Cerdelga

CERDELGA- eliglustat capsule
Genzyme Corporation

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)].

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

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).

3 DOSAGE FORMS AND STRENGTHS

Capsules: 84 mg of eliglustat is in a capsule with a pearl blue-green opaque cap and pearl white opaque body imprinted with “GZ02” in black.

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 [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 WARNINGS AND PRECAUTIONS

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 ADVERSE REACTIONS

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	Patientsn (%)	Patientsn (%)
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)*

	CERDELGA(N=106)	Imiglucerase(N=53)
Adverse Reaction	Patientsn (%)	Patientsn (%)
* Trial 2 was not designed to support comparative claims for CERDELGA for the adverse reactions reported in this table.
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.