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Eliglustat

Pronunciation

(el i GLOO stat)

Index Terms

  • Eliglustat Tartrate
  • Genz-112638

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Cerdelga: 84 mg [contains fd&c blue #2 (indigotine)]

Brand Names: U.S.

  • Cerdelga

Pharmacologic Category

  • Enzyme Inhibitor
  • Glucosylceramide Synthase Inhibitor

Pharmacology

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.

Absorption

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

Distribution

Vd: 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%

Use: Labeled 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 (IMs).

Contraindications

Concomitant use of a moderate or strong CYP2D6 inhibitor with a moderate or strong CYP3A inhibitor in extensive metabolizers (EMs) or intermediate metabolizers (IMs); concomitant use of a strong CYP3A inhibitor in poor metabolizers (PMs) or IMs

Dosing: Adult

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. Note: Dosage has not been studied; however the predicted systemic exposures in these patients are within the range of those observed in clinical studies.

Missed dose: If a dose is missed, take the prescribed dose at the next scheduled time; do not double the next dose.

Dosage adjustment for concomitant therapy with strong or moderate CYP2D6 or CYP3A4 inhibitors:

EMs and IMs taking strong or moderate CYP2D6 inhibitors: 84 mg once daily

EMs taking strong or moderate CYP3A inhibitors: 84 mg once daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Mild renal impairment: No dosage adjustment necessary.

Moderate to severe renal impairment: Use is not recommended (has not been studied).

End-stage renal disease (ESRD): Use is not recommended (has not been studied).

Dosing: Hepatic Impairment

Use is not recommended (has not been studied).

Administration

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

Dietary Considerations

Avoid grapefruit or grapefruit juice.

Storage

Store at 20ºC to 25ºC (68ºF to 77ºF); excursions are permitted between 15ºC and 30ºC (59ºF and 86ºF).

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosutinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bosutinib. Avoid combination

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP2D6 Inhibitors (Moderate): May increase the serum concentration of Eliglustat. Management: Reduce the eliglustat dose to 84 mg daily. Avoid use of eliglustat in combination with a moderate CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor. Consider therapy modification

CYP2D6 Inhibitors (Strong): May increase the serum concentration of Eliglustat. Management: Reduce the eliglustat dose to 84 mg daily. Avoid use of eliglustat in combination with a strong CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Eliglustat. Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Eliglustat. Management: Use should be avoided under some circumstances. See full drug interaction monograph for details. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Eliglustat. Management: Use should be avoided under some circumstances. See full drug interaction monograph for details. Consider therapy modification

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Digoxin: Eliglustat may increase the serum concentration of Digoxin. Management: In patients receiving digoxin, measure digoxin serum concentrations prior to initiating eliglustat. Preemptively reduce digoxin doses by 30% and continue monitoring following eliglustat initiation. Consider therapy modification

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Grapefruit Juice: May increase the serum concentration of Eliglustat. Avoid combination

Highest Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Highest Risk QTc-Prolonging Agents. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Indapamide: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Consider therapy modification

Ivabradine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

MiFEPRIStone: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of Eliglustat. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vinflunine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Adverse Reactions

>10%:

Central nervous system: Headache (13% to 40%), fatigue (14%)

Gastrointestinal: Diarrhea (12%), nausea (10% to 12%)

Neuromuscular & skeletal: Arthralgia (45%), back pain (12%), limb pain (11%)

1% to 10%:

Cardiovascular: Palpitations (5%)

Central nervous system: Migraine (10%), dizziness (8%)

Dermatologic: Skin rash (5%)

Gastrointestinal: Flatulence (10%), upper abdominal pain (10%), dyspepsia (7%), gastroesophageal reflux disease (7%), constipation (5%)

Neuromuscular & skeletal: Weakness (8%)

Respiratory: Oropharyngeal pain (10%), cough (7%)

Warnings/Precautions

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: Use is not recommended 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: Not recommended in hepatic impairment or cirrhosis (has not been studied).

• Renal impairment: Not recommended in patients with moderate to severe renal impairment or end-stage renal disease (ESRD); use with caution in patients with mild renal impairment.

• Poor metabolizers: Dosing has not been studied in poor metabolizers (PMs); however, the predicted systemic exposures in these patients are within the range of those observed in clinical studies; monitor these patients for adverse reactions.

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 at https://www.registrynxt.com or by calling 1-800-745-4447 (ext.15500).

Monitoring Parameters

Adverse reactions (especially in PMs)

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies.

Uncontrolled type 1 Gaucher disease is associated an increased risk of spontaneous abortion; maternal hepatosplenomegaly and thrombocytopenia may also occur and lead to adverse pregnancy outcomes.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience abdominal pain, diarrhea, nausea, flatulence, back pain, headache, loss of strength and energy, joint pain, pharyngitis, mouth irritation, or painful extremities. Have patient report immediately to prescriber tachycardia, passing out, arrhythmia, or dizziness (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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