Cerdelga - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Cerdelga 84 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipient(s) with known effect:

Each capsule contains 106 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule

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 × 6.4 mm).

4. CLINICAL PARTICULARS4.1 Therapeutic indications

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).

4.2 Posology and method of administration

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).

Missed dose

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

Special populations

CYP2D6 ultra-rapid metabolisers (URMs) and indeterminate metabolisers

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

Patients with hepatic impairment

In CYP2D6 extensive metabolisers (EMs) with severe (Child-Pugh class C) hepatic impairment, eliglustat is contraindicated (see sections 4.3 and 5.2).

In CYP2D6 extensive metabolisers (EMs) with moderate hepatic impairment (Child-Pugh class B), eliglustat is not recommended (see sections 4.4 and 5.2).

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, eliglustat is not recommended (see sections 4.4 and 5.2).

In CYP2D6 extensive metabolisers (EMs) with mild or moderate hepatic impairment taking a strong or moderate CYP2D6 inhibitor, Cerdelga is contraindicated (see sections 4.3 and 5.2).

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 (see sections 4.4 and 5.2).

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 (see sections 4.4 and 5.2).

In CYP2D6 EMs with end stage renal disease (ESRD), eliglustat is not recommended (see sections 4.4 and 5.2).

In CYP2D6 intermediate metabolisers (IMs) or poor metabolisers (PMs) with mild, moderate or severe renal impairment or ESRD, eliglustat is not recommended (see sections 4.4 and 5.2).

Elderly

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

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.

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

4.3 Contraindications

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

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 (see section 4.4 and 4.5).

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 (see sections 4.2 and 5.2).

4.4 Special warnings and precautions for use

Initiation of therapy: CYP2D6 genotyping

Before initiation of treatment with Cerdelga, patients should be genotyped for CYP2D6 to determine the CYP2D6 metaboliser status (see section 4.2, Special populations).

Drug-drug interactions

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 (see section 4.3).

For use of eliglustat with one strong or moderate inhibitor of CYP2D6 or CYP3A, see section 4.5.

Use of eliglustat with strong CYP3A inducers substantially decreases the exposure to eliglustat, which may reduce the therapeutic effectiveness of eliglustat; therefore concomitant administration is not recommended (see section 4.5).

Patients with pre-existing cardiac conditions

Use of eliglustat 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 eliglustat 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 eliglustat in these patients is not recommended (see sections 4.2. and 5.2).

Limited or no data are available in CYP2D6 intermediate metabolisers (IMs) or poor metabolisers (PMs) with any degree of hepatic impairment. Use of eliglustat in these patients is not recommended (see sections 4.2 and 5.2).

Concomitant use of eliglustat 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 (see sections 4.2 and 5.2).

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 eliglustat in these patients is not recommended (see sections 4.2 and 5.2).

Monitoring of clinical response

Some treatment-naive 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 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, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

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.

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 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 (see section 4.3). 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 Cmax and AUC0–12, 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: see sections 4.2, 4.3 and 4.4.

In extensive metabolisers (EMs) with severe hepatic impairment: see sections 4.2 and 4.3.

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 Cmax and AUC0–12, 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: see sections 4.2 and 4.4.

In extensive metabolisers (EMs) with moderate or severe hepatic impairment: see sections 4.2 and 4.3.

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 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 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 Cmax and AUC0–12 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 Cmax and AUClast, 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 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).

4.6 Fertility, pregnancy and lactation

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 (see section 5.3). 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 (see section 5.3). 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 (see section 5.3). The relevance of these findings for humans is not known.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

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).

The most frequently reported adverse reaction with Cerdelga is dyspepsia, in approximately 6% of the clinical trial patients.

Tabulated list of adverse reactions

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 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

System Organ Class	Common
Nervous system disorders	Headache*, dizziness*, dysgeusia
Cardiac disorders	Palpitations
Respiratory, thoracic and mediastinal disorders	Throat irritation
Gastrointestinal disorders	Dyspepsia, abdominal pain upper*, diarrhoea*, nausea, constipation, abdominal pain*, gastrooesophageal reflux disease, abdominal distension*, gastritis, dysphagia, vomiting*, dry mouth, flatulence
Skin and subcutaneous tissue disorders	Dry skin, urticaria*
Musculoskeletal and connective tissue disorders	Arthralgia, pain in extremity*, back pain*
General disorders and administration site conditions	Fatigue

• * 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 in

4.9 Overdose

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.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

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-naive GDI 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 (see section 4.2) 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-naive GDI 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-naive patients with GD1 receiving treatment with Cerdelga in study 02507

	Placebo* (n=20) a	Cerdelga (n=20) a	Difference (Cerdelga -Placebo) [95% CI]	p valueb
Percentage Change in Spleen Volume MN (%) (primary endpoint)	2.26	–27.77	–30.0 [-36.8, –23.2]	<0.0001
Absolute Change in Haemoglobin Level (g/dL) (secondary endpoint)	–0.54	0.69	1.22 [0.57, 1.88]	0.0006
Percentage Change in Liver Volume MN (%) (secondary endpoint)	1.44	–5.20	–6.64 [-11.37, –1.91]	0.0072
Percentage Change in Platelet Count (%) (secondary endpoint)	–9.06	32.00	41.06 [23.95, 58.17]	<0.0001

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 × 109/L, respectively.

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

5.2 Pharmacokinetic properties

Absorption

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 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 in non-PMs and once daily in PMs, steady state was reached by 4 days, with an accumulation ratio of 3-fold or less.

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 Cmax 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, Cmax and AUC0–12 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, Cmax and AUC0–24 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 (see sections 4.2 and 4.4).

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 (see sections 4.2, 4.3 and 4.4).

Renal impairment:

Effect of severe renal impairment was evaluated in a single dose phase 1 study. After a single 84 mg dose, eliglustat Cmax 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 (see sections 4.2 and 4.4).

5.3 Preclinical safety data

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 Cmax; sodium ion channel-mediated effects in an ex-vivo electrophysiology study in dog Purkinje fibres (2-fold of predicted human unbound plasma Cmax); 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 Cmax, or 2-fold of predicted human unbound plasma Cmax.

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.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

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

Black iron oxide (E172)

Propylene glycol

Ammonia solution, concentrated

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

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.

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

Genzyme Europe B.V., Paasheuvelweg 25, 1105 BP Amsterdam, The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/974/001 56 capsules

EU/1/14/974/0­02 196 capsules

EU/1/14/974/003 14 capsules

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19 January 2015

Date of latest renewal: 16 December 2019