Eliglustat

1 INDICATIONS AND USAGE CERDELGA is indicated for the long-term treatment of adult patients with Gaucher disease type 1 (GD1) who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by an FDA-cleared test [see Dosage and Administration (2.1) ] . CERDELGA is a glucosylceramide synthase inhibitor indicated for the long-term treatment of adult patients with Gaucher disease type 1 who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by an FDA-cleared test. ( 1 ) Limitations of Use : CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of CERDELGA to achieve a therapeutic effect. ( 1 ) A specific dosage cannot be recommended for CYP2D6 indeterminate metabolizers. ( 1 ) 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 DOSAGE AND ADMINISTRATION Patient Selection ( 2.1 ) : Select patients using an FDA-cleared test for determining CYP2D6 genotype. Recommended Dosage Based on CYP2D6 Metabolizer Status ( 2.2 ) : EMs and IMs: 84 mg orally twice daily. PMs: 84 mg orally once daily. See the Full Prescribing Information for dosing recommendations in patients receiving CYP2D6 and/or CYP3A inhibitors, or with renal or hepatic impairment. ( 2.2 , 4 , 7.1 , 8.6 , 8.7 ) Administration ( 2.4 ) : Swallow capsules whole, do not crush, dissolve or open capsules. ( 2.4 ) Avoid eating grapefruit or drinking grapefruit juice. ( 2.4 ) 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. Table 1: Recommended Dosage Regimen by CYP2D6 Metabolizer Status CYP2D6 Metabolizer Status CERDELGA Dosage EMs 84 mg twice daily IMs PMs 84 mg once daily 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) ] . Table 2: Recommended Dosage of CERDELGA 84 mg Once Daily based on CYP2D6 Metabolizer, Hepatic Impairment Status, and Concomitant CYP Inhibitors CYP2D6 Metabolizer Status Hepatic Impairment Status Concomitant CYP Inhibitor EMs Without Hepatic Impairment Taking a strong or moderate CYP2D6 inhibitor Taking a strong or moderate CYP3A inhibitor Mild (Child-Pugh Class A) Hepatic Impairment Taking a weak CYP2D6 inhibitor Taking a strong, moderate, or weak CYP3A inhibitor IMs Without Hepatic Impairment Taking a strong or moderate CYP2D6 inhibitor 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).

6 ADVERSE REACTIONS Most common adverse reactions (≥10%) are: fatigue, headache, nausea, diarrhea, back pain, pain in extremities, and upper abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation at 1-800-745-4447 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 3: Adverse Reactions Occurring in ≥10% of Treatment-Naive GD1 Patients and More Frequently than Placebo (Trial 1) CERDELGA (N=20) Placebo (N=20) Adverse Reaction Patients n (%) Patients n (%) Arthralgia 9 (45) 2 (10) Headache 8 (40) 6 (30) Migraine 2 (10) 0 (0) Flatulence 2 (10) 1 (5) Nausea 2 (10) 1 (5) Oropharyngeal pain 2 (10) 1 (5) 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. Table 4: Adverse Reactions Occurring in ≥5% of GD1 Patients Switching from Enzyme Replacement Therapy to CERDELGA and More Frequently than Imiglucerase (Trial 2) Trial 2 was not designed to support comparative claims for CERDELGA for the adverse reactions reported in this table. CERDELGA (N=106) Imiglucerase (N=53) Adverse Reaction Patients n (%) Patients n (%) Fatigue 15 (14) 1 (2) Headache 14 (13) 1 (2) Nausea 13 (12) 0 (0) Diarrhea 13 (12) 2 (4) Back pain 13 (12) 3 (6) Pain in extremity 12 (11) 1 (2) Upper abdominal pain 11 (10) 0 (0) Dizziness 9 (8) 0 (0) Asthenia 9 (8) 0 (0) Cough 7 (7) 2 (4) Dyspepsia 7 (7) 1 (2) Gastroesophageal reflux disease 7 (7) 0 (0) Constipation 5 (5) 0 (0) Palpitations 5 (5) 0 (0) Rash 5 (5) 0 (0) 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.

12.3 Pharmacokinetics Absorption The oral bioavailability of eliglustat was less than 5% in CYP2D6 EMs following a single 84 mg dose of CERDELGA. In CYP2D6 EMs, the eliglustat pharmacokinetics is time-dependent and the systemic exposure increases in a more than dose-proportional manner over the dose range of 42 to 294 mg (0.5 to 3.5 times the recommended dosage). In addition, after multiple oral doses of 84 mg twice daily in EMs, eliglustat systemic exposure (AUC 0–12 ) increased up to about 2-fold at steady state compared to after the first dose (AUC 0–∞ ). The pharmacokinetics of eliglustat in CYP2D6 PMs is expected to be linear and time-independent. Compared to EMs, the systemic exposure following 84 mg twice daily at steady state is 7-fold to 9-fold higher in PMs. Dosing of CERDELGA 84 mg once daily has not been studied in PMs. The predicted C max and AUC 0–24hr in PMs using a physiologically based pharmacokinetic (PBPK) model with 84 mg once daily were 75 ng/mL and 956 hr∙ng/mL, respectively. Table 7 describes the pharmacokinetic parameters for eliglustat in healthy subjects following multiple doses of 84 mg CERDELGA twice daily. Table 7: Pharmacokinetic Parameters for Eliglustat following Multiple Doses of 84 mg CERDELGA Twice Daily Parameter CYP2D6 Metabolizer Status EMs (n=96) IMs (n=1) PMs 84 mg twice daily is not the recommended dosage in PMs [see Dosage and Administration (2.2) ] . (n=9) C max (ng/mL) Range of the mean (CV%) values from multiple studies. 12.1 (42%) to 25.0 (141%) 44.6 113 (32%) to 137 (40%) AUC tau (ng∙hr/mL) 76.3 (37%) to 143 (160%) 306 922 (33%) to 1057 (38%) Median T max (hr) [min to max] Range of the median time to reach maximum plasma concentration (T max ) from multiple studies. 1.5 [0.5 to 3.0] to 2 [1.5 to 2.1] 2 3 [2 to 4] Administration of CERDELGA with a high fat meal (approximately 1000 calories with 50% calories from fat) resulted in a 15% decrease in C max (not clinically significant) but no change in AUC. Distribution Following intravenous administration, the volume of distribution of eliglustat was 835 L in EMs. Plasma protein binding of eliglustat ranges from 76% to 83%. Elimination Eliglustat terminal elimination half-life was approximately 6.5 hours in CYP2D6 EMs, and 8.9 hours in PMs. Following intravenous administration of 42 mg (0.5 times the recommended oral dose) in healthy subjects, the mean (range) of eliglustat total body clearance was 88 L/h (80 to 105 L/h) in EMs. Metabolism CERDELGA is primarily metabolized by CYP2D6 and to a lesser extent by CYP3A4. Excretion After oral administration of radiolabeled eliglustat, the majority of the administered dose is excreted in urine (42%) and feces (51%), mainly as metabolites. Specific Populations No clinically significant differences in the pharmacokinetics of eliglustat were observed based on age (18 to 71 years), sex, race (mostly were Caucasian, including those of Ashkenazi Jewish descent; however, it included the following populations: African American, American Indians, Hispanics, and Asians), or body weight (41 to 136 kg). Patients with renal impairment Eliglustat pharmacokinetics was similar in CYP2D6 EMs with severe renal impairment and healthy CYP2D6 EMs. Eliglustat pharmacokinetics in EMs with ESRD and in IMs or PMs with any degree of renal impairment is unknown [see Use in Specific Populations (8.6) ] . Patients with hepatic impairment Table 8 describes the effect of mild and moderate hepatic impairment on the pharmacokinetics of eliglustat in CYP2D6 EMs compared to EMs with normal hepatic function following a single 84 mg dose. The effect of hepatic impairment is highly variable with the coefficients of variation (CVs%) of 135% and 110% for C max and 171% and 121% for AUC in CYP2D6 EMs with mild and moderate hepatic impairment, respectively. Table 8: Effect of Hepatic Impairment on Eliglustat Pharmacokinetics following a Single Dose of 84 mg CERDELGA in CYP2D6 EMs Mild Hepatic Impairment (n=6) Moderate Hepatic Impairment (n=7) C max ↑ 1.2-fold ↑ 2.8-fold AUC ↑ 1.2-fold ↑ 5.2-fold Steady-state pharmacokinetics of eliglustat in CYP2D6 IMs and PMs with mild and moderate hepatic impairment is unknown. The effect of severe hepatic impairment in subjects with any CYP2D6 phenotype is unknown [see Use in Specific Populations (8.7) ] . Drug Interaction Studies Effect of other drugs on CERDELGA Table 9 describes the effect of drug interactions on the pharmacokinetics of eliglustat [see Drug Interactions (7.1) ] . Table 9: Drug Interactions Affecting Eliglustat Concentrations Concomitant Drug(s) CYP2D6 Metabolizer Status EMs IMs PMs C max AUC tau C max AUC tau C max AUC tau ↑ = Increased; ↓ = Decreased CYP2D6 Inhibitor Paroxetine (strong) ↑ 7.0-fold ↑ 8.4-fold ↑ 2.1-fold Predicted pharmacokinetic parameters based on PBPK models. ↑ 2.3-fold No increase expected Due to little or no CYP2D6 activity in CYP2D6 PMs. Terbinafine (moderate) ↑ 3.8-fold ↑ 4.5-fold ↑ 1.6-fold CYP3A Inhibitor Ketoconazole (strong) ↑ 4.0-fold ↑ 4.4-fold ↑ 4.4-fold ↑ 5.4-fold ↑ 4.3- fold , Following coadministration with CERDELGA 84 mg once daily. ↑ 6.2- fold , Fluconazole (moderate) ↑ 2.8-fold ↑ 3.2-fold ↑ 2.5-fold ↑ 2.9-fold ↑ 2.4- fold , ↑ 3.0- fold , CYP2D6 Inhibitors Concomitantly with CYP3A Inhibitors Paroxetine with ketoconazole ↑ 16.7-fold ↑ 24.2-fold ↑ 7.5-fold ↑ 9.8-fold Expected similar increase as with CYP3A inhibitors alone Terbinafine with fluconazole ↑ 10.2-fold ↑ 13.6-fold ↑ 4.2-fold ↑ 5.0-fold CYP3A Inducers Rifampin (strong) ↓ 90% Following coadministration with CERDELGA 127 mg twice daily (1.5 times the recommended dosage). ↓ 95% No clinically significant pharmacokinetic changes were observed for eliglustat when coadministered with intravenous rifampin (an OATP inhibitor), or gastric pH modifying drugs (e.g., aluminum hydroxide, magnesium hydroxide, calcium carbonate, pantoprazole). In vitro , eliglustat is a substrate of P-glycoprotein (P-gp). The effect of P-gp inhibitors on eliglustat pharmacokinetics is unknown. Effect of CERDELGA on other drugs CYP2D6 substrates Following multiple doses of CERDELGA 127 mg twice daily (1.5 times the recommended dosage), metoprolol (a CYP2D6 substrate) mean C max and AUC increased by 1.7-fold and 2.3-fold in CYP2D6 EMs, respectively, and by 1.2-fold and 1.6-fold in IMs, respectively [see Drug Interactions (7.2) ] . P-gp substrates Following multiple doses of CERDELGA 127 mg twice daily (1.5 times the recommended dosage) in CYP2D6 EMs and IMs, or 84 mg twice daily in PMs, digoxin (a P-gp substrate) mean C max increased by 1.7-fold and AUC increased by 1.5-fold [see Drug Interactions (7.2) ] . Oral contraceptives Repeated doses of CERDELGA 84 mg twice daily did not change the exposures to norethindrone (1.0 mg) and ethinyl estradiol (0.035 mg).