4.1. Therapeutic indications

Adults

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 minimum body weight of 15 kg, who are stable on enzyme replacement therapy (ERT), and who are CYP2D6 PMs, IMs or 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.

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) or indeterminate metabolisers (see section 4.4).

Posology

Adults

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 daily

25 to <50 kg

84 mg twice daily

42 mg once daily

15 to <25 kg

42 mg twice daily

21 mg once daily

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

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

Elderly

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

Patients with hepatic impairment

Table 2: Patients with hepatic impairment

CYP2D6 metaboliser type

Hepatic Impairment

Inhibitors

Dose Adjustment

EM

Mild (Child-Pugh Class A)

Eliglustat alone

No dose adjustment required

Moderate (Child-Pugh Class B)

Eliglustat alone

Not recommended (see section 5.2)

Severe (Child-Pugh Class C)

Eliglustat alone

Eliglustat + Any CYP inhibitor

Contraindicated (see sections 4.3 and 5.2)

Mild (Child-Pugh Class A) or moderate (Child-Pugh Class B)

Eliglustat + strong or moderate inhibitor of CYP2D6

Contraindicated (see sections 4.3 and 5.2)

Mild (Child-Pugh Class A)

Eliglustat + weak inhibitor of CYP2D6; or strong, moderate or weak inhibitor of CYP3A

Once daily dose should be considered (see sections 4.4 and 5.2)

IM or PM

Any

N/A

Not recommended (see section 5.2)

Patients with renal impairment

Table 3: Patients with renal impairment

CYP2D6 metaboliser type

Renal Impairment

Dose Adjustment

EM

Mild, moderate or severe

No dose adjustment required (see sections 4.4 and 5.2)

End stage renal disease (ESRD)

Not recommended (see sections 4.4 and 5.2)

IM or PM

Mild, moderate or severe, or ESRD

Not recommended (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. There are no data to support the use of eliglustat in children weighing less than 15 kg. Currently available data are described in section 5.1.

Method of administration

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

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

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

4.3. Contraindications

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 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

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 and concomitant use with other medicinal products

Concomitant use of eliglustat with CYP2D6 or CYP3A4 inhibitors in CYP2D6 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 EMs with mild hepatic impairment taking a weak CYP2D6 inhibitor or strong, moderate or weak CYP3A inhibitor, a once daily dose is recommended (e.g. if a dose of 84 mg eliglustat is taken twice daily, it should be adjusted to 84 mg eliglustat once daily) (see sections 4.2 and 5.2).

Patients with renal impairment

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 not recommended (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 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 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 these conditions 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 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. Once a day dosing of eliglustat for EMs and 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 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.

CYP2D6 inhibitors in EMs with mild or moderate hepatic impairment

See sections 4.2, 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 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.

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 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 IMs and 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 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 may affect the ability to drive and use machines in patients who experience dizziness after its administration.

4.8. Undesirable effects

Summary of the safety profile

The most frequently reported adverse reaction with eliglustat is dyspepsia, reported in approximately 6% of the pooled adult clinical trial patients, and in 10.5% (for both cohorts) of paediatric patients from the ELIKIDS study. Overall, the safety profile of eliglustat in paediatric patients observed in clinical development setting was consistent with the established safety profile in adults.

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 4. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 4: 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, cough

Gastrointestinal disorders

Dyspepsia, abdominal pain upper*, diarrhoea*, nausea, constipation, abdominal pain*, gastroesophageal 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 eliglustat in the placebo-controlled pivotal study.

Paediatric population

In the ELIKIDS paediatric study Cohort 1 (eliglustat monotherapy), the most common adverse reactions were dyspepsia (9.8%) and dry skin (3.6%). In Cohort 2 (eliglustat/imiglucerase combination therapy), the most common adverse reactions were headache, dyspepsia, gastritis, and fatigue (each experienced 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 by age group, gender, or GD type. No patients permanently discontinued treatment due to TEAE.

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

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.