Eliglustat

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

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.

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

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.

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).

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.

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.

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.

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.

In intermediate (IMs) and extensive metabolisers (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 poor metabolisers (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.

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.

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.

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

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.

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 eliglustat during pregnancy.

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 eliglustat 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.

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