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Eliglustat
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Patient selection:
NOTE: Eliglustat carries the FDA designation of Orphan Drug for the treatment of Gaucher disease.
84 mg PO twice daily. If coadministered with a strong or moderate CYP2D6 inhibitor or a strong or moderate CYP3A inhibitor, reduce dose to 84 mg PO once daily. Coadministration of a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor is contraindicated.[57803]
84 mg PO twice daily. If coadministered with a strong or moderate CYP2D6 inhibitor, reduce dose to 84 mg PO once daily. Coadministration of a strong CYP3A inhibitor or a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor is contraindicated. Coadministration of a moderate CYP3A inhibitor is not recommended.[57803]
84 mg PO once daily. Monitor closely for adverse events. Coadministration of a strong CYP3A inhibitor is contraindicated. Coadministration of a weak or moderate CYP3A inhibitor is not recommended.[57803]
CYP2D6 extensive metabolizers (EMs): 84 mg/dose PO twice daily.
CYP2D6 intermediate metabolizers (IMs): 84 mg/dose PO twice daily.
CYP2D6 poor metabolizers (PMs): 84 mg/dose PO once daily.
CYP2D6 extensive metabolizers (EMs): 84 mg/dose PO twice daily.
CYP2D6 intermediate metabolizers (IMs): 84 mg/dose PO twice daily.
CYP2D6 poor metabolizers (PMs): 84 mg/dose PO once daily.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Use eliglustat in patients with hepatic impairment based on CYP2D6 metabolizer status and concomitant use of CYP2D6 or CYP3A inhibitors.[57803]
Extensive metabolizers
Mild hepatic impairment (Child-Pugh Class A) not taking a CYP2D6 or CYP3A inhibitor: No dosage adjustment necessary.
Mild hepatic impairment (Child-Pugh Class A) taking a weak CYP2D6 inhibitor or a strong, moderate, or weak CYP3A inhibitor: 84 mg once daily.
Mild hepatic impairment (Child-Pugh Class A) taking a strong to moderate CYP2D6 inhibitor: Use is contraindicated.
Moderate or severe hepatic impairment (Child-Pugh Class B or C): Use is contraindicated.
Intermediate and Poor metabolizers
Use is contraindicated in patients with any degree of hepatic impairment.
Use eliglustat in patients with renal impairment based on the patient's CYP2D6 metabolizer status.[57803]
Extensive metabolizers
CrCl 15 mL/minute or more: No dosage adjustment needed.
CrCl less than 15 mL/minute: Do not use in patients with end-stage renal disease (not on dialysis or requiring dialysis).
Intermediate and Poor metabolizers
Avoid in patients with any degree of renal impairment.
† Off-label indicationEliglustat is an oral glucosylceramide synthase inhibitor indicated for the long-term treatment of adult patients with Gaucher disease type 1 (GD1). Unlike enzyme replacement therapies, which break down fatty deposits that build up in cells of patients with Gaucher disease, eliglustat slows the accumulation of the fatty deposits by inhibiting the metabolic process that forms them.[57819] Although ease of oral administration provides substantial benefit over intravenous enzyme replacement therapy, eliglustat use is somewhat limited by cytochrome P450 (CYP450) 2D6 genotype. Eliglustat is primarily metabolized via CYP2D6 and, to a lesser extent, CYP3A. Patient selection should take into account CYP2D6 metabolizer status, as established by a FDA-cleared test. Patients who are CYP2D6 ultra-rapid metabolizers may not achieve therapeutic concentrations of eliglustat. Poor metabolizers require dosage reduction. In addition, depending on the patient's CYP2D6 metabolizer status, concomitant administration of some CYP2D6 and CYP3A inhibitors may be contraindicated or require dosage adjustment to reduce the risk of potentially significant ECG changes.[57803] Eliglustat was approved by the FDA in August 2014.
For storage information, see the specific product information within the How Supplied section.
Headache (13—40%) and fatigue (14%) were among the most common adverse reactions reported in eliglustat-treated patients (n = 126) during clinical trials. Headache (40%) and migraine (10%) were common in treatment-naive patients (n = 20), while headache (13%), fatigue (14%), dizziness (8%), and asthenia (8%) were frequently reported in patients switching from enzyme replacement therapy (n = 106).[57803]
Back pain (12%) and extremity pain (11%) were among the most common adverse reactions reported in eliglustat-treated patients (n = 126) during clinical trials; both were reported more frequently that placebo in patients switching from enzyme replacement therapy (n = 106). Arthralgia (45%) was also reported in treatment-naive patients (n = 20).[57803]
Nausea (10—12%), diarrhea (12%), and upper abdominal pain (10%) were among the most commonly reported adverse events occurring in eliglustat-treated patients (n = 126) during clinical trials. Nausea, flatulence, and oropharyngeal pain occurred in 10% of treatment-naive patients (n = 20). Similar rates of nausea (12%) were reported in patients switching from enzyme replacement therapy (n = 106); in this population, diarrhea (12%), upper abdominal pain (10%), dyspepsia (7%), gastroesophageal reflux (7%), and constipation (5%) were also reported.[57803]
Cough and rash (unspecified) were reported in 7% an 5% of patients, respectively, being treated with eliglustat (n = 106) during an open-label imiglucerase-controlled trial of patients switching from enzyme replacement therapy.[57803]
Palpitations were reported in 5% of patients being treated with eliglustat (n = 106) during an open-label imiglucerase-controlled trial of patients switching from enzyme replacement therapy. Eliglustat is predicted to cause QT prolongation and other increases in ECG intervals (e.g., PR, QRS) and, potentially, cardiac arrhythmias (arrhythmia exacerbation) at substantially elevated plasma concentrations. Although clinically relevant interval prolongation did not occur during a double-blind, single-dose, placebo- and positive-controlled crossover study in 42 healthy subjects (highest mean eliglustat concentration: 237 ng/ml), concentration-related increases for the placebo-corrected change from baseline in PR, QRS, and QT intervals were observed. Based on pharmacokinetic and pharmacodynamic modeling, eliglustat concentrations of 500 ng/ml are predicted to cause mean increase in the PR, QRS, and QTcF intervals of 22, 7, and 13 msec, respectively. Hence, eliglustat is not recommended for use in patients with pre-existing cardiac disease, long QT syndrome, or in combination with a Class IA or Class III antiarrhythmic. Eliglustat is contraindicated in patients at risk for significantly increased eliglustat plasma concentrations; these patients include extensive or intermediate CYP2D6 metabolizers taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor and intermediate or poor CYP2D6 metabolizers taking a strong CYP3A inhibitor. In addition, eliglustat use is not recommended in poor or intermediate CYP2D6 metabolizers taking a moderate CYP3A inhibitor or poor CYP2D6 metabolizers taking a weak CYP3A inhibitor.[57803]
Due to the risk of QT prolongation, the use of eliglustat in patients with pre-existing cardiac disease (e.g., congestive heart failure, recent acute myocardial infarction), bradycardia, cardiac arrhythmias, or congenital long QT syndrome is not recommended. Use eliglustat with caution in patients with conditions that may increase the risk of QT prolongation including AV block, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. In addition, because eliglustat is a CYP2D6 and CYP3A substrate, drugs that inhibit these metabolic pathways may significantly increase the exposure to eliglustat, resulting in prolongation of cardiac intervals and cardiac arrhythmia. For this reason, depending on the patient's CYP2D6 metabolizer status, some CYP2D6 and CYP3A inhibitors are contraindicated with eliglustat; coadministration of other CYP2D6 and CYP3A inhibitors may require eliglustat dosage adjustment.[28432] [28457] [56592] [65180] [57803]
Eliglustat clearance is reduced in patients with hepatic disease. Dosage adjustments are required in patients who are extensive metabolizers with mild hepatic impairment (Child-Pugh A) taking a weak CYP2D6 inhibitor or a strong, moderate, or weak CYP3A inhibitor. Eliglustat is contraindicated in patients who are extensive metabolizers with moderate or severe hepatic impairment (Child-Pugh B or C) or mild hepatic impairment (Child-Pugh A) taking a strong or moderate CYP2D6 inhibitor. Additionally, eliglustat is contraindicated in patients who are intermediate or poor metabolizers with any degree of hepatic impairment. Decreased metabolism may lead to increased exposure and a higher risk of QT prolongation and cardiac arrhythmia.[57803]
Use eliglustat in patients with renal impairment and renal failure based on the patient's CYP2D6 metabolizer status. In patients who are extensive metabolizers, no dosage adjustment is recommended in patients with mild, moderate, or severe renal impairment (estimated creatinine clearance at least 15 mL/minute). Avoid eliglustat use in extensive metabolizers with end-stage renal disease (estimated creatinine clearance less than 15 mL/minute) and in intermediate and poor metabolizers with any degree of renal impairment.[57803]
Adequate and well-controlled studies have not been conducted in pregnant women. In animal reproduction studies, a spectrum of anomalies at eliglustat doses 6 times the recommended human dose were observed in orally dosed rats; these anomalies included an increased number of late resorptions, dead fetuses and post implantation loss, reduced fetal body weight, fetal cerebral variations (dilated cerebral ventricles), fetal skeletal variations (poor bone ossification), and fetal skeletal malformations (abnormal number of ribs or lumbar vertebra). However, no fetal harm was observed with oral administration to pregnant rabbits at doses 10 times the recommended human dose. In development studies, eliglustat did not show any significant adverse effects on pre- and postnatal development in rats at doses 5 times the recommended human dose. Eliglustat should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.[57803]
According to the manufacturer, a decision should be made whether to discontinue breast-feeding or discontinue eliglustat. It is not known whether eliglustat is present in human milk.[57803] For women who wish to breast-feed, potential alternative treatments might include enzyme replacement therapies. Enzymes such as alglucerase, imiglucerase, taliglucerase alfa, and velaglucerase alfa are likely to be degraded by the infant's digestive sytem and unlikely to reach the systemic circulation of a nursing infant. Limited data in a report from a panel of clinicians that treat Gaucher's disease indicated that breast-feeding complications were reduced in women treated with alglucerase or imiglucerase postpartum. No adverse effects on the nursing infants were reported secondary to enzyme replacement therapy. Consider reducing the duration of breast-feeding to avoid excessive bone loss in the mother.[49246] Consider the benefits of breast-feeding, the risk of potential drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Eliglustat is a specific inhibitor of glucosylceramide (GL-1) synthase that acts as a substrate reduction therapy for Gaucher disease type 1 (GD1). Gaucher disease is a lysosomal storage disorder characterized by a deficiency in the enzyme acid beta-glucosidase (glucocerebrosidase). Acid beta-glucosidase catalyzes the conversion of the sphingolipid glucocerebroside into glucose and ceramide. Enzymatic deficiency results in accumulation of the beta-glucosidase substrate, GL-1, primarily in the lysosomal compartment of macrophages, giving rise to foam cells or "Gaucher cells". As an inhibitor of GL-1 synthase, eliglustat reduces the synthesis of the substrate GL-1 to balance production with the impaired rate of degradation.[57803][57818] [57819]
Clinical features of GD1 are reflective of accumulation of Gaucher cells in the liver, spleen, bone marrow, and other organs. Presence of Gaucher cells in the bone marrow and spleen lead to clinically significant anemia and thrombocytopenia. Accumulation of Gaucher cells in the liver, spleen, and bone marrow results in organomegaly and skeletal disease. Clinically, the use of eliglustat has reduced spleen and liver size and improved anemia and thrombocytopenia.[57803][57818]
Revision Date: 11/20/2024, 01:31:00 AMEliglustat is administered orally. It is moderately bound to plasma proteins (76% to 83%) and, in the blood, is mainly distributed in the plasma (not red blood cells). The large Vd (835 L) after intravenous administration to CYPD26 extensive metabolizers (EMs) suggests wide tissue distribution. Eliglustat is extensively metabolized in the liver primarily by CYP2D6 and to a lesser extent CYP3A4. Primary metabolic pathways involve sequential oxidation of the octanoyl moiety followed by oxidation of the 2,3-dihydro-1,4-benzodioxane moiety (or a combination of the 2 pathways) resulting in multiple inactive oxidative metabolites. No active metabolites have been identified. The majority of the administered dose is excreted as metabolites in the urine (42%) and feces (51%). In healthy CYP2D6 EMs, clearance is approximately 88 L/hour. Terminal half-life is approximately 6.5 hours in CYP2D6 EMs and 8.9 hours in poor metabolizers (PMs).[57803]
Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6, CYP3A4, and P-gp
Eliglustat is metabolized primarily by CYP2D6 and to a lesser extent CYP3A4; eliglustat is also a P-glycoprotein (P-gp) substrate. Drugs that inhibit CYP2D6 and CYP3A pathways may significantly increase eliglustat exposure; elevated eliglustat concentrations can result in PR, QRS, and/or QT prolongation and cardiac arrhythmias. CYP2D6 metabolizer status plays a critical role in determining eliglustat's pharmacokinetics. In extensive or intermediate CYP2D6 metabolizers, taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor is a contraindication for eliglustat use. In intermediate or poor CYP2D6 metabolizers, taking a strong CYP3A inhibitor is a contraindication for eliglustat use; concomitant use of a moderate CYP3A inhibitor and eliglustat is not recommended. In poor CYP2D6 metabolizers, concomitant use of a weak CYP3A inhibitor and eliglustat is not recommended. Eliglustat is also an inhibitor of CYP2D6 and the efflux transporter P-gp. Hence, co-administration of eliglustat with drugs that are substrates for CYP2D6 or P-gp may result in increased concentrations of the concomitant drug.[57803]
Oral bioavailability of eliglustat is low (less than 5% in EMs) due to significant first-pass metabolism. Systemic exposure (Cmax and AUC) depends on CYP2D6 phenotype. Food does not have a clinically significant effect on eliglustat pharmacokinetics. During pharmacokinetic analysis, administration with a high fat meal decreased Cmax by 15% with no change in AUC.[57803]
CYP2D6 extensive metabolizers (EMs)
In CYP2D6 EMs, eliglustat pharmacokinetics are time-dependent and systemic exposure increases in a more than dose proportional manner. After multiple doses of 84 mg PO twice daily, AUC increases approximately 2-fold from time after the first dose to steady state. After multiple doses (84 mg PO twice daily), a mean Cmax of 12 to 25 ng/mL occurs 1.5 to 2 hours after administration. Mean AUC ranges from 76 to 143 hours x ng/mL.[57803]
CYP2D6 intermediate metabolizers (IMs)
In CYP2D6 IMs, eliglustat pharmacokinetics are time-dependent and systemic exposure increases in a more than dose proportional manner. In a single IM subject, the Cmax and AUC after multiple doses (84 mg PO twice daily) were 45 ng/mL and 306 hours x ng/mL, respectively.[57803]
CYP2D6 poor metabolizers (PMs)
In CYP2D6 PMs, eliglustat pharmacokinetics are expected to be linear and time-independent. Compared to EMs, systemic exposure after similar doses at steady state is 7- to 9-fold higher in PMs. After multiple doses (84 mg PO twice daily) a mean Cmax of 113 to 137 ng/mL occurs 3 hours after administration. Mean AUC ranges from 922 to 1,057 hours x ng/mL. Oral dosing of eliglustat 84 mg PO once daily has not been studied in PMs; however, using a physiologically-based pharmacokinetic model, the predicted Cmax and AUC are 75 ng/mL and 956 hours x ng/mL, respectively, after this dose.[57803]
In patients who were extensive metabolizers (EMs) with mild hepatic impairment (n = 6) and moderate hepatic impairment (n = 7), the Cmax was increased by 1.2- fold and 2.8- fold, respectively, compared to EMs with normal hepatic function. The AUC was also increased in patients who were EMs with mild hepatic impairment (1.2- fold increase) and moderate hepatic impairment (5.2- fold increase). The effect of hepatic impairment is highly variable with the coefficients of variation (CVs%) of 135% and 110% for Cmax and 171% and 121% for AUC in CYP2D6 EMs with mild and moderate hepatic impairment, respectively. Eliglustat has not been studied in patients who are CYP2D6 intermediate and poor metabolizers with mild and moderate hepatic impairment. The effect of severe hepatic impairment in patients with any CYP2D6 phenotype is unknown.[57803]
Eliglustat pharmacokinetics were similar in CYP2D6 extensive metabolizers (EMs) with severe renal impairment and healthy CYP2D6 EMs. Eliglustat has not been studied in patients who are EMs with end-stage renal disease (ESRD) or in intermediate or poor metabolizers with any degree of renal impairment.[57803]
Age (18 to 71 years) does not appear to affect eliglustat pharmacokinetics.[57803]
Gender does not appear to affect eliglustat pharmacokinetics.[57803]
Race (most were Caucasian, including those of Ashkenazi Jewish descent; however, the following populations were included: African American, American Indians, Hispanics, and Asians) does not appear to affect eliglustat pharmacokinetics.[57803]
Adequate and well-controlled studies have not been conducted in pregnant women. In animal reproduction studies, a spectrum of anomalies at eliglustat doses 6 times the recommended human dose were observed in orally dosed rats; these anomalies included an increased number of late resorptions, dead fetuses and post implantation loss, reduced fetal body weight, fetal cerebral variations (dilated cerebral ventricles), fetal skeletal variations (poor bone ossification), and fetal skeletal malformations (abnormal number of ribs or lumbar vertebra). However, no fetal harm was observed with oral administration to pregnant rabbits at doses 10 times the recommended human dose. In development studies, eliglustat did not show any significant adverse effects on pre- and postnatal development in rats at doses 5 times the recommended human dose. Eliglustat should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.[57803]
According to the manufacturer, a decision should be made whether to discontinue breast-feeding or discontinue eliglustat. It is not known whether eliglustat is present in human milk.[57803] For women who wish to breast-feed, potential alternative treatments might include enzyme replacement therapies. Enzymes such as alglucerase, imiglucerase, taliglucerase alfa, and velaglucerase alfa are likely to be degraded by the infant's digestive sytem and unlikely to reach the systemic circulation of a nursing infant. Limited data in a report from a panel of clinicians that treat Gaucher's disease indicated that breast-feeding complications were reduced in women treated with alglucerase or imiglucerase postpartum. No adverse effects on the nursing infants were reported secondary to enzyme replacement therapy. Consider reducing the duration of breast-feeding to avoid excessive bone loss in the mother.[49246] Consider the benefits of breast-feeding, the risk of potential drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
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