This section contains excerpted ¹ information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

2018 Statement from the US Food and Drug Administration (FDA):

The recommended dosage of Eliglustat in adults is based on the patient's CYP2D6 metabolizer status.

[…]

Reduce dosage frequency of Eliglustat 84 mg to once daily in CYP2D6 NMs and IMs with or without hepatic impairment taking CYP2D6 or CYP3A inhibitors.

Table [5] : Recommended Dosage of Eliglustat: 84 mg Once Daily based on CYP2D6 Metabolizer, Hepatic Impairment Status, and Concomitant CYP Inhibitors

4 CONTRAINDICATIONS

Eliglustat is contraindicated in the following patients based on CYP2D6 metabolizer status due to the risk of cardiac arrhythmias from prolongation of the PR, QTc, and/or QRS cardiac intervals.

NMs

• Taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor
• Moderate or severe hepatic impairment
• Mild hepatic impairment and taking a strong or moderate CYP2D6 inhibitor

IMs

• Taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor
• Taking a strong CYP3A inhibitor Any degree of hepatic impairment

PMs

• Taking a strong CYP3A inhibitor
• Any degree of hepatic impairment

7 DRUG INTERACTIONS

7.1 Effect of other drugs on Eliglustat

Coadministration of Eliglustat with:

• CYP2D6 or CYP3A inhibitors may increase eliglustat concentrations which may increase the risk of cardiac arrhythmias from prolongation of the PR, QTc, and/or QRS cardiac interval.
• strong CYP3A inducers decreases eliglustat concentrations which may reduce efficacy.

Table [6] : Prevention and Management Strategies of Drug Interactions Affecting eliglustat based on CYP2D6 Metabolizer status and Concomitant Interacting drug

8 Use In Specific Populations

8.6 Renal Impairment

Use eliglustat in patients with renal impairment based on the patient's CYP2D6 metabolizer status

NMs

• Avoid eliglustat in patients with end-stage renal disease (ESRD) (estimated creatinine clearance (eCLcr) less than 15 mL/min not on dialysis or requiring dialysis).
• No dosage adjustment is recommended in patients with mild, moderate, or severe renal impairment (eCLcr at least 15 mL/min).

IMs and PMs

Avoid eliglustat in patients with any degree of renal impairment.

8.7 Hepatic Impairment

Use eliglustat in patients with hepatic impairment based on CYP2D6 metabolizer status and concomitant use of CYP2D6 or CYP3A inhibitors

NMs

Eliglustat is contraindicated in patients with [see Contraindications]:

• severe (Child-Pugh Class C) hepatic impairment
• moderate (Child-Pugh Class B) hepatic impairment
• mild (Child-Pugh Class A) hepatic impairment taking a strong or moderate CYP2D6 inhibitor

Reduce dosage frequency of eliglustat 84 mg to once daily [see Dosage and Administration] in patients with mild hepatic impairment taking:

• a weak CYP2D6 inhibitor
• a strong, moderate, or weak CYP3A inhibitor

No dosage adjustment is recommended in patients with mild hepatic impairment, unless otherwise specified above.

IMs and PMs

Eliglustat is contraindicated in patients with any degree of hepatic impairment [see Contraindications].Please review the complete therapeutic recommendations that are located here: (1).

2018 Summary of recommendations from the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP)

CYP2D6 UM:

Eliglustat is contra-indicated.

1. choose an alternative if possible

CYP2D6 IM :

Recommendation:

• Co-medication with BOTH a MODERATE to STRONG CYP2D6 INHIBITOR AND a MODERATE to STRONG CYP3A INHIBITOR: Eliglustat is contra-indicated.
  1. choose an alternative if possible

Strong CYP2D6 inhibitor: for example paroxetine, fluoxetine, quinidine, bupropione. Moderate CYP2D6 inhibitor: for example duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone. Strong CYP3A inhibitor: for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir. Moderate CYP3A inhibitor: for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine.

• Co-medication with a STRONG CYP2D6 INHIBITOR (e.g. paroxetine, fluoxetine, quinidine, bupropione):
  1. use a dose of 84 mg eliglustat 1x daily
• Co-medication with a MODERATE CYP2D6 INHIBITOR (for example duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone):
  1. consider a dose of 84 mg eliglustat 1x daily
  2. be alert to side effects
• Co-medication with a STRONG CYP3A INHIBITOR (for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir):

-1. choose an alternative if possible

• if an alternative is not an option:
• consider a dose of 84 mg eliglustat 1x daily
• be alert to side effects
  • Co-medication with a MODERATE CYP3A INHIBITOR (for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine):
    1. choose an alternative
    2. if an alternative is not an option:
       1. consider a dose of 84 mg eliglustat 1x daily
       2. be alert to side effects
  • Co-medication with a STRONG CYP3A INDUCER (for example rifampicin, carbamazepine, phenobarbital, phenytoin, rifabutine, hypericum): Eliglustat is not recommended. The plasma concentration may decrease so sharply that a therapeutic effect cannot be achieved.
    1. choose an alternative if possible
  • NO co-medication with a moderate or strong CYP2D6 or CYP3A inhibitor or strong CYP3A inducer:
    1. use the standard dose of 84 mg 2x daily

CYP2D6 PM:

Recommendation:

• Co-medication with a STRONG CYP3A INHIBITOR (for example ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir):

Eliglustat is contra-indicated.

1. choose an alternative if possible
   • Co-medication with a MODERATE CYP3A INHIBITOR (for example erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine):

Eliglustat is not recommended.

1. choose an alternative if possible
   • Co-medication with a WEAK CYP3A INHIBITOR (for example amlopidine [amlodipine], cilostazole [cilostazol], fluvoxamine, goldenseal, isoniazide [isoniazid], ranitidine, ranolazine):
     1. choose an alternative for the weak CYP3A inhibitor if possible
     2. if an alternative is not an option:
        1. use a dose of 84 mg eliglustat 1x daily
        2. be alert to side effects
   • Co-medication with a STRONG CYP3A INDUCER (for example rifampicin, carbamazepine, phenobarbital, phenytoin, rifabutine, hypericum):

Eliglustat is not recommended. The plasma concentration may decrease so sharply that a therapeutic effect cannot be achieved.

1. choose an alternative if possible
   • NO co-medication with a CYP3A inhibitor or strong CYP3A inducer:
     1. use a dose of 84 mg 1x daily

Please review the complete therapeutic recommendations that are located here:( 4 ).

¹ The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labeled all formulations containing the generic drug. Certain terms, genes and genetic variants may be corrected in accordance with nomenclature standards, where necessary. We have given the full name of abbreviations, shown in square brackets, where necessary.