CERDELGA

). 2 CONTRAINDICATIONS CERDELGA is contraindicated in patients (all CYP2D6 metabolizer types) with: • Hypersensitivities to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the

1 Adverse Reaction Overview Based on the initial pooled clinical trial data representing 535 patient-years of treatment exposure in 393 adult patients, the most commonly reported adverse reactions with CERDELGA (occurring in ≥5% of patients) were headache and dizziness.

The most frequently reported serious adverse event was syncope (1%). The most common adverse events leading to discontinuation of CERDELGA and/or withdrawal from the studies were ventricular tachycardia (1%) and (acute) myocardial infarction (1%).

2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use. The adverse reaction profile of CERDELGA is based on two controlled studies, ENGAGE (GZGD02507) and ENCORE (GZGD02607).

Table 4 presents adverse reactions in patients receiving CERDELGA in the 9- month double-blind, randomized, placebo-controlled trial of 40 treatment-naïve patients (ENGAGE). 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 - Summary of Treatment-Emergent Adverse Reactions (considered treatment-related by Investigator) in Treatment-Naïve Gaucher Disease Type 1 Patients receiving CERDELGA as compared to Patients receiving Placebo (ENGAGE Trial) Adverse Reaction MedDRA System Organ Class Preferred Term CERDELGA (N=20) Placebo (N=20) Patients n (%) Patients n (%) Gastrointestinal disorders Diarrhea 2 ( 10) 4 ( 20) Abdominal pain 1 ( 5) 2 ( 10) Flatulence 2 ( 10) 1 ( 5) Gastritis 1 ( 5) 0 ( 0) Nausea 1 ( 5) 0 ( 0) Vomiting 1 ( 5) 0 ( 0) Nervous system disorders Headache 1 ( 5) 3 ( 15) Paresthesia 1 ( 5) 0 ( 0) Skin and subcutaneous tissue disorders Acne 1 ( 5) 0 ( 0) Skin lesion 1 ( 5) 0 ( 0) Eye disorders Vitreous detachment 1 ( 5) 0 ( 0) General disorders and administration site conditions Chest pain 1 ( 5) 0 ( 0) Edema peripheral 1 ( 5) 0 ( 0) Metabolism and nutrition disorders Decreased appetite 1 ( 5) 1 ( 5) Blood and lymphatic system disorders Adverse Reaction MedDRA System Organ Class Preferred Term CERDELGA (N=20) Placebo (N=20) Patients n (%) Patients n (%) Splenic hemorrhage 1 ( 5) 0 ( 0) Infections and infestations Oral fungal infection 1 ( 5) 0 ( 0) Musculoskeletal and connective tissue disorders Arthralgia 1 ( 5) 0 ( 0) Renal and urinary disorders Dysuria 1 ( 5) 0 ( 0) Hematuria 1 ( 5) 0 ( 0) Error!

and 4 DOSAGE AND ADMINISTRATION). 2 CONTRAINDICATIONS CERDELGA is contraindicated in patients (all CYP2D6 metabolizer types) with: • Hypersensitivities to this drug or to any ingredient in the formulation or component of the container.

1 Dosing Considerations Therapy with CERDELGA should be initiated and supervised by a physician knowledgeable in the management of Gaucher disease. Before initiation of treatment with CERDELGA, patients must be genotyped for CYP2D6 to determine the CYP2D6 metabolizer status (predicted phenotype).

CERDELGA is indicated for patients who are CYP2D6 PMs, IMs or EMs, as determined by CYP2D6 genotype testing (see 1 INDICATIONS). CERDELGA should not be used in patients who are CYP2D6 URMs or indeterminate metabolizers (see 1 INDICATIONS, Limitations of use).

For patients currently treated with imiglucerase, velaglucerase alfa, or taliglucerase alfa, CERDELGA may be administered 24 hours after the last dose of the previous ERT. 2 Recommended Dose and Dosage Adjustment The recommended dose of CERDELGA depends on CYP2D6 metabolizer status, as follows: • CYP2D6 Extensive metabolizer (EM): CERDELGA dosage is 84 mg twice daily • CYP2D6 Intermediate metabolizer (IM): CERDELGA dosage is 84 mg twice daily • CYP2D6 Poor metabolizer (PM): CERDELGA dosage is 84 mg once daily The recommended dose of CERDELGA also depends on concomitant medication use as well as hepatic and renal impairment as follows in Table 1, Table 2 and Table 3 (see 2 CONTRAINDICATIONS, 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, 7 WARNINGS AND PRECAUTIONS, Renal and 9 DRUG INTERACTIONS): Table 1 – Dosing Recommendations for CERDELGA Due to Drug-Drug Interactions with CYP Inhibitors and Inducers in CYP2D6 Extensive Metabolizers, Intermediate Metabolizers and Poor Metabolizers.

g. g. rifampin, carbamazepine, phenobarbital, phenytoin, rifabutin) Not recommended Not recommended Not recommended aNo clinical data provided to make a dosing recommendation Table 2 – Recommended Dose for CERDELGA Based on Presence and Severity of Hepatic and Renal Impairment Status by CYP2D6 Metabolizer Status Organ Dysfunction status Dosing Recommendations Extensive Metabolizers (EMs) Intermediate Metabolizers (IMs) Poor Metabolizers (PMs) Hepatic impairment status: […]

CERDELGA is contraindicated in patients (all CYP2D6 metabolizer types) with: • Hypersensitivities to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING section of the product monograph • Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption CERDELGA is contraindicated in the following patients based on CYP2D6 metabolizer status due to the risk of significantly increased eliglustat plasma concentrations, which may increase the risk of cardiac arrhythmias from prolongation of the PR, QTc and/or QRS cardiac intervals (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular): EMs • Taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor (see 9 DRUG INTERACTIONS) • Mild hepatic impairment and taking a strong or moderate CYP2D6 inhibitor (see 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic,