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 . 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. Limitations of Use : CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of CERDELGA to achieve a therapeutic effect. A specific dosage cannot be recommended for CYP2D6 indeterminate metabolizers.

Limitations of Use : Patients who are CYP2D6 ultra-rapid metabolizers (URMs) may not achieve adequate concentrations of CERDELGA to achieve a therapeutic effect . A specific dosage cannot be recommended for those patients whose CYP2D6 genotype cannot be determined (indeterminate metabolizers) .

Patient Selection : Select patients using an FDA-cleared test for determining CYP2D6 genotype. Recommended Dosage Based on CYP2D6 Metabolizer Status : 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 : Swallow capsules whole, do not crush, dissolve or open capsules. Avoid eating grapefruit or drinking grapefruit juice.

2.1Patient 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 .

2.2Recommended 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

2.3Dosage 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 . 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

2.4Important 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 . 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).

Changes and Potential for Cardiac Arrhythmias : Not recommended in patients with pre-existing cardiac disease, long QT syndrome, and concomitant use of Class IA and Class III antiarrhythmics.

5.1ECG 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 . 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

4 CONTRAINDICATIONS CERDELGA 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. EMs Taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor. ( 4 , 5.1 , 7.1 , 12.3 ) Moderate or severe hepatic impairment. ( 4 , 5.1 , 8.7 , 12.3 ) Mild hepatic impairment taking a strong or moderate CYP2D6 inhibitor. ( 4 , 5.1 , 8.7 , 12.3 ) IMs Taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor. ( 4 , 5.1 , 7.1 , 12.3 ) Taking a strong CYP3A inhibitor. ( 4 , 5.1 , 7.1 , 12.3 ) Any degree of hepatic impairment. ( 4 , 5.1 , 8.7 , 12.3 ) PMs Taking a strong CYP3A inhibitor ( 4 , 5.1 , 7.1 , 12.3 ) Any degree of hepatic impairment ( 4 , 5.1 , 8.7 , 12.3 ) EMs 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

8.1Pregnancy Risk Summary Available

data on CERDELGA use in pregnant women includes 20 pregnancies that occurred during the clinical development program and a small number of post-marketing case reports. These data are not sufficient to assess drug-associated risks major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies in pregnant rats administered oral eliglustat during organogenesis, a spectrum of various developmental abnormalities were observed at doses 6 times the recommended human dose.

No adverse developmental outcomes were observed with oral administration of eliglustat to pregnant rabbits at dose levels 10 times the recommended human dose . The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Women with Gaucher disease type 1 have an increased risk of spontaneous abortion, especially if disease symptoms are not treated and controlled pre-conception and during a pregnancy. Pregnancy may exacerbate existing Gaucher disease type 1 symptoms or result in new disease manifestations. Gaucher disease type 1 manifestations may lead to adverse pregnancy outcomes including, hepatosplenomegaly which can interfere with the normal growth of a pregnancy and thrombocytopenia which can lead to increased bleeding and possible hemorrhage.

Data Animal data Reproduction studies have been performed in pregnant rats at oral doses up to 120 mg/kg/day (about 6 times the recommended human dose based on body surface area) and in pregnant rabbits at oral doses up to 100 mg/kg/day (about 10 times the recommended human dose based on body surface area) following administration of eliglustat during the period of organogenesis (gestation days 6 to 17 in the rat and 6 to 18 in the rabbit). In rats, at 120 mg/kg/day (about 6 times the recommended human dose based on body surface area), eliglustat increased the number of late resorptions, dead fetuses and post implantation loss, reduced fetal body weight, and caused fetal cerebral variations (dilated cerebral ventricles), fetal skeletal variations (poor bone ossification) and fetal skeletal malformations (abnormal number of ribs or lumbar vertebra). Eliglustat-related effects on fetal rats were observed in association with signs of maternal toxicity.

Eliglustat did not cause fetal harm in rabbits at oral doses up to 100 mg/kg/day (about 10 times the recommended human dose based on body surface area). Mild maternal toxicity was observed at the 100 mg/kg/day dose. In a pre and postnatal development study in rats (dosed daily from gestation day 6 to postpartum day 21), eliglustat did not show any significant adverse effects on pre and postnatal development at doses up to 100 mg/kg/day (about 5 times the recommended human dose based on body surface area).

Most common adverse reactions (≥10%) are: fatigue, headache, nausea, diarrhea, back pain, pain in extremities, and upper abdominal pain. 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.

6.1Clinical 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 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 2 Headache 8 6 Migraine 2 0 Flatulence 2 1 Nausea 2 1 Oropharyngeal pain 2 1 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 1 Headache 14 1 Nausea 13 0 Diarrhea 13 2 Back pain 13 3 Pain in extremity 12 1 Upper abdominal pain 11 0 Dizziness 9 0 Asthenia 9 0 Cough 7 2 Dyspepsia 7 1 Gastroesophageal reflux disease 7 0 Constipation 5 0 Palpitations 5 0 Rash 5 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.