Cerdelga (Eliglustat) is an oral medicine that is indicated for the treatment of patients with Gaucher disease type 1 (who are extensive metabolizers).

Cerdelga (Eliglustat) Uses:

• Gaucher disease:

  • Treatment of adult patients with Gaucher disease type 1 (GD1) the ones 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 attain adequate concentrations of eliglustat to achieve a therapeutic effect.
    • A specific dosage cannot be suggested for those patients whose CYP2D6 genotype cannot be determined (indeterminate metabolizers).

Adult dose:

Cerdelga (Eliglustat) Dose in the treatment of Gaucher disease: Oral:

Note:

• Dosage is based on patient CYP2D6 metabolizer status (extensive metabolizers [EMs], intermediate metabolizers [IMs], or poor metabolizers [PMs]) determined by an FDA-cleared test.
• EMs and IMs:
  • 84 mg twice daily
• PMs:
  • 84 mg once daily.

• Missed dose:

  • Though in case a dose is missed, take the prescribed dose at the next scheduled time; no need to double the next dose.

• Cerdelga (Eliglustat) Dosage adjustment for concomitant therapy with CYP2D6 or CYP3A4 inhibitors:

  • EMs taking strong or moderate CYP2D6 inhibitor:
    • 84 mg once daily
  • EMs taking strong or moderate CYP3A inhibitor:
    • 84 mg once daily
  • EMs taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor:
    • Use is contraindicated.
  • IMs taking strong or moderate CYP2D6 inhibitor:
    • 84 mg once daily
  • IMs taking strong CYP3A inhibitor:
    • Use is contraindicated.
  • IMs taking moderate CYP3A inhibitor:
    • Avoid its use.
  • IMs taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor:
    • Use is contraindicated.
  • PMs taking strong CYP3A inhibitor:
    • Use is contraindicated.
  • PMs taking moderate or weak CYP3A inhibitor:
    • Avoid using it.

• Conversion from imiglucerase, velaglucerase alfa, or taliglucerase alfa:

  • Eliglustat may be administered 24 hours after the last dose of the previous enzyme replacement therapy (ERT).

Use in Children:

Not indicated.

Pregnancy Risk Category: B3

• • • Some adverse events were seen in animal reproduction studies.
    • Type 1 Gaucher disease, which is uncontrolled, can increase the risk of spontaneous abortion. Maternal hepatosplenomegaly or thrombocytopenia could also increase and cause adverse pregnancy outcomes.

Eliglustat can be used during lactation

• • It is not known if eliglustat can be added to breast milk.
  • According to the manufacturer, when deciding whether to discontinue or continue breastfeeding during therapy, it is important to consider the risks to infant exposure, the benefits to the infant and the benefits to the mother.

Cerdelga (Eliglustat) Dose in Kidney disease: 

Note: Its use in patients with renal impairment is based on patient CYP2D6 metabolizer status.

• Mild to severe renal impairment (CrCl ≥15 mL/minute):

  • Extensive metabolizers (EMs):
    • No dosage adjustment is necessary.
  • Intermediate metabolizers (IMs) and poor metabolizers (PMs):
    • Avoid using it.

• ESRD (CrCl <15 mL/minute with or without dialysis):

  • EMs, IMs, and PMs:
    • Avoid use.

Cerdelga (Eliglustat) Dose in Liver disease:

Note: Its use in patients with hepatic impairment is based on patient CYP2D6 metabolizer status and concomitant use of CYP2D6 or CYP3A inhibitors.

• Mild hepatic impairment (Child-Pugh class A):

  • Extensive metabolizers (EMs) (without concomitant use of CYP2D6 or CYP3A inhibitors):
    • No dosage adjustment is necessary.
  • EMs taking a weak CYP2D6 inhibitor or a strong, moderate, or weak CYP3A4 inhibitor:
    • 84 mg once a day.
  • EMs taking a strong or moderate CYP2D6 inhibitor:
    • Use is contraindicated.
  • Intermediate metabolizers (IMs):
    • Use is contraindicated.
  • Poor metabolizers (PMs):
    • Use is contraindicated.

• Moderate to severe hepatic impairment (Child-Pugh class B and C):

  • EMs, IMs, and PMs:
    • Use is contraindicated.

Common Side Effects of Cerdelga (Eliglustat):

• Central nervous system:

  • Headache
  • Fatigue

• Gastrointestinal:

  • Diarrhea
  • Nausea

• Neuromuscular & skeletal:

  • Arthralgia
  • Back pain
  • Limb pain

Less Common Side Effects of Cerdelga (Eliglustat):

• Cardiovascular:

  • Palpitations

• Central nervous system:

  • Migraine
  • Dizziness

• Dermatologic:

  • Skin rash

• Gastrointestinal:

  • Flatulence
  • Upper abdominal pain
  • Dyspepsia
  • Gastroesophageal reflux disease
  • Constipation

• Neuromuscular & skeletal:

  • Weakness

• Respiratory:

  • Oropharyngeal pain
  • Cough

Contraindications to Cerdelga (Eliglustat):

• • • Use in severe or moderate hepatic impairment with extensive metabolizers (EMs);
    • Use in intermediate metabolizers or poor metabolizers with any degree of hepatic impairment.
    • Concomitant use in EMs and IMs of a strong or moderate CYP2D6 inhibitor with a strong or moderately weak CYP3A inhibitor;
    • Use of a strong CYP3A inhibitor in PMs or IMs concurrently
    • Concomitant use a strong or moderate CYP2D6 inhibitor in EMs with mild hepatic impairment.

Canadian labeling: Additional contraindications not in the US labeling

• • • Hypersensitivity to eliglustat and any component of the formula
    • Hereditary problems such as glucose-galactose malabsorption or galactose intolerance;
    • Concomitant use a strong CYP3A4 inhibitor in EMs with mild hepatic impairment

Warnings and precautions

• • Arrhythmias:

    • At substantially higher eliglustat plasma levels, it may cause an increase in ECG intervals (PRQTc and QRS).

  • Cardiovascular disease

    • Avoid use in patients with preexisting heart disease (CHF), bradycardia (recent acute MI), ventricular arrhythmia (long QT syndrome) and in combination with Class IIA (eg quinidine, procainamide) or Class III (e.g. amiodarone, sotalol) antiarrhythmic medications (has not been studied).

  • Hepatic impairment

    • It is not recommended for extensive metabolizers with severe hepatic impairment, intermediate metabolizers or poor metabolizers with any degree of hepatic impairment.
    • Concomitant use in EMs with mild hepatic impairment of a strong or moderate CYP2D6 inhibitor is also not recommended.

  • Renal impairment

    • Avoid use in IMs or PMs with any degree renal impairment, and in EMs that have ESRD.

Eliglustat: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

  Risk Factor C (Monitor therapy).
  Ajmaline	High risk of Inhibitors increasing serum concentrations of CYP2D6 Substrates
  ARIPiprazole	CYP2D6 inhibitors (Weak), may increase serum levels of ARIPiprazole. Monitoring for increased aripiprazole-pharmacologic effects is important. Aripiprazole dosage adjustments may be necessary depending on the indication and/or concomitant therapy. For more information, consult the full interaction monograph.
  Bosentan	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
  Brentuximab Vedotin	Brentuximab Vedotin may be increased by P-glycoprotein/ABCB1 inhibitors. Concentrations of the monomethyl auristatin E component (MMAE) may increase.
  Celiprolol	The serum concentration of Celiprolol may be increased by P-glycoprotein/ABCB1 inhibitors
  CloBAZam	High risk of Inhibitors increasing serum concentrations of CYP2D6 Substrates
  Clofazimine	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Moderate CYP3A4 Inducers	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
  Deferasirox	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
  Erdafitinib	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
  Erdafitinib	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Everolimus	Everolimus serum concentration may be increased by P-glycoprotein/ABCB1 inhibitors
  Fosaprepitant	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Haloperidol	QT-prolonging agents (Indeterminate risk - Avoid) can increase the QTcprolonging effects of Haloperidol.
  Ivosidenib	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
  Larotrectinib	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Larotrectinib	The serum concentration of Larotrectinib may be increased by P-glycoprotein/ABCB1 inhibitors
  Lumefantrine	High risk of Inhibitors increasing serum concentrations of CYP2D6 Substrates
  Naldemedine	The serum concentrations of Naldemedine may be increased by P-glycoprotein/ABCB1 inhibitors.
  Naloxegol	The serum concentrations of Naloxegol may be increased by P-glycoprotein/ABCB1 inhibitors.
  Palbociclib	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Panobinostat	High risk of Inhibitors increasing serum concentrations of CYP2D6 Substrates
  Peginterferon Alfa-2b	High risk with inhibitors. May lower serum concentrations of CYP2D6 substrates. Peginterferon Alf-2b could increase serum concentrations of CYP2D6 Substrates.
  P-glycoprotein/ABCB1 Substrates	P-glycoprotein/ABCB1 inhibitors may increase serum levels of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors can also increase the distribution of p.glycoprotein substrates in specific cells/tissues/organs that have high levels (e.g. brain, T-lymphocytes and testes). Loperamide is an exception.
  Prucalopride	The serum concentrations of Prucalopride may be increased by P-glycoprotein/ABCB1 inhibitors.
  Agents that prolong QT (Highest risk)	QT-prolonging agents (Indeterminate risk - Avoid) can increase the QTc prolonging effect QT-prolonging agents (Highest risk). When using these agents together, be sure to monitor for QTc interval prolongation or ventricular arrhythmias. Patients at higher risk for QTc prolongation might have additional risk factors.
  QuiNINE	High risk of Inhibitors increasing serum concentrations of CYP2D6 Substrates
  Ranolazine	Ranolazine may be increased by P-glycoprotein/ABCB1 inhibitors.
  RifAXIMin	The serum concentrations of RifAXIMin may be increased by P-glycoprotein/ABCB1 inhibitors
  Sarilumab	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
  Silodosin	The serum concentrations of Silodosin may be increased by P-glycoprotein/ABCB1 inhibitors.
  Siltuximab	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
  Simeprevir	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Talazoparib	Talazoparib serum concentration may be increased by P-glycoprotein/ABCB1 inhibitors. Management: The following exceptions are addressed in separate interaction monographs.
  Tocilizumab	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
  Risk Factor D (Consider therapy modifications)
  Abiraterone Acetate	High risk of Inhibitors causing an increase in serum concentrations of CYP2D6 substrates. When possible, avoid concurrent use of abiraterone and CYP2D6 Substrates with a narrow therapeutic index. If concurrent use cannot be avoided, closely monitor patients for signs and symptoms of toxic effects.
  Afatinib	The serum concentrations of Afatinib may be increased by P-glycoprotein/ABCB1 inhibitors. If afatinib is not tolerated, reduce the dose by 10mg according to US labeling. Canadian labeling states that it is best to avoid combination therapy. If you must use the P-gp inhibitor, do so simultaneously with or after afatinib.
  Asunaprevir	High risk of Inhibitors increasing serum concentrations of CYP2D6 Substrates
  Betrixaban	The serum concentration of Betrixaban may be increased by P-glycoprotein/ABCB1 inhibitors. Management: Reduce the initial dose of betrixaban to 80 mg, followed by 40 mg daily if taken with a Pglycoprotein inhibitor.
  Bilastine	Bilastine may be increased by P-glycoprotein/ABCB1 inhibitors. Patients with severe or moderate renal impairment who are on p-glycoprotein inhibitors should consider other options.
  Colchicine	The serum Colchicine concentration may be increased by P-glycoprotein/ABCB1 inhibitors. The distribution of Colchicine into specific tissues, such as the brain, may be increased. Patients with impaired renal and hepatic function, who are also taking a p-glycoprotein inhibitor, should not be given colchicine. Reduce the dose of colchicine for those with normal renal or hepatic function. See full monograph for details.
  Moderate CYP2D6 inhibitors	Eliglustat serum concentration may increase Management: Lower the daily eliglustat dose by 84 mg. Use eliglustat only in combination with a mild CYP2D6 inhibitor or a strong/moderate CYP3A4 inhibitor.
  Strong CYP2D6 inhibitors	Eliglustat serum concentration may increase Management: Lower the daily eliglustat dose by 84 mg. Use eliglustat only in combination with a strong CYP2D6 inhibitor and a strong, moderate or strong CYP3A4 inhibitor.
  Moderate CYP3A4 inhibitors	Eliglustat serum concentration may increase Under certain circumstances, Eliglustat should not be used. For more information, please refer to the full drug interaction monograph.
  Strong CYP3A4 inhibitors	Eliglustat serum concentration may increase Under certain circumstances, Eliglustat should not be used. For more information, please refer to the full drug interaction monograph.
  Dabigatran Etexilate	The serum concentrations may be increased by P-glycoprotein/ABCB1 inhibitors. Treatment: Dabigatran dosage reductions may be necessary. Particular recommendations can vary depending on the labeling of the US and Canada, specific Pgp inhibitors, renal function, indications for dabigatran therapy, and other factors. Refer to the full monograph and dabigatran labeling.
  Dabrafenib	High risk of Inducers causing a decrease in serum CYP3A4 substrates. Management: If possible, seek alternatives to the CYP3A4 substrate. Concomitant therapy should be avoided if possible. Monitor the clinical effects of the substrate carefully (especially therapeutic effects).
  Dacomitinib	High risk of Inhibitors causing an increase in serum concentrations of CYP2D6 substrates. Management: Do not use dacomitinib concurrently with CYP2D6 Substrates that have a narrow therapeutic Index.
  Digoxin	The serum Digoxin concentration may be increased by Eliglustat. Treatment: Before initiating eliglustat, take digoxin serum levels from patients who are taking digoxin. Reduce digoxin doses 30% before eliglustat initiation. Continue monitoring.
  DOXOrubicin (Conventional)	P-glycoprotein/ABCB1 inhibitors may increase serum levels of DOXOrubicin (Conventional). Treatment: If you are treated with doxorubicin, consider alternative P-glycoprotein inhibitors. These combinations should be avoided according to one U.S. manufacturer, Pfizer Inc.
  Edoxaban	The serum concentrations of Edoxaban may be increased by P-glycoprotein/ABCB1 inhibitors. Management: See full monograph for details. Patients receiving edoxaban to treat venous embolism are advised to take lower doses when taking it with P-gp inhibitors. For patients with atrial fibrillation, edoxaban should not be adjusted in the same way.
  Lorlatinib	High risk of Inducers causing a decrease in serum concentrations of CYP3A4 substrates. Management: Do not use lorlatinib concurrently with any CYP3A4 Substrates. Even a slight decrease in serum concentrations could cause therapeutic failure or serious clinical consequences.
  MiFEPRIStone	High risk of Inhibitors causing an increase in serum concentrations of CYP3A4 substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid dihydroergotamine and ergotamine.
  Pitolisant	High risk of Inducers causing a decrease in serum concentrations of CYP3A4 substrates Management: Avoid combining pitolisant and a CYP3A4 substrat with a low therapeutic index. Pitolisant should not be combined with other CYP3A4 sub-substances.
  Stiripentol	High risk of Inhibitors causing an increase in serum concentrations of CYP3A4 substrates. Management: Avoid stiripentol use with CYP3A4 Substrates that have a narrow therapeutic Index. This is to avoid adverse effects and toxicities. Monitoring of any CYP3A4 substrate that is used with stiripentol should be closely done.
  Venetoclax	Venetoclax may be increased by P-glycoprotein/ABCB1 inhibitors. Treatment: Patients who are concomitantly treated with P-glycoprotein inhibitors (P-gp), should consider a venetoclax dose decrease of at least 50%.
  Risk Factor X (Avoid Combination)
  Conivaptan	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Strong CYP3A4 Inducers	Eliglustat serum concentration may be decreased
  Fusidic Acid (Systemic).	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  Grapefruit Juice	Eliglustat serum concentration may be increased
  Idelalisib	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
  PAZOPanib	P-glycoprotein/ABCB1 inhibitors may increase serum levels of PAZOPanib.
  St John's Wort	Eliglustat serum concentration may be decreased
  Topotecan	Topotecan serum concentrations may be increased by P-glycoprotein/ABCB1 inhibitors
  VinCRIStine (Liposomal)	The serum VinCRIStine (Liposomal) concentration may be increased by P-glycoprotein/ABCB1 inhibitors

Monitoring parameters:

• Severe reactions (especially in PMs)
• CBC, platelets, prothrombin, electrolytes, chitotriosidase, angiotensin-converting enzyme (ACE), tartrate-resistant acid phosphatase (TRAP)
• MRI or CT scan (liver and spleen volume), skeletal x-rays, DXA; pulmonary function tests
• hepatic and renal function, ECG/echocardiography
• growth in pediatric patients.

How to administer Cerdelga (Eliglustat)?

Oral: Administer it with or without food. Swallow capsules whole with water; do not crush, dissolve, or open. Though, avoid grapefruit or grapefruit juice. 

Mechanism of action of Cerdelga (Eliglustat):

Eliglustat blocks the enzyme required to make glycosphingolipids. It also decreases the rate at which glycosphingolipids glucosylceramide are formed. Type 1 Gaucher disease is where glucosylceramide builds up, which can lead to complications. Absorption:

• Systemic exposure depends upon the patient's CYP2D6 phenotype;
• systemic exposure is up to 9-fold higher in poor metabolizers (PMs).

Protein binding:

• 76% to 83%

Metabolism:

• Extensive by CYP2D6 (major) and CYP3A4

Bioavailability:

• EMs: <5%

Half-life elimination:

• EMs: 6.5 hours;
• PMs: 8.9 hours

Time to peak:

• EMs: 1.5 to 2 hours;
• PMs: 3 hours

Excretion:

• Urine (41.8%) and feces (51.4%) as inactive metabolites

International Brand Names of Eliglustat:

• Cerdelga

Eliglustat Brand Names in Pakistan:

No Brands Available in Pakistan.