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 in adults is based on the patient's CYP2D6 metabolizer status.

2.3 Dosage Adjustment in EMs and IMs With or Without Hepatic Impairment and Concomitant Use of CYP2D6 or CYP3A Inhibitors

Reduce dosage frequency of CERDELGA 84 mg to once daily in CYP2D6 EMs and IMs with or without hepatic impairment taking CYP2D6 or CYP3A inhibitors, as shown in Table 2 [see Warnings and Precautions (5.1), Drug Interactions (7.1), Use in Specific Populations (8.7)].

2.4 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 (strong CYP3A inhibitors) with CERDELGA [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).

EMs

• Taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor [see Drug Interactions (7.1)]
• Moderate or severe hepatic impairment [see Use in Specific Populations (8.7)]
• Mild hepatic impairment and taking a strong or moderate CYP2D6 inhibitor [see Use in Specific Populations (8.7)]

IMs

• Taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor [see Drug Interactions (7.1)]
• Taking a strong CYP3A inhibitor [see Drug Interactions (7.1)]
• Any degree of hepatic impairment [see Use in Specific Populations (8.7)]

PMs

• Taking a strong CYP3A inhibitor [see Drug Interactions (7.1)]
• Any degree of hepatic impairment [see Use in Specific Populations (8.7)]

5.1 ECG Changes and Potential for Cardiac Arrhythmias

CERDELGA is predicted to cause increases in ECG intervals (PR, QTc, and QRS) at substantially elevated eliglustat plasma concentrations and may increase the risk of cardiac arrhythmias.

• Use of CERDELGA is contraindicated, to be avoided, or requires dosage adjustment in patients taking CYP2D6 or CYP3A inhibitors, depending on CYP2D6 metabolizer status, type of inhibitor, or degree of hepatic impairment [see Dosage and Administration (2.3), Contraindications (4), Drug Interactions (7.1)].

Use of CERDELGA in patients with pre-existing cardiac conditions has not been studied during clinical trials. Avoid use of CERDELGA in patients with:

• pre-existing cardiac disease (congestive heart failure, recent acute myocardial infarction, bradycardia, heart block, ventricular arrhythmia)
• long QT syndrome
• in combination with Class IA (e.g., quinidine, procainamide) or 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 [see Clinical Studies (14.1, 14.2)]. Table 3 presents the profile from the 9-month double-blind, randomized, placebo-controlled trial of 40 treatment-naive 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 4 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 a separate uncontrolled study, with up to 4 years of treatment in 26 naive GD1 patients, the types and incidences of adverse reactions were similar to Trials 1 and 2.

7.1 Effect of Other Drugs on CERDELGA

Coadministration of CERDELGA 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 [see Warnings and Precautions (5.1), Clinical Pharmacology (12.3)].
• strong CYP3A inducers decrease eliglustat concentrations which may reduce CERDELGA efficacy [see Clinical Pharmacology (12.3)].

See Table 5 for prevention and management of interactions with drugs affecting CERDELGA. Use of CERDELGA is contraindicated, to be avoided, or may require dosage adjustment depending on the concomitant drug and CYP2D6 metabolizer status [see Dosage and Administration (2.2, 2.3), Contraindications (4), Drug Interactions (7.1)].

7.2 Effect of CERDELGA on Other Drugs

See Table 6 for clinically relevant interactions affecting P-gp or CYP2D6 substrates when coadministered with CERDELGA.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of CERDELGA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Clinical experience has not identified differences in responses between the elderly and younger patients.

8.6 Renal Impairment

Use CERDELGA in patients with renal impairment based on the patient's CYP2D6 metabolizer status [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Use CERDELGA in patients with hepatic impairment based on CYP2D6 metabolizer status and concomitant use of CYP2D6 or CYP3A inhibitors [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Gaucher disease is caused by a deficiency of the lysosomal enzyme acid β-glucosidase. Acid β-glucosidase catalyzes the conversion of the sphingolipid glucocerebroside into glucose and ceramide. The enzymatic deficiency causes an accumulation of glucosylceramide (GL-1) primarily in the lysosomal compartment of macrophages, giving rise to foam cells or "Gaucher cells."

The clinical features of this lysosomal storage disorder (LSD) are reflective of the accumulation of Gaucher cells in the reticuloendothelial system (liver, spleen, bone marrow, and other organs). The accumulation of Gaucher cells in the liver, spleen, and bone marrow leads to organomegaly and skeletal disease. Presence of Gaucher cells in the bone marrow and spleen leads to clinically significant anemia and thrombocytopenia.

CERDELGA is a specific inhibitor of glucosylceramide synthase (IC50=10 ng/mL) and acts as a substrate reduction therapy for GD1 by reducing the production of GL-1. By reducing GL-1 production, CERDELGA alleviates the accumulation of GL-1 in the target organs.

12.2 Pharmacodynamics

Effects on spleen and liver volume, hemoglobin, and platelets increased with increasing steady-state average trough concentrations of eliglustat ranging up to 14 ng/mL in treatment naive patients in Trial 1. In patients previously treated with enzyme-replacement therapy in Trial 2 [see Clinical Studies (14.2)], no clinically relevant exposure-response relationship was observed.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 CERDELGA in Treatment-Naive GD1 Patients – Trial 1

Trial 1 (NCT00891202) was a randomized, double-blind, placebo-controlled, multicenter clinical study evaluating the efficacy and safety of CERDELGA in 40 treatment- naive GD1 patients 16 years of age or older (median age 30.4 years) with pre-existing splenomegaly and hematological abnormalities. Patients were required to have received no treatment with substrate reduction therapy within 6 months or ERT within 9 months prior to randomization; all but 5 patients in the study had no prior therapy. Patients were stratified according to baseline spleen volume (≤20 or >20 multiples of normal [MN]) and randomized in a 1:1 ratio to receive CERDELGA or placebo for the duration of the 9-month blinded primary analysis period. The CERDELGA treatment group was comprised of IM (5%), EM (90%) and URM (5%) patients. Patients randomized to CERDELGA treatment received a starting dose of 42 mg twice daily, with a dose increase to 84 mg twice daily possible at Week 4 based on the plasma trough concentration at Week 2. The majority of patients (17 [85%]) received a dose escalation to 84 mg twice daily at Week 4, and 3 (15%) continued to receive 42 mg twice daily for the duration of the 9-month blinded primary analysis period.

The primary endpoint was the percentage change in spleen volume (in MN) from baseline to 9 months as compared to placebo. Secondary endpoints were absolute change in hemoglobin level, percentage change in liver volume (in MN), and percentage change in platelet count from baseline to 9 months compared to placebo.

At baseline, mean spleen volumes were 12.5 and 13.9 MN in the placebo and CERDELGA groups, respectively, and mean liver volumes were 1.4 MN for both groups. Mean hemoglobin levels were 12.8 and 12.1 g/dL, and platelet counts were 78.5 and 75.1 × 109/L, respectively.

During the 9-month primary analysis period, CERDELGA demonstrated statistically significant improvements in all primary and secondary endpoints compared to placebo, as shown in Table 10.

In the open-label extension phase of Trial 1 in naive GD1 patients, 38 of 40 patients who continued treatment with CERDELGA for 2 years demonstrated the following changes in clinical parameters from baseline to 2 years: mean (SD) percent change in spleen volume (MN) -51.1% (10.7); mean (SD) percent change in liver volume (MN) -16.1% (11.3); mean (SD) absolute change in hemoglobin level (g/dL) 1.3 (1.2), and mean (SD) percent change in platelet count (mm3) 65.3% (40.9).

In a separate uncontrolled study (NCT00358150) of treatment-naive GD1 patients, improvements in spleen and liver volume, hemoglobin level, and platelet count continued through the 4-year treatment period.

14.2 Patients Switching from Enzyme Replacement Therapy to CERDELGA – Trial 2

Trial 2 (NCT00943111) was a randomized, open-label, active-controlled, non- inferiority, multicenter clinical study evaluating the efficacy and safety of CERDELGA compared with imiglucerase in 159 treated GD1 patients (median age 37.4 years) previously treated with enzyme replacement therapy (≥3 years of enzyme replacement therapy, dosed at 30–130 U/kg/month in at least 6 of the prior 9 months) who met pre-specified therapeutic goals at baseline. Pre-specified baseline therapeutic goals included: no bone crisis and free of symptomatic bone disease within the last year; mean hemoglobin level of ≥11 g/dL in females and ≥12 g/dL in males; mean platelet count ≥100,000/mm3; spleen volume <10 times normal and liver volume <1.5 times normal.

Patients were randomized 2:1 to receive CERDELGA or imiglucerase for the duration of the 12-month primary analysis period. Seventy-five percent of patients randomized to CERDELGA were previously treated with imiglucerase; 21% with velaglucerase alfa and 4% were unreported. Patients randomized to CERDELGA treatment received a starting dose of 42 mg twice daily, with dose increases to 84 mg twice daily and 127 mg twice daily possible at Weeks 4 and 8 based on plasma trough concentrations of CERDELGA at Weeks 2 and 6, respectively. The percentage of patients receiving the 3 possible CERDELGA doses was: 42 mg twice daily (20%), 84 mg twice daily (32%) and 127 mg twice daily (48%). The CERDELGA treatment group was comprised of PM (4%), IM (10%), EM (80%) and URM (4%) patients.

At baseline, mean spleen volumes were 2.6 and 3.2 MN in the imiglucerase and CERDELGA groups, respectively, and liver volumes were 0.9 MN in both groups. Mean hemoglobin levels were 13.8 and 13.6 g/dL, and platelet counts were 192 and 207 × 109/L, respectively.

The primary composite endpoint required stability in all four component domains (hemoglobin level, platelet count, liver volume, and spleen volume) based on changes between baseline and 12 months. Stability was defined by the following pre-specified thresholds of change: hemoglobin level <1.5 g/dL decrease, platelet count <25% decrease, liver volume <20% increase and spleen volume <25% increase. The percentages of patients meeting the criteria for stability in the individual components of the composite endpoint were assessed as secondary efficacy endpoints.

CERDELGA met the criteria to be declared non-inferior to imiglucerase in maintaining patient stability. After 12 months of treatment, the percentage of patients meeting the primary composite endpoint was 84.8% for the CERDELGA group compared to 93.6% for the imiglucerase group. The lower bound of the 95% CI of the 8.8% difference, -17.6%, was within the pre-specified non-inferiority margin of -25%. At Month 12, the percentages of CERDELGA and imiglucerase patients respectively, who met stability criteria for the individual components of the composite endpoint were: hemoglobin level, 94.9% and 100%; platelet count, 92.9% and 100%; spleen volume, 95.8% and 100%; and liver volume, 96.0% and 93.6%. Of the patients who did not meet stability criteria for the individual components, 12 of 15 CERDELGA patients and 3 of 3 imiglucerase patients remained within therapeutic goals for GD1.

Mean changes from baseline in the hematological and visceral parameters through 12 months of treatment are shown in Table 11. There were no clinically meaningful differences between groups for any of the four parameters.

In the open-label extension phase of Trial 2, 141 of 146 patients (42 patients previously treated with enzyme treatment therapy and 99 who continued treatment with CERDELGA) were evaluated for stability, as defined in the initial 12 months of the trial, in clinical parameters (composite of spleen and liver volume, hemoglobin level, and platelet count). Stability was shown in 120/141 (85%) patients at one year and 111/129 (86%) patients at 2 years of CERDELGA exposure.

Store at 68°F–77°F (20°C–25°C) with excursions permitted between 59°F and 86°F (15°C to 30°C) [see USP Controlled Room Temperature].

Drug Interactions

Advise patients to discuss all the medications they are taking, including any herbal supplements or vitamins with their healthcare provider [see Contraindications (4), Warnings and Precautions (5), Drug Interactions (7)].

ECG Changes and Potential for Cardiac Arrhythmias

Advise patients to inform their healthcare provider of the following: history of congestive heart failure; recent acute myocardial infarction; bradycardia; heart block; ventricular arrhythmia; and long QT syndrome [see Warnings and Precautions (5.1)].

Advise patients to inform their healthcare provider if they develop new symptoms such as palpitations, fainting, and dizziness.

Administration Instructions

[See Dosage and Administration (2.4).]

Advise patients:

• Swallow capsules whole, preferably with water, and do not crush, dissolve, or open the capsules.
• CERDELGA can be taken with or without food.
• If a dose of CERDELGA is missed, take the prescribed dose at the next scheduled time; do not double the next dose.
• Avoid consumption of grapefruit or its juice.
• 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).