eliglustat 84 MG Oral Capsule [Cerdelga]

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) ] .

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).

WARNINGS AND PRECAUTIONS ECG 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. ( 5.1 ) 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) ]

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 [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) ]

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 (IC 50 =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.