Dosing and uses of Cerdelga (eliglustat)
Adult dosage forms and strengths
capsule
- 84mg
Gaucher Disease
Indicated for the long-term treatment of adults with Gaucher disease type 1 who are CYP2D6 extensive metabolizers (EM), intermediate metabolizers (IM), or poor metabolizers (PM) as detected by an FDA-cleared test for genotype
Dose is based on patient's CYP2D6 metabolizer status
CYP2D6 EMs or IMs: 84 mg PO BId
CYP2D6 PMs: 84 mg PO qDay
Dosage modifications
Drugs that inhibit CYP2D6 and CYP3A pathways may significantly increase systemic exposure to eliglustat and result in prolongation of the PR, QTc, and/or QRS cardiac interval, which could result in cardiac arrhythmias
Some CYP2D6 and CYP3A inhibitors are contraindicated with eliglustat, depending on the patient’s metabolizer status
Coadministration of eliglustat with other CYP2D6 and CYP3A inhibitors may require dose reduction of eliglustat, depending on the patient’s CYP2D6 metabolizer status, to reduce the exposure to eliglustat
Hepatic impairment (all stages): Use not recommended
Renal impairment
- Mild: No dosage adjustment required
- Moderate-to-severe or end-stage renal disease: Has not been studied and use is not recommended
Dosing Considerations
Patients who are CYP2D6 ultra-rapid metabolizers (URMs) may not achieve adequate serum concentrations to achieve a therapeutic effect
CYP2D6 genotype not determined: Specific dosage cannot be recommended for indeterminate metabolizers
Administration
Swallow capsules whole, do not crush, dissolve, or open capsules
May take with or without food
Avoid eating grapefruit or drinking grapefruit juice
Pediatric dosage forms and strengths
Safety and efficacy not established
Geriatric dosage forms and strengths
Studies did not include sufficient numbers of subjects aged ≥65 yr to determine whether they respond differently from younger subjects
Clinical experience has not identified differences in responses between elderly and younger patients
Cerdelga (eliglustat) adverse (side) effects
>10%
Arthralgia (45%)
Headache (13-40%)
Fatigue (14%)
Nausea (10-12%)
Diarrhea (12%)
Back pain (12%)
Extremity pain (11%)
1-10%
Upper abdominal pain (10%)
Migraine (10%)
Flatulence (10%)
Oropharyngeal pain (10%)
Dizziness (8%)
Asthenia (8%)
Cough (7%)
Dyspepsia (7%)
GERD (7%)
Constipation (5%)
Palpitations (5%)
Rash (5%)
Warnings
Contraindications
Extensive/intermediate metabolizers taking a strong or moderate CYP2D6 inhibitor with a strong or moderate CYP3A inhibitor
Intermediate/poor metabolizers taking a strong CYP3A inhibitor
Cautions
CYP2D6 and CYP3A substrate; drugs that inhibit CYP2D6 and CYP3A metabolism may significantly increase eliglustat systemic exposure and result in prolongation of the PR, QTc, and/or QRS cardiac intervals
Some CYP2D6 and CYP3A inhibitors are contraindicated with eliglustat, depending on the patient’s CYP2D6 metabolizer status
Eliglustat inhibits P-gp and CYP2D6; coadministration with P-gp or CYP2D6 substrates may result in increased concentrations of the concomitant drug
Increases in ECG intervals (PR, QTc, and QRS) occurs at substantially elevated eliglustat plasma concentrations; avoid use in patients with pre-existing cardiac conditions (eg, CHF, recent acute MI, bradycardia, heart block, ventricular arrhythmia), long QT syndrome, and in combination with class IA (eg, quinidine, procainamide) and class III (eg, amiodarone, sotalol) antiarrhythmics
Pregnancy and lactation
Pregnancy category: C
Women with Gaucher disease type 1 have an increased risk of spontaneous abortion, especially if disease symptoms are not treated and controlled preconception and during a pregnancy
In animal reproduction studies, a spectrum of anomalies at doses 6 times the recommended human dose were observed in orally dosed rats; no fetal harm was observed with oral administration to pregnant rabbits at dose levels 10 times the recommended human dose
Use during pregnancy only if the potential benefit justifies the potential risk to the fetus
Lactation: Unknown if distributed in human breast milk; not recommended; 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
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Cerdelga (eliglustat)
Mechanism of action
Gaucher disease is caused by a deficiency of the lysosomal enzyme acid β-glucosidase (ie, glucocerebrosidase), which 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"
Eliglustat is a specific inhibitor of glucosylceramide synthase, thereby reducing production of glucosylceramide
Absorption
Peak plasma concentration, peak plasma time, and AUC dependent on CYP2D6 phenotype
CYP2D6 Em
- Bioavailability: <5% (single dose, significant first-pass metabolism)
- Peak plasma time: 1.5-2 hr
- Peak plasma concentration: 12.1-25 ng/mL
- AUC: 76.3-143 hr•ng/mL
CYP2D6 Im
- Peak plasma concentration: 44.6 ng/mL
- AUC: 306 hr•ng/mL
CYP2D6 Pm
- Peak plasma time: 3 hr (BID dosing)
- Peak plasma concentration: 113-137 ng/mL (BID dose); 75 ng/mL (predicted for once-daily dose)
- AUC: 922-1057 hr•ng/mL (BID dose); 956 hr•ng/mL (predicted for once-daily dose)
Distribution
Protein bound: 76-83%
In the blood, it is mainly distributed in plasma and not RBCs
Vd: 835 L
Metabolism
Extensively metabolized in the liver with high clearance, mainly by CYP2D6 and to a lesser extent CYP3A4
No active metabolites have been identified
Elimination
Half-life: 6.5 hr (EM); 8.9 hr (PM)
Total body clearance: 88 L/hr
Excretion: 51.4% feces; 41.8% urine
Excreted mainly as metabolites
Pharmacogenomics
Dosage is based the patient’s CYP2D6 metabolizer status
