Cerdelga

Cerdelga 84 mg capsules, hard

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

Excipient(s) with known effect:

Each capsule contains 106 mg lactose (as monohydrate).

Capsule, hard.

Capsule with pearl blue-green opaque cap and pearl white opaque body with “GZ02” printed in black on the body of the capsule. The size of the capsule is 'size 2' (dimensions 18.0 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).

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

Posology

The recommended dose is 84 mg eliglustat twice daily in CYP2D6 intermediate metabolisers (IMs) and extensive metabolisers (EMs). The recommended dose is 84 mg eliglustat once daily in CYP2D6 poor metabolisers (PMs). If a dose is missed, the prescribed dose should be taken at the next scheduled time; the next dose should not be doubled.

The capsules may be taken with or without food. Consumption of grapefruit or its juice should be avoided.

Special populations

CYP2D6 ultra-rapid metabolisers (URMs) and indeterminate metabolisers

Cerdelga should not be used in patients who are CYP2D6 ultra-rapid metabolisers (URMs) or indeterminate metabolisers.

Patients with hepatic impairment

In CYP2D6 extensive metabolisers (EMs) with severe (Child-Pugh class C) hepatic impairment, Cerdelga is contraindicated.

In CYP2D6 extensive metabolisers (EMs) with moderate hepatic impairment (Child-Pugh class B), Cerdelga is not recommended.

In CYP2D6 extensive metabolisers (EMs) with mild hepatic impairment (Child-Pugh class A), no dosage adjustment is required and the recommended dose is 84 mg eliglustat twice daily.

In CYP2D6 intermediate metabolisers (IMs) or poor metabolisers (PMs) with any degree of hepatic impairment, Cerdelga is not recommended.

In CYP2D6 extensive metabolisers (EMs) with mild or moderate hepatic impairment taking a strong or moderate CYP2D6 inhibitor, Cerdelga is contraindicated.

In CYP2D6 extensive metabolisers (EMs) with mild hepatic impairment taking a weak CYP2D6 inhibitor or a strong, moderate or weak CYP3A inhibitor, a dose of 84 mg eliglustat once daily should be considered.

Patients with renal impairment

In CYP2D6 extensive metabolisers (EMs) with mild, moderate or severe renal impairment, no dosage adjustment is required and the recommended dose is 84 mg eliglustat twice daily.

In CYP2D6 EMs with end stage renal disease (ESRD), Cerdelga is not recommended.

In CYP2D6 intermediate metabolisers (IMs) or poor metabolisers (PMs) with mild, moderate or severe renal impairment or ESRD, Cerdelga is not recommended.

Elderly patients (>65 years)

A limited number of patients aged 65 and over were enrolled in clinical trials. No significant differences were found in the efficacy and safety profiles of elderly patients and younger patients.

Paediatric population

The safety and efficacy of Cerdelga in children and adolescents under the age of 18 years has not been established. No data are available.

Method of administration

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

Patients who are CYP2D6 intermediate metabolisers (IMs) or extensive metabolisers (EMs) taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor, and patients who are CYP2D6 poor metabolisers (PMs) taking a strong CYP3A inhibitor. Use of Cerdelga under these conditions results in substantially elevated eliglustat plasma concentrations.

Due to significantly increased eliglustat plasma concentrations, Cerdelga is contraindicated in CYP2D6 extensive metabolisers (EMs) with severe hepatic impairment and in CYP2D6 extensive metabolisers (EMs) with mild or moderate hepatic impairment taking a strong or moderate CYP2D6 inhibitor.

Initiation of therapy: CYP2D6 genotyping

Before initiation of treatment with Cerdelga, patients should be genotyped for CYP2D6 to determine the CYP2D6 metaboliser status.

Drug-drug interactions

Cerdelga is contraindicated in patients who are CYP2D6 intermediate metabolisers (IMs) or extensive metabolisers (EMs) taking a strong (e.g. paroxetine, fluoxetine, quinidine) or moderate (e.g. duloxetine, terbinafine) CYP2D6 inhibitor concomitantly with a strong (e.g. clarithromycin, itraconazole) or moderate (e.g. erythromycin, fluconazole) CYP3A inhibitor, and in patients who are CYP2D6 poor metabolisers (PMs) taking a strong CYP3A inhibitor.).

Use of Cerdelga with strong CYP3A inducers substantially decreases the exposure to eliglustat, which may reduce the therapeutic effectiveness of eliglustat; therefore concomitant administration is not recommended.

Patients with pre-existing cardiac conditions

Use of Cerdelga in patients with pre-existing cardiac conditions has not been studied during clinical trials. Because eliglustat is predicted to cause mild increases in ECG intervals at substantially elevated plasma concentrations, use of Cerdelga should be avoided in patients with cardiac disease (congestive heart 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

Limited data are available in CYP2D6 extensive metabolisers (EMs) with moderate hepatic impairment. Use of Cerdelga in these patients is not recommended.

Limited or no data are available in CYP2D6 intermediate metabolisers (IMs) or poor metabolisers (PMs) with any degree of hepatic impairment. Use of Cerdelga in these patients is not recommended.

Concomitant use of Cerdelga with CYP2D6 or CYP3A4 inhibitors in CYP2D6 extensive metabolisers (EMs) with mild hepatic impairment can result in further elevation of eliglustat plasma concentrations, with the magnitude of the effect depending on the enzyme inhibited and the potency of the inhibitor. In CYP2D6 extensive metabolisers (EMs) with mild hepatic impairment taking a weak CYP2D6 inhibitor or strong, moderate or weak CYP3A inhibitor, a dose of 84 mg eliglustat mg once daily should be considered.

Patients with Renal Impairment

Limited or no data are available in CYP2D6 extensive metabolisers (EMs), intermediate metabolisers (IMs) or poor metabolisers (PMs) with ESRD and in CYP2D6 intermediate metabolisers (IMs) or poor metabolisers (PMs) with mild, moderate, or severe renal impairment; use of Cerdelga in these patients is not recommended.

Monitoring of clinical response

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

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

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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

-drug interactions with eliglustat.

Agents that may increase eliglustat exposure

Cerdelga is contraindicated in patients who are CYP2D6 intermediate metabolisers (IMs) or extensive metabolisers (EMs) taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor , and in patients who are CYP2D6 poor metabolisers (PMs) taking a strong CYP3A inhibitor. Use of Cerdelga under these conditions results in substantially elevated eliglustat plasma concentrations.

CYP2D6 inhibitors

In intermediate (IMs) and extensive metabolisers (EMs):

After repeated 84 mg twice daily doses of eliglustat in non-PMs, concomitant administration with repeated 30 mg once daily doses of paroxetine, a strong inhibitor of CYP2D6, resulted in a 7.3- and 8.9-fold increase in eliglustat C_max and AUC_0-12, respectively. A dose of eliglustat 84 mg once daily should be considered 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 of moderate CYP2D6 inhibitors (e.g. duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone) would increase eliglustat exposure approximately up to 4-fold. Caution should be used with moderate CYP2D6 inhibitors in IMs and EMs.

In extensive metabolisers (EMs) with mild or moderate hepatic impairment: 3 and 4.4.

In extensive metabolisers (EMs) with severe hepatic impairment: 3.

CYP3A inhibitors

In intermediate (IMs) and extensive metabolisers (EMs):

After repeated 84 mg twice daily doses of eliglustat in non-PMs, concomitant administration with repeated 400 mg once daily doses of ketoconazole, a strong inhibitor of CYP3A, resulted in a 3.8 and 4.3-fold increase in eliglustat C_max and AUC_0-12, respectively; similar effects would be expected for other 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 IMs and EMs.

At 84 mg twice daily dosing with eliglustat in non-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 eliglustat exposure approximately up to 3-fold. Caution should be used with moderate CYP3A inhibitors in IMs and EMs.

In extensive metabolisers (EMs) with mild hepatic impairment: 4.

In extensive metabolisers (EMs) with moderate or severe hepatic impairment: 3.

In poor metabolisers (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 C_max and AUC_0-24 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 C_max and AUC_0-24 of eliglustat 2.4- and 3.0-fold, respectively. Use of a moderate CYP3A inhibitor with eliglustat is not recommended 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 intermediate (IMs) and extensive metabolisers (EMs):

At 84 mg twice daily dosing with eliglustat in non-PMs, it is predicted that the concomitant use of strong or moderate CYP2D6 inhibitors and strong or moderate CYP3A inhibitors would increase C_max and AUC_0-12 up to 17- and 25-fold, respectively_. The use of a strong or moderate CYP2D6 inhibitor concomitantly 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 plasma concentrations 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 of repeated 600 mg once daily doses of rifampicin (a strong inducer of CYP3A as well as the efflux transporter P-gp) resulted in an approximately 85% decrease in eliglustat exposure. After repeated 84 mg twice daily doses of eliglustat in PMs, concomitant administration of repeated 600 mg once daily doses of rifampicin resulted in an approximately 95% decrease in eliglustat exposure. Use of a strong 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

P-gp substrates

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

CYP2D6 substrates

After a single 50 mg dose of metoprolol, a CYP2D6 substrate, concomitant administration of repeated 127 mg twice daily doses of eliglustat resulted in a 1.5- and 2.1-fold increase in metoprolol C_max 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).

Pregnancy

There are no or limited amount of data from the use of eliglustat in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is recommended to avoid the use of Cerdelga during pregnancy.

Breast-feeding

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

Fertility

Effects on testes and reversible inhibition of spermatogenesis were observed in rats. The relevance of these findings for humans is not known.

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

Summary of the safety profile

The majority of adverse reactions are mild and transient. The most frequently reported adverse reaction with Cerdelga is dyspepsia, in approximately 6% of the patients. About 2% of patients receiving Cerdelga in clinical trials permanently discontinued treatment due to any adverse reaction.

The most frequently reported serious adverse reaction in clinical studies was syncope (0.8%). All events were associated with predisposing risk factors and appeared to be vasovagal in nature. None of these events led to discontinuation from the study.

Tabulated list of adverse reactions

The overall adverse reaction profile of Cerdelga is based on 1400 patient-years of treatment exposure and pooled results from the primary analysis periods and extension periods of two pivotal Phase 3 studies (ENGAGE and ENCORE), one 8-year, long term Phase 2 study (Study 304) and one supporting Phase 3b study (EDGE). In these four studies a total of 393 patients between the ages of 16-75 years received eliglustat for a median duration of 3.5 years (up to 9.3 years).

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)]). All adverse reactions reported in >2% of the patients are presented in Table 1.Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Tabulated list of adverse reactions

A cut-off of >2% was applied

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed below:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

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

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

Pharmacotherapeutic group: Other alimentary tract and metabolism products, Various alimentary tract and metabolism products, ATC code: A16AX10.

Mechanism of action

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

Pharmacodynamic effects

In clinical trials in treatment-naïve GD1 patients, plasma GL-1 levels were elevated in the majority of these patients and decreased upon Cerdelga treatment. Additionally, in a clinical trial in GD1 patients stabilised on enzyme replacement therapy (ERT) (i.e. having already achieved therapeutic goals on ERT prior to initiating Cerdelga treatment), plasma GL-1 levels were normal in most patients and decreased upon Cerdelga treatment.

Clinical efficacy and safety

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

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

Study 02507 was a randomized, double-blind, placebo-controlled, multicenter clinical study in 40 patients with GD1. In the Cerdelga group 3 (15%) patients received a starting dose of 42 mg eliglustat twice daily during the 9-month primary analysis period and 17 (85%) patients received a dose escalation to 84 mg twice daily based on plasma trough concentration.

Table 2: Change from baseline to Month 9 (primary analysis period) in treatment-naïve patients with GD1 receiving treatment with Cerdelga in study 02507

MN = Multiples of Normal, CI = confidence interval

^a At baseline, mean spleen volumes were 12.5 and 13.9 MN in the placebo and Cerdelga groups, respectively, and mean liver volumes were 1.4 MN for both groups. Mean haemoglobin levels were 12.8 and 12.1 g/dL, and platelet counts were 78.5 and 75.1 x 10⁹/L, respectively.

^b Estimates and p-values are based on an ANCOVA model

* All patients transitioned to Cerdelga treatment after Month 9.

During the open-label long term treatment period with Cerdelga (extension phase), all patients with complete data who continued to receive Cerdelga showed further improvements throughout the extension phase. Results (change from baseline) after 18 months, 30 months and 4.5 years of exposure to Cerdelga on the following endpoints were: absolute change in haemoglobin level (g/dL) 1.1 (1.03) [n=39], 1.4 (0.93) [n=35], and 1.4 (1.31) [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, multicenter study of Cerdelga in 26 patients. Nineteen patients completed 4 years of treatment. Fifteen (79%) of these patients received a dose escalation to 84 mg eliglustat twice daily; 4 (21%) patients continued to receive 42 mg twice daily.

Eighteen patients completed 8 years of treatment. One patient (6%) received a further dose escalation to 127 mg twice daily. Fourteen (78%) continued on 84 mg Cerdelga twice daily. Three (17%) patients continued to receive 42 mg twice daily. Sixteen patients had an efficacy endpoint assessment at year 8.

Cerdelga showed sustained improvements in organ volume and haematological parameters over the 8 year treatment period (see Table 3).

Table 3: Change from baseline to year 8 in study 304

MN = Multiples of Normal

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

Study 02607 was a randomized, open-label, active-controlled, non-inferiority, multicenter clinical study in 159 patients previously stabilised with ERT. In the Cerdelga group 34 (32%) patients received a dose escalation to 84 mg eliglustat twice daily and 51 (48%) to 127 mg twice daily during the 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, Cerdelga met the criteria set in this study to be declared non-inferior to Cerezyme (imiglucerase) in maintaining patient stability. After 12 months of treatment, the percentage of patients meeting the primary composite endpoint (composed of all four components mentioned in Table 4) was 84.8% [95% confidence interval 76.2% - 91.3%] for the Cerdelga group compared to 93.6% [95% confidence interval 82.5% - 98.7 %] for the Cerezyme group. Of the patients who did not meet stability criteria for the individual components, 12 of 15 Cerdelga patients and 3 of 3 Cerezyme patients remained within therapeutic goals for GD1.

There were no clinically meaningful differences between groups for any of the four individual disease parameters (see Table 4).

Table 4: Changes from baseline to Month 12 (primary analysis period) in patients with GD1 switching to Cerdelga in study 02607

MN = Multiples of Normal, CI = confidence interval

* Excludes patients with a total splenectomy.

** All patients transitioned to Cerdelga treatment after 52 weeks

^a The stability criteria based on changes between baseline and 12 months: haemoglobin level ≤1.5 g/dL 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 Cerdelga (extension phase) the percentage of patients 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 of extension 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 count remained stable through 4 years (see Table 5).

Table 5: Changes from Month 12 (primary analysis period) to Month 48 in patients with GD1 in the Long Term Treatment Period on Cerdelga in study 02607

MN = Multiples of Normal, CI = confidence interval

* Excludes patients with a total splenectomy.

a Cerezyme/Cerdelga - Originally Randomized to Cerezyme

b Cerdelga - Originally Randomized to Cerdelga

Clinical experience in CYP2D6 poor metabolisers (PMs) and ultra-rapid metabolisers (URMs)

There is limited experience with Cerdelga treatment of patients who are PMs or URMs. In the primary analysis periods of the three clinical studies, a total of 5 PMs and 5 URMs were treated with Cerdelga. All PMs received 42 mg eliglustat twice daily, and four of these (80%) had an adequate clinical response. The majority of URMs (80%) received a dose escalation to 127 mg eliglustat twice daily, all of which had adequate clinical responses. The one URM who received 84 mg twice daily did not have an adequate response.

The predicted exposures with 84 mg eliglustat once daily in patients who are PMs are expected to be similar to exposures observed with 84 mg eliglustat twice daily in CYP2D6 intermediate metabolisers (IMs). Patients who are URMs may not achieve adequate concentrations to achieve a therapeutic effect. No dosing recommendation for URMs can be given.

Effects on skeletal pathology

After 9 months of treatment, in Study 02507, bone marrow infiltration by Gaucher cells, as determined by the total Bone Marrow Burden (BMB) score (assessed by MRI in lumbar spine and femur) decreased by a mean of 1.1 points in Cerdelga treated patients (n=19) compared to no change in patients receiving placebo (n=20). Five Cerdelga-treated patients (26%) achieved a reduction of at least 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) and 2.7 (n=15), respectively for the patients originally randomised to Cerdelga, compared to a mean decrease of 1 point (n=20) and 0.8 (n=16) in those originally randomised to placebo.

After 18 months of Cerdelga 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 further increased 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 during at least 8 years of treatment with Cerdelga.

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

Electrocardiographic evaluation

No clinically significant QTc prolonging effect of eliglustat was observed for single doses up to 675 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 healthy subjects. 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 below 10 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 the predicted human C_max 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.

Paediatric population

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Absorption

Median time to reach maximum plasma concentrations occurs between 1.5 to 3 hours after dosing, with low oral bioavailability (<5%) due to significant first-pass metabolism. Eliglustat is a substrate of the efflux transporter P-gp. Food does not have a clinically relevant effect on eliglustat pharmacokinetics. Following repeated dosing of eliglustat 84 mg twice daily, steady state was reached by 4 days, with an accumulation ratio of 3-fold or less. Oral dosing of 84 mg eliglustat once daily has not been studied in CYP2D6 poor metabolisers (PMs).

Distribution

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

Biotransformation

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 octanoyl moiety followed by oxidation of the 2,3-dihydro-1,4-benzodioxane moiety, or a combination of the two pathways, resulting in multiple oxidative metabolites.

Elimination

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

Characteristics in specific groups

CYP2D6 phenotype

Population pharmacokinetic analysis shows that the CYP2D6 predicted phenotype based on genotype is the most important factor affecting pharmacokinetic variability. Individuals with a CYP2D6 poor metaboliser predicted phenotype (approximately 5 to 10% of the population) exhibit higher eliglustat concentrations 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 or no impact on the pharmacokinetics of eliglustat.

Hepatic Impairment:

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

After repeated 84 mg twice daily doses of Cerdelga, C_max and AUC_0-12 are predicted to be 2.4- and 2.9-fold higher in CYP2D6 extensive metabolisers (EMs) with mild hepatic impairment and 6.4- and 8.9-fold higher in CYP2D6 extensive metabolisers (EMs) with moderate hepatic impairment compared to healthy CYP2D6 extensive metabolisers (EMs).

After repeated 84 mg once daily doses of Cerdelga, C_max and AUC_0-24 are predicted to be 3.1- and 3.2 -fold higher in CYP2D6 extensive metabolisers (EMs) with moderate hepatic impairment compared to healthy CYP2D6 extensive metabolisers (EMs ) receiving Cerdelga 84 mg twice daily.

Steady state PK exposure could not be predicted in CYP2D6 intermediate metabolisers (IMs) and poor metabolisers (PMs) with mild and moderate hepatic impairment due to limited or no single-dose data. The effect of severe hepatic impairment was not studied in subjects with any CYP2D6 phenotype.

Renal Impairment:

Effect of severe renal impairment was evaluated in a single dose phase 1 study. After a single 84 mg dose, eliglustat C_max and AUC were similar in CYP2D6 extensive metabolisers (EMs) with severe renal impairment and healthy CYP2D6 extensive metabolisers (EMs).

Limited or no data were available in patients with ESRD and in CYP2D6 intermediate metabolisers (IMs) or poor metabolisers(PMs) with severe renal impairment.

The principal target organs for eliglustat in toxicology studies are the GI tract, lymphoid organs, the liver in rat only and, in the male rat only, the reproductive system. Effects of eliglustat in toxicology studies were reversible and exhibited no evidence of delayed or recurring toxicity. Safety margins for the 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 CNS or respiratory functions. Concentration-dependent cardiac effects were observed in nonclinical studies: inhibition of human cardiac ion channels, including potassium, sodium, and calcium, at concentrations > 7-fold of predicted human C_max; sodium ion channel-mediated effects in an ex-vivo electrophysiology study in dog Purkinje fibres (2-fold of predicted human unbound plasma C_max); and increases in QRS and PR intervals in dog telemetry and cardiac conduction studies in anaesthesised dogs, with effects seen at concentrations 14-fold of predicted human total plasma C_max, or 2-fold of predicted human unbound plasma C_max.

Eliglustat was not mutagenic in a standard battery of genotoxicity tests and did not show any carcinogenic potential in standard lifetime bioassays in mice and rats. Exposures in the carcinogenicity studies were approximately 4-fold and 3-fold greater in mice and rats, respectively, than the mean predicted 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 human exposure based on AUC, a systemically toxic dose. In rat repeated dose toxicity studies, seminiferous epithelial degeneration and segmental hypoplasia of the testes was seen at 10-fold of predicted human exposure 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 during 24 hours post-dose, indicating milk excretion of eliglustat and/or its related materials.

Capsule contents:

Microcrystalline cellulose

Lactose monohydrate

Hypromellose

Glycerol dibehenate

Capsule shell:

Gelatin

Potassium aluminium silicate (E555)

Titanium dioxide (E171)

Yellow iron oxide (E172)

Indigotine (E132)

Printing ink:

Shellac glaze

Black iron oxide (E172)

Propylene glycol

Ammonium hydroxide 28%

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

PETG/COC.PETG/PCTFE-aluminium blister

Each blister wallets contains 14 hard capsules.

Each pack contains 14, 56 or 196 hard capsules.

Not all pack sizes may be marketed.

Any unused product or waste material should be disposed of in accordance with local requirements.

Genzyme Europe B.V., Gooimeer 10, 1411DD, Naarden, The Netherlands

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

08 June 2018