CERDELGA (eliglustat) capsules

CERDELGA (eliglustat) capsules contain eliglustat tartrate, which is a small molecule inhibitor of glucosylceramide synthase that resembles the ceramide substrate for the enzyme, with the chemical name N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)octanamide (2R,3R)-2,3-dihydroxysuccinate. Its molecular weight is 479.59, and the empirical formula is C₂₃H₃₆N₂O₄+½(C₄H₆O₆)

Each capsule of CERDELGA for oral use contains 84 mg of eliglustat, equivalent to 100 mg of eliglustat tartrate (hemitartrate salt). The inactive ingredients are microcrystalline cellulose, lactose monohydrate, hypromellose and glyceryl behenate, gelatin, candurin silver fine, yellow iron oxide, and FD&C blue 2.

Indications and usage

CERDELGA is a glucosylceramide synthase inhibitor indicated for the longterm 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

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”. CERDELGA is a specific inhibitor of glucosylceramide synthase (IC₅₀ = 10 ng/mL), and acts as a substrate reduction therapy for GD1. In clinical trials CERDELGA reduced spleen and liver size, and improved anemia and thrombocytopenia.

In this lysosomal storage disorder (LSD), clinical features are reflective of the accumulation of Gaucher cells in the 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 lead to clinically significant anemia and thrombocytopenia.

Dosage and administration

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

Recommended Adult Dosage: The recommended dosage of CERDELGA is 84 mg twice daily in CYP2D6 EMs and IMs. The recommended dosage in CYP2D6 PMs is 84 mg once daily; appropriate adverse event monitoring is recommended. The predicted exposures with 84 mg once daily in patients who are CYP2D6 PMs are expected to be similar to exposures observed with 84 mg twice daily in CYP2D6 IMs.

Some inhibitors of CYP2D6 and CYP3A are contraindicated with CERDELGA depending on the patient’s metabolizer status. Co administration of CERDELGA with other CYP2D6 and CYP3A inhibitors may require dosage adjustment depending on the patient’s CYP2D6 metabolizer status to reduce the risk of potentially significant adverse reactions

Reduce the dosage of CERDELGA to 84 mg once daily for:

• CYP2D6 EMs and IMs taking strong or moderate CYP2D6 inhibitors
• CYP2D6 EMs taking strong or moderate CYP3A inhibitors

Adverse reactions

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

Contraindications

CERDELGA is contraindicated in the following patients due to the risk of significantly increased eliglustat plasma concentrations which may result in prolongation of the PR, QTc, and/or QRS cardiac intervals that could result in cardiac arrhythmias.

• • EMs or IMs taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor.
• IMs or PMs taking a strong CYP3A inhibitor.

Warnings and precautions

Drug-Drug Interactions: Eliglustat is a CYP2D6 and CYP3A substrate. Drugs that inhibit CYP2D6 and CYP3A metabolism pathways may significantly increase the exposure to eliglustat and result in prolongation of the PR, QTc, and/or QRS cardiac intervals that could result in cardiac arrhythmias. Some drugs that are inhibitors of CYP2D6 and CYP3A are contraindicated with CERDELGA depending on the patient’s CYP2D6 metabolizer status

ECG Changes and Potential for Cardiac Arrhythmias: Use of CERDELGA in patients with pre-existing cardiac conditions has not been studied during clinical trials. Because CERDELGA is predicted to cause increases in ECG intervals (PR, QTc, and QRS) at substantially elevated eliglustat plasma concentrations, use of CERDELGA is not recommended in patients with pre-existing cardiac disease (congestive heart failure, recent acute myocardial infarction, bradycardia, heart block, ventricular arrhythmia), long QT syndrome, and in combination with Class IA (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications

Drug interaction

CYP2D6 and CYP3A Inhibitors: Drugs that inhibit CYP2D6 and CYP3A pathways may significantly increase the exposure to eliglustat and result in prolongation of the PR, QTc, and/or QRS cardiac interval which could result in cardiac arrhythmias:

CYP450 Inhibitors	EM	IM
Strong or Moderate CYP2D6 inhibitors concomitantly with Strong or Moderate CYP3A inhibitors	contraindicated	contraindicated
Strong CYP2D6 inhibitors e.g., paroxetine	84 mg once daily	84 mg once daily
Moderate CYP2D6 inhibitors e.g., terbinafine	84 mg once daily	84 mg once daily
Strong CYP3A inhibitors e.g., ketoconazole	84 mg once daily	Contraindicated
Moderate CYP3A inhibitors e.g., fluconazole	84 mg once daily	Not recommended

CYP450 Inhibitors	Recommended CERDELGA Dosage for PMs
Strong CYP3A inhibitors e.g., ketoconazole	Contraindicated
Moderate CYP3A inhibitors e.g., fluconazole	Not recommended
Weak CYP3A inhibitors e.g., ranitidine	Not recommended

CYP3A Inducers: Co-administration of CERDELGA with strong CYP3A inducers significantly decreases eliglustat exposure. Use of CERDELGA with strong CYP3A inducers (e.g., rifampin, carbamazepine, phenobarbital, phenytoin, and St. John’s Wort) is not recommended in EMs, IMs, and PMs.

Use in specific populations

Pregnancy: Pregnancy Category C. There are no adequate or well-controlled studies with CERDELGA in pregnant women.

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.

Nursing Mothers: It is not known whether CERDELGA is present in human milk. Because many drugs are present in human milk, and because of the potential for serious adverse reactions in nursing infants from CERDELGA, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the lactating woman.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: Clinical studies of CERDELGA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Clinical experience has not identified differences in responses between the elderly and younger patients.

Renal Impairment: There is no dosage adjustment required for patients with mild renal impairment. CERDELGA has not been studied in patients with moderate to severe renal impairment or end-stage renal disease (ESRD). Use of CERDELGA in these patients is not recommended.

Hepatic Impairment: CERDELGA has not been studied in patients with hepatic impairment. Use of CERDELGA is not recommended in all stages of hepatic impairment or cirrhosis.

Poor Metabolizers: Dosing of CERDELGA 84 mg once daily has not been studied in PMs, however the predicted systemic exposures in these patients are within the range of those observed in clinical studies. Appropriate adverse event monitoring is recommended.

Overdosage

The highest eliglustat plasma concentration experienced to date occurred in a single-dose, dose escalation study in healthy subjects, in a subject taking a dose equivalent toapproximately 21 times the recommended dose for GD1 patients. At the time of the highest plasma concentration (59-fold higher than normal therapeutic conditions), the subject experienced dizziness marked by disequilibrium, hypotension, bradycardia, nausea, and vomiting.

In the event of acute overdose, the patient should be carefully observed and given symptomatic and supportive treatment.

Hemodialysis is unlikely to be beneficial given that eliglustat has a large volume of distribution