Eliglustat
Eliglustat reduces the formation of a certain protein in the body in people with type 1 Gaucher disease.
Gaucher disease is a genetic condition in which the body lacks the enzyme needed to break down certain fatty materials (lipids). Lipids can build up in the body, causing symptoms such as easy bruising or bleeding, weakness, anemia, bone or joint pain, enlarged liver or spleen, or weakened bones that are easily fractured.
Eliglustat is used to treat mild to moderate type 1 Gaucher disease in adults. Eliglustat is used only if a specific liver enzyme (2D6) in your body breaks down or metabolizes drugs at a certain rate.
Eliglustat may improve the condition of the liver, spleen, bones, and blood cells in people with Type I Gaucher disease. However, eliglustat is not a cure for this condition.
Gaucher disease is a genetic condition in which the body lacks the enzyme needed to break down certain fatty materials (lipids). Lipids can build up in the body, causing symptoms such as easy bruising or bleeding, weakness, anemia, bone or joint pain, enlarged liver or spleen, or weakened bones that are easily fractured.
Eliglustat is used to treat mild to moderate type 1 Gaucher disease in adults. Eliglustat is used only if a specific liver enzyme (2D6) in your body breaks down or metabolizes drugs at a certain rate.
Eliglustat may improve the condition of the liver, spleen, bones, and blood cells in people with Type I Gaucher disease. However, eliglustat is not a cure for this condition.
Mechanism of effect
Eliglustat inhibits the enzyme needed to produce glycosphingolipids and decreases the rate of glycosphingolipid glucosylceramide formation. Glucosylceramide accumulates in type 1 Gaucher disease, causing complications specific to this disease.
Pharmacokinetics
Absorption:
Systemic exposure depends upon the patient's CYP2D6 phenotype; systemic exposure is up to 9-fold higher in poor metabolizers (PMs).
Distribution:
Vd: Extensive metabolizers (EMs): 835 L
Metabolism:
Extensive by CYP2D6 (major) and CYP3A4
Excretion:
Urine (41.8%) and feces (51.4%) as inactive metabolites
Time to Peak:
EMs: 1.5 to 2 hours; PMs: 3 hours
Half-Life Elimination:
EMs: 6.5 hours; PMs: 8.9 hours.
Protein Binding:
76% to 83%
Systemic exposure depends upon the patient's CYP2D6 phenotype; systemic exposure is up to 9-fold higher in poor metabolizers (PMs).
Distribution:
Vd: Extensive metabolizers (EMs): 835 L
Metabolism:
Extensive by CYP2D6 (major) and CYP3A4
Excretion:
Urine (41.8%) and feces (51.4%) as inactive metabolites
Time to Peak:
EMs: 1.5 to 2 hours; PMs: 3 hours
Half-Life Elimination:
EMs: 6.5 hours; PMs: 8.9 hours.
Protein Binding:
76% to 83%
Drug indications
Gaucher disease: Treatment of adult patients with Gaucher disease type 1 (GD1) who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs).
Limitations of use: Patients who are CYP2D6 ultra-rapid metabolizers (URMs) may not achieve adequate concentrations of eliglustat to achieve a therapeutic effect. A specific dosage cannot be recommended for those patients whose CYP2D6 genotype cannot be determined (indeterminate metabolizers).
Limitations of use: Patients who are CYP2D6 ultra-rapid metabolizers (URMs) may not achieve adequate concentrations of eliglustat to achieve a therapeutic effect. A specific dosage cannot be recommended for those patients whose CYP2D6 genotype cannot be determined (indeterminate metabolizers).
Dosage
Usual Adult Dose for Gaucher Disease
Dose recommendations are provided based on CYP450 2D6 Metabolizer Status:
Extensive metabolizers (EM); Intermediate metabolizers (IM); Poor metabolizers (PM)
EM: 84 mg orally twice a day
IM: 84 mg orally twice a day
PM: 84 mg orally once a day
Dose Reduction: 84 mg orally once a day recommended for:
-EM or IM taking a strong or moderate CYP450 2D6 inhibitors
-EM taking a strong or moderate CYP450 3A inhibitor
-EM with mild hepatic impairment taking a weak CYP450 2D6 inhibitor
-EM with mild hepatic impairment taking a strong, moderate, or weak CYP450 3A inhibitor
Comments:
-CYP450 2D6 ultra-rapid metabolizers (URM) may not achieve adequate drug concentrations to achieve a therapeutic effect.
-Dose recommendations cannot be provided for patients whose genotype cannot be determined (indeterminate metabolizers).
Use: For the long-term treatment of patients with Gaucher disease type 1 who are CYP450 2D6 extensive metabolizers, intermediate metabolizers, or poor metabolizers as detected by an FDA-cleared test.
Dose recommendations are provided based on CYP450 2D6 Metabolizer Status:
Extensive metabolizers (EM); Intermediate metabolizers (IM); Poor metabolizers (PM)
EM: 84 mg orally twice a day
IM: 84 mg orally twice a day
PM: 84 mg orally once a day
Dose Reduction: 84 mg orally once a day recommended for:
-EM or IM taking a strong or moderate CYP450 2D6 inhibitors
-EM taking a strong or moderate CYP450 3A inhibitor
-EM with mild hepatic impairment taking a weak CYP450 2D6 inhibitor
-EM with mild hepatic impairment taking a strong, moderate, or weak CYP450 3A inhibitor
Comments:
-CYP450 2D6 ultra-rapid metabolizers (URM) may not achieve adequate drug concentrations to achieve a therapeutic effect.
-Dose recommendations cannot be provided for patients whose genotype cannot be determined (indeterminate metabolizers).
Use: For the long-term treatment of patients with Gaucher disease type 1 who are CYP450 2D6 extensive metabolizers, intermediate metabolizers, or poor metabolizers as detected by an FDA-cleared test.
Drug contraindications
Use in extensive metabolizers (EMs) with moderate or severe hepatic impairment; use in intermediate metabolizers (IMs) or poor metabolizers (PMs) with any degree of hepatic impairment; concomitant use of a moderate or strong CYP2D6 inhibitor with a moderate or strong CYP3A inhibitor in EMs or IMs; concomitant use of a strong CYP3A inhibitor in PMs or IMs; concomitant use of a moderate or strong CYP2D6 inhibitor in EMs with mild hepatic impairment.
Canadian labeling: Additional contraindications (not in the US labeling): Hypersensitivity to eliglustat or any component of the formulation; hereditary problems of galactose intolerance, glucose-galactose malabsorption, or the Lapp lactase deficiency; concomitant use of a strong CYP3A4 inhibitor in EMs with mild hepatic impairment.
Canadian labeling: Additional contraindications (not in the US labeling): Hypersensitivity to eliglustat or any component of the formulation; hereditary problems of galactose intolerance, glucose-galactose malabsorption, or the Lapp lactase deficiency; concomitant use of a strong CYP3A4 inhibitor in EMs with mild hepatic impairment.
Side effects
Side effects requiring immediate medical attention
Along with its needed effects, eliglustat may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur while taking eliglustat:
Less common:
Fast, irregular, pounding, or racing heartbeat or pulse
Incidence not known
Dizziness
fainting
Get emergency help immediately if any of the following symptoms of overdose occur while taking eliglustat:
Symptoms of overdose:
Blurred vision
chest pain or discomfort
confusion
dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
nausea
sweating
unusual tiredness or weakness
vomiting
Side effects not requiring immediate medical attention
Some side effects of eliglustat may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.
Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:
More common
Back pain
belching
bloated
cough
diarrhea
difficulty with moving
excess air or gas in the stomach or bowels
full feeling
headache
heartburn
indigestion
lack or loss of strength
muscle pain or stiffness
pain in the arms or legs
pain in the joints
passing gas
sore throat
stomach discomfort, upset, or pain
upper abdominal or stomach pain
Less common
Difficulty having a bowel movement
rash
Along with its needed effects, eliglustat may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur while taking eliglustat:
Less common:
Fast, irregular, pounding, or racing heartbeat or pulse
Incidence not known
Dizziness
fainting
Get emergency help immediately if any of the following symptoms of overdose occur while taking eliglustat:
Symptoms of overdose:
Blurred vision
chest pain or discomfort
confusion
dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
nausea
sweating
unusual tiredness or weakness
vomiting
Side effects not requiring immediate medical attention
Some side effects of eliglustat may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.
Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:
More common
Back pain
belching
bloated
cough
diarrhea
difficulty with moving
excess air or gas in the stomach or bowels
full feeling
headache
heartburn
indigestion
lack or loss of strength
muscle pain or stiffness
pain in the arms or legs
pain in the joints
passing gas
sore throat
stomach discomfort, upset, or pain
upper abdominal or stomach pain
Less common
Difficulty having a bowel movement
rash
Interactions
Daunorubicin , Ranolazine , Mirabegron , Nefazodone , nelfinavir , Zileuton , carfilzomib , Quinine , Lorcaserin , Tipranavir , Etravirine , Dabrafenib , Darifenacin , Mibefradil , Nicardipine , cobicistat , Delavirdine , Desloratadine , Crizotinib , Edoxaban , Entrectinib , Amiodarone , Aprepitant , Erythromycin , Itraconazole , Isoniazid , Imatinib , rolapitant , Troleandomycin , Ceritinib , Brexpiprazole , conivaptan , givosiran , fosaprepitant , Abiraterone , Celecoxib , Telaprevir , Isavuconazonium , Fedratinib , Dacomitinib , Ribociclib , Dofetilide , Ibutilide , Diphenhydramine , Fosphenytoin , Idelalisib , Mifepristone , Telithromycin , boceprevir , Indinavir , Procainamide , Panobinostat , dronedarone , ritonavir , saquinavir , mitotane , Amprenavir , Fosamprenavir , Enzalutamide , Flecainide , Rifabutin , Rifapentine , Darunavir , propoxyphene , Carbamazepine , Ketoconazole , Clarithromycin , Colchicine , Clobazam , Clotrimazole , Fluconazole , Phenobarbital , Phenytoin , Miconazole , Verapamil , Voriconazole , Cimetidine , Sertraline , Sotalol , Ciprofloxacin , Cinacalcet , Fluoxetine , Thioridazine , Duloxetine , Docetaxel , Disopyramide , Diltiazem , Rifampin , Paroxetine , Propafenone , Primidone , Posaconazole , Pimozide , Terbinafine , oleandomycin , Naltrexone and Bupropion , Bepridil , Sarecycline , lasmiditan , talazoparib , stiripentol , Venetoclax , dexmedetomidine , Fidaxomicin
st. john's wort
Alerts
Concerns related to adverse effects:
• Arrhythmias: May cause increases in ECG intervals (PR, QTc, and QRS) at substantially elevated eliglustat plasma concentrations.
Disease-related concerns:
• Cardiovascular disease: Avoid use in patients with preexisting cardiac disease (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) antiarrhythmic medications (has not been studied).
• Hepatic impairment: Use is contraindicated in extensive metabolizers (EMs) with moderate to severe hepatic impairment and intermediate metabolizers (IMs) or poor metabolizers (PMs) with any degree of hepatic impairment; concomitant use of a moderate or strong CYP2D6 inhibitor in EMs with mild hepatic impairment is also contraindicated.
• Renal impairment: Avoid use in IMs and PMs with any degree of renal impairment and in EMs with ESRD.
Concurrent drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Other warnings/precautions:
• Registry: A registry has been established and all patients with Gaucher disease, and health care providers who treat Gaucher disease are encouraged to participate. Information on the International Collaborative Gaucher Group (ICGG) Gaucher Registry may be obtained .
• Arrhythmias: May cause increases in ECG intervals (PR, QTc, and QRS) at substantially elevated eliglustat plasma concentrations.
Disease-related concerns:
• Cardiovascular disease: Avoid use in patients with preexisting cardiac disease (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) antiarrhythmic medications (has not been studied).
• Hepatic impairment: Use is contraindicated in extensive metabolizers (EMs) with moderate to severe hepatic impairment and intermediate metabolizers (IMs) or poor metabolizers (PMs) with any degree of hepatic impairment; concomitant use of a moderate or strong CYP2D6 inhibitor in EMs with mild hepatic impairment is also contraindicated.
• Renal impairment: Avoid use in IMs and PMs with any degree of renal impairment and in EMs with ESRD.
Concurrent drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Other warnings/precautions:
• Registry: A registry has been established and all patients with Gaucher disease, and health care providers who treat Gaucher disease are encouraged to participate. Information on the International Collaborative Gaucher Group (ICGG) Gaucher Registry may be obtained .
Points of recommendation
You should not use eliglustat if you have severe liver or kidney disease.
Eliglustat can cause a serious heart problem, especially if you use certain other medicines at the same time. Tell your doctor about all medicines you use.
Sometimes it is not safe to use certain medications at the same time. Some drugs can raise or lower your blood levels of eliglustat, which may cause side effects or make eliglustat less effective. Eliglustat can also affect blood levels of certain other drugs, making them less effective or increasing side effects.
Your doctor may need to change your treatment plan if you use any of the following drugs:
St. John's wort;
antifungal medicine;
tuberculosis medicine;
seizure medicine;
heart or blood pressure medications;
an antidepressant; or
medicine to treat a mental illness.
You should not use eliglustat if you are allergic to it, or if you have:
severe liver disease.
Tell your doctor if you have ever had:
long QT syndrome or other heart rhythm disorder;
heart disease or a heart attack;
liver disease; or
kidney disease.
It is not known whether eliglustat will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.
You should not breast-feed while using this medicine.
Eliglustat is not approved for use by anyone younger than 18 years old.
Your doctor will perform a genotype blood test to make sure eliglustat is the right treatment for you.
Follow all directions on your prescription label and read all medication guides or instruction sheets. Your doctor may occasionally change your dose. Use the medicine exactly as directed.
If you switched to eliglustat from another enzyme replacement medicine, wait at least 24 hours after your last dose of the other medicine before you start taking eliglustat.
Eliglustat is usually taken 1 or 2 times per day, based on the results of your genotype test. Follow your doctor's dosing instructions very carefully.
Take this medicine with a full glass of water.
Take the medicine at the same time each day, with or without food.
Swallow the capsule whole and do not crush, chew, break, or open it.
Eliglustat can cause a serious heart problem. Your heart function may be checked with an electrocardiograph or ECG (sometimes called an EKG) before you take this medicine.
Store at room temperature away from moisture and heat.
Storage
Store at 20ºC to 25ºC (68ºF to 77ºF); excursions are permitted between 15ºC and 30ºC (59ºF and 86ºF).
Eliglustat can cause a serious heart problem, especially if you use certain other medicines at the same time. Tell your doctor about all medicines you use.
Sometimes it is not safe to use certain medications at the same time. Some drugs can raise or lower your blood levels of eliglustat, which may cause side effects or make eliglustat less effective. Eliglustat can also affect blood levels of certain other drugs, making them less effective or increasing side effects.
Your doctor may need to change your treatment plan if you use any of the following drugs:
St. John's wort;
antifungal medicine;
tuberculosis medicine;
seizure medicine;
heart or blood pressure medications;
an antidepressant; or
medicine to treat a mental illness.
You should not use eliglustat if you are allergic to it, or if you have:
severe liver disease.
Tell your doctor if you have ever had:
long QT syndrome or other heart rhythm disorder;
heart disease or a heart attack;
liver disease; or
kidney disease.
It is not known whether eliglustat will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.
You should not breast-feed while using this medicine.
Eliglustat is not approved for use by anyone younger than 18 years old.
Your doctor will perform a genotype blood test to make sure eliglustat is the right treatment for you.
Follow all directions on your prescription label and read all medication guides or instruction sheets. Your doctor may occasionally change your dose. Use the medicine exactly as directed.
If you switched to eliglustat from another enzyme replacement medicine, wait at least 24 hours after your last dose of the other medicine before you start taking eliglustat.
Eliglustat is usually taken 1 or 2 times per day, based on the results of your genotype test. Follow your doctor's dosing instructions very carefully.
Take this medicine with a full glass of water.
Take the medicine at the same time each day, with or without food.
Swallow the capsule whole and do not crush, chew, break, or open it.
Eliglustat can cause a serious heart problem. Your heart function may be checked with an electrocardiograph or ECG (sometimes called an EKG) before you take this medicine.
Store at room temperature away from moisture and heat.
Storage
Store at 20ºC to 25ºC (68ºF to 77ºF); excursions are permitted between 15ºC and 30ºC (59ºF and 86ºF).
Pregnancy level
HAVE NOT BEEN ESTABLISHEDBenefit should outweigh risk
AU TGA pregnancy category: B3
US FDA pregnancy category: Not Assigned
Risk Summary: Limited data are not sufficient to assess drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
Comments:
-Women with Gaucher disease are at an increased risk of spontaneous abortion, especially if disease symptoms are not controlled prior to conception and during pregnancy.
AU TGA pregnancy category: B3
US FDA pregnancy category: Not Assigned
Risk Summary: Limited data are not sufficient to assess drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
Comments:
-Women with Gaucher disease are at an increased risk of spontaneous abortion, especially if disease symptoms are not controlled prior to conception and during pregnancy.
Breast feeding warning
Benefit should outweigh risk
Excreted into human milk: Unknown
Excreted into animal milk: Yes
Comments: The effects in the nursing infant are unknown.
Excreted into human milk: Unknown
Excreted into animal milk: Yes
Comments: The effects in the nursing infant are unknown.
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