CERDELGA Hard capsule Ref.[8493] Active ingredients: Eliglustat

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-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.

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 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: 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 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: 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 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 (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.

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

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:

Nervous system disorders

Common: Headache*, dizziness*, dysgeusia

Cardiac disorders

Common: Palpitations

Respiratory, thoracic and mediastinal disorders

Common: Throat irritation

Gastrointestinal disorders

Common: 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

Common: Dry skin, urticaria*

Musculoskeletal and connective tissue disorders

Common: Arthralgia, pain in extremity*, back pain*

General disorders and administration site conditions

Common: 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 Appendix V.

Not applicable.