule shell21 mg hard capsule

Gelatin (E441)

Potassium aluminium silicate (E555)

Titanium dioxide (E171)84 mg hard capsule

Gelatin

Potassium aluminium silicate (E555)

Titanium dioxide (E171)

Yellow iron oxide (E172)

Indigotine (E132)

Shellac

Black iron oxide (E172)

Propylene glycol (E1520)

Ammonia solution, concentrated (E527)

Not applicable.

Cerdelga 21 mg hard capsule2 years

Cerdelga 84 mg hard capsule3 years

This medicinal product does not require any special storage conditions.

PETG/COC.PETG/PCTFE-aluminium blister

Cerdelga 21 mg hard capsule

Each blister contains 14 hard capsules.

Each pack contains 56 hard capsules.

Pack size: 56 hard capsules in 4 blisters of 14 capsules each.

Cerdelga 84 mg hard capsule

Each blister wallet contains 14 hard capsules.

Each pack contains 14, 56 or 196 hard capsules.

Pack size: 14 hard capsules in 1 blister wallet, 56 hard capsules in 4 blister wallets of 14 capsules eachor 196 hard capsules in 14 blister wallets of 14 capsules each.

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Cerdelga 21 mg hard capsule

EU/1/14/974/004 56 capsules

Cerdelga 84 mg hard capsule

EU/1/14/974/001 56 capsules

EU/1/14/974/002 196 capsules

EU/1/14/974/003 14 capsules

Date of first authorisation: 19 January 2015

Date of latest renewal: 16 December 2019

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

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