Limitations of Use:

• Patients who are CYP2D6 ultra-rapid metabolizers (URMs) may not achieve adequate concentrations of CERDELGA to achieve a therapeutic effect [see Clinical Studies (14)].
• A specific dosage cannot be recommended for those patients whose CYP2D6 genotype cannot be determined (indeterminate metabolizers) [see Clinical Studies (14)].

2.1 Patient Selection

Select patients with Gaucher disease type 1 based on their CYP2D6 metabolizer status. It is recommended patient genotypes be established using an FDA-cleared test for determining CYP2D6 genotype [see Indications and Usage (1)].

2.2 Recommended Adult Dosage

The recommended dosage of CERDELGA is 84 mg twice daily in CYP2D6 EMs and IMs. The recommended dosage in CYP2D6 PMs is 84 mg once daily; appropriate adverse event monitoring is recommended [see Adverse Reactions (6.1)]. The predicted exposures with 84 mg once daily in patients who are CYP2D6 PMs are expected to be similar to exposures observed with 84 mg twice daily in CYP2D6 IMs [see Clinical Pharmacology (12.3)].

Some inhibitors of CYP2D6 and CYP3A are contraindicated with CERDELGA depending on the patient's metabolizer status [see Contraindications (4)]. Co-administration of CERDELGA with other CYP2D6 and CYP3A inhibitors may require dosage adjustment depending on the patient's CYP2D6 metabolizer status to reduce the risk of potentially significant adverse reactions [see Table 3 and Table 4 in Drug Interactions (7.1)].

Reduce the dosage of CERDELGA to 84 mg once daily for:

• CYP2D6 EMs and IMs taking strong or moderate CYP2D6 inhibitors
• CYP2D6 EMs taking strong or moderate CYP3A inhibitors

2.3 Important Administration Instructions

• Swallow capsules whole, preferably with water, and do not crush, dissolve, or open the capsules.
• CERDELGA can be taken with or without food.
• Avoid the consumption of grapefruit or grapefruit juice with CERDELGA because grapefruit is a strong CYP3A inhibitor [see Drug Interactions (7.1)].
• If a dose of CERDELGA is missed, take the prescribed dose at the next scheduled time; do not double the next dose.
• For patients currently treated with imiglucerase, velaglucerase alfa, or taliglucerase alfa, CERDELGA may be administered 24 hours after the last dose of the previous enzyme replacement therapy (ERT).

5.1 Drug-Drug Interactions

Eliglustat is a CYP2D6 and CYP3A substrate. Drugs that inhibit CYP2D6 and CYP3A metabolism pathways may significantly increase the exposure to eliglustat and result in prolongation of the PR, QTc, and/or QRS cardiac intervals that could result in cardiac arrhythmias [see Clinical Pharmacology (12.2)]. Some drugs that are inhibitors of CYP2D6 and CYP3A are contraindicated with CERDELGA depending on the patient's CYP2D6 metabolizer status [see Contraindications (4)]. See Table 3 and Table 4 for other potentially significant drug interactions [see Drug Interactions (7.1)].

5.2 ECG Changes and Potential for Cardiac Arrhythmias

Use of CERDELGA in patients with pre-existing cardiac conditions has not been studied during clinical trials. Because CERDELGA is predicted to cause increases in ECG intervals (PR, QTc, and QRS) at substantially elevated eliglustat plasma concentrations, use of CERDELGA is not recommended in patients with pre-existing 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, procainamide) and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications [see Clinical Pharmacology (12.2)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reactions to CERDELGA (occurring in ≥10% of the 126 GD1 patients treated with CERDELGA across Trials 1 and 2) were fatigue, headache, nausea, diarrhea, back pain, pain in extremities, and upper abdominal pain.

The adverse reaction profile of CERDELGA is based on two controlled studies, Trials 1 and 2. Table 1 presents the profile from the 9-month double-blind, randomized, placebo-controlled trial of 40 treatment-naïve patients (Trial 1). Patients were between the ages of 16 and 63 on the date of the first dose of study drug, and included 20 males and 20 females.

Table 2 presents the profile from the 12-month open-label, randomized, imiglucerase-controlled trial of 159 treated patients switching from enzyme replacement therapy (ERT) (Trial 2). Patients were between the ages of 18 and 69 on the date of the first dose of CERDELGA, and included 87 females and 72 males.

In an uncontrolled study, with up to 4 years of treatment, in 26 patients, the types and incidences of adverse reactions were similar to Trials 1 and 2.

7.1 Potential for Other Drugs to Affect CERDELGA

Eliglustat is a CYP2D6 and CYP3A substrate.

7.2 Potential for CERDELGA to Affect Other Drugs

Eliglustat is an inhibitor of P-gp and CYP2D6. Co-administration of CERDELGA with drugs that are substrates for P-gp or CYP2D6 may result in increased concentrations of the concomitant drug as shown in Table 5.