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ELIGLUSTAT

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Eliglustat is a glucosylceramide synthase inhibitor that is used for the long-term treatment of adult patients with Gaucher disease type 1 (a disease that leads to accumulation of glucosylceramide) who are CYP2D6 extensive metabolizers, intermediate metabolizers or poor metabolizers.

Specific Substances

    1) Eliglustat tartrate
    2) Genz-112638
    1.2.1) MOLECULAR FORMULA
    1) C23H36N2O4+1/2(C4H6O6)

Available Forms Sources

    A) FORMS
    1) Eliglustat is supplied as 84 mg hard gelatin capsule with a blue-green opaque cap and pearl white opaque body imprinted with "GZ02" in black. A capsule contains 100 mg eliglustat tartrate, with is equivalent to 84 mg of eliglustat (Prod Info CERDELGA (TM) oral capsules, 2014).
    B) USES
    1) Eliglustat, a glucosylceramide synthase inhibitor, is used orally for the long-term treatment of adult patients with Gaucher disease type 1 (GD1) who are CYP2D6 extensive metabolizers, intermediate metabolizers or poor metabolizers. Treatment results in the reduced production of glucosylceramide (Prod Info CERDELGA (TM) oral capsules, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Eliglustat, a glucosylceramide synthase inhibitor, is used orally for the long-term treatment of adult patients with Gaucher disease type 1 (GD1) who are CYP2D6 extensive metabolizers, intermediate metabolizers or poor metabolizers. It is a CYP2D6 and CYP3A substrate. Treatment results in the reduced production of glucosylceramide.
    B) PHARMACOLOGY: Eliglustat acts as a substrate reduction therapy. In Gaucher disease, patients are deficient in acid beta-glucosidase, a lysosomal enzyme. This deficiency leads to accumulation of glucosylceramide in lysosomal compartments of macrophages and formation of Gaucher cells (foam cells). Eliglustat inhibits glucosylceramide synthase, which thereby reduces glucosylceramide accumulation.
    C) EPIDEMIOLOGY: Exposure is rare. There are no reports of overdose.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: The most frequently reported adverse events occurring in greater than 10% of patients include fatigue, headache, nausea, back pain, pain in extremities and upper abdominal pain. OTHER EVENTS: Adverse events reported less frequently with eliglustat therapy are dizziness, asthenia, cough, dyspepsia, gastroesophageal reflux disease, constipation, palpitations and rash.
    2) ECG CHANGES: In patients with a history of cardiac disease, long QT syndromes, and in combination with Class IA (ie, quinidine, procainamide) and Class III (ie, amiodarone, sotalol) antiarrhythmic medications, the administration of eliglustat is not recommended because it may cause an increase in ECG intervals (ie, PR, QTc, and QRS intervals) at substantially increased plasma concentrations and a potential for cardiac dysrhythmias.
    3) DRUG-DRUG INTERACTIONS: Drugs that inhibit CYP2D6 and CYP3A may significantly increase plasma concentrations of eliglustat resulting in increases in PR, QTc and/or QRS intervals that could potentially lead to cardiac dysrhythmias.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited data. Clinical events are anticipated to be an extension of events reported with therapeutic use.
    2) MILD TO MODERATE TOXICITY: Gastrointestinal (ie, nausea, vomiting, diarrhea) and CNS (ie, headache) events are likely to occur.
    3) SEVERE TOXICITY: In a single-dose escalation study in healthy subjects, a dose approximately equivalent to 21 times (59-fold higher than normal therapeutic concentrations) the recommended dose for Gaucher disease type 1 patients (approximately 1764 mg) produced nausea, vomiting, hypotension, bradycardia, and dizziness resulting in significant disequilibrium.
    0.2.20) REPRODUCTIVE
    A) Eliglustat is classified as FDA pregnancy C. There are no adequate or well-controlled studies of eliglustat in pregnant women. In animal studies, the administration of eliglustat (approximately 6 times the recommended human dose based on body surface area) produced an increase in the number of late resorptions, fetal death, post implantation loss, reduced fetal weight, fetal skeletal variations and fetal skeletal malformations. It is not known whether eliglustat is excreted into human breast milk.

Laboratory Monitoring

    A) Monitor vital signs and neurologic function.
    B) Monitor fluid and electrolyte balance in patients with persistent vomiting and/or diarrhea or as indicated.
    C) Obtain a baseline ECG and institute continuous cardiac monitoring following a significant exposure or in patients with a history of cardiac disease (eg, CHF, myocardial infarction, bradycardia, heart block or dysrhythmias) or coadministration of drugs that are Class lA (procainamide, quinidine) or Class IIl (amiodarone, sotalol) antiarrhythmic medications, or drugs that inhibit CYP2D6 and CYP3A.
    D) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Overdose information is limited. Significant toxicity is not anticipated following a mild to moderate exposure. Monitor vital signs and neurologic function. Gastrointestinal events (ie, nausea, vomiting and/or diarrhea) are likely to occur. Monitor fluid and serum electrolytes as indicated. Replace fluids (oral or IV fluids) and electrolytes as necessary.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant electrolyte abnormalities in patients with severe vomiting and/or diarrhea. HYPOTENSION: Treat moderate to severe hypotension with IV fluids, dopamine or norepinephrine as necessary. ECG CHANGES/POTENTIAL DYSRHYTHMIAS: Obtain a baseline ECG and institute continuous cardiac monitoring following a significant exposure or in patients at risk (ie, a history of cardiac disease including CHF, myocardial infarction, heart block, dysrhythmias, patients taking Class IA (ie, quinidine, procainamide ) or Class III (ie, sotalol, amiodarone) antiarrhythmic medications, or patients with known drug-drug interactions (ie, CYP2D6 and CYP3A inhibitors).
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital activated charcoal is unlikely to be necessary.
    2) HOSPITAL: Consider activated charcoal if a recent large overdose or significant coingestants are suspected and the patient is not vomiting and the airway is protected.
    D) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary unless the patient has a had a significant exposure or more toxic agents are involved.
    E) ANTIDOTE
    1) There is no known antidote.
    F) HYPOTENSION
    1) Administer IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids.
    G) VENTRICULAR DYSRHYTHMIAS
    1) Theoretically, eliglustat is likely to cause an increase in PR, QTc and QRS intervals at significantly elevated plasma concentrations; therefore, it is not recommend in patients with a history of cardiac disease, long QT syndromes, and in combination with Class IA (ie, quinidine, procainamide) and Class III (ie, amiodarone, sotalol) antiarrhythmic medications due to the increased risk of cardiac arrhythmias. In addition, eliglustat is a CYP2D6 and CYP3A substrate and drugs that inhibit these pathways may significantly increase plasma concentrations of eliglustat resulting in increases in PR, QTc and/or QRS intervals that could potentially lead to cardiac dysrhythmias. Obtain an ECG, institute continuous cardiac monitoring and administer oxygen as indicated. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Correct electrolyte abnormalities. Consider lidocaine for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution. Unstable rhythms require immediate cardioversion.
    H) ENHANCED ELIMINATION
    1) Eliglustat has a large volume of distribution (835 L) and moderately protein bound (76% to 83%); therefore, hemodialysis is UNLIKELY to be effective.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic adults with an inadvertent ingestion of 1 to 2 extra doses or an adult with mild gastrointestinal symptoms can be monitored at home. An asymptomatic child with an inadvertent ingestion (1 tablet) or mild gastrointestinal symptoms can be monitored at home with adult supervision.
    2) OBSERVATION CRITERIA: Patients that have more than mild gastrointestinal symptoms or had a deliberate ingestion should be referred to a healthcare facility for evaluation and treatment.
    3) ADMISSION CRITERIA: Patients that develop persistent signs or symptoms of hypotension and bradycardia, alterations in neurologic function, significant dehydration/electrolyte imbalance or other toxicity should be admitted.
    4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for patients with severe toxicity or in whom the diagnosis is unclear.
    J) PHARMACOKINETICS
    1) CYP2D6 EXTENSIVE METABOLIZERS (EMs): Tmax was 1.5 to 2 hours with a mean Cmax between 12.1 to 25 nanograms/mL following oral administration of 84 mg orally twice daily. CYP2D6 POOR METABOLIZERS (PMs): Tmax was 3 hours with a mean Cmax between 113 to 137 nanograms/mL following oral administration of 84 mg orally twice daily. Oral bioavailability is less than 5% in EMs. It is moderately (76% to 83%) bound to plasma proteins. Vd is 835 L in EMs after IV administration. It is extensively metabolized in the liver, primarily by CYP2D6, and by CYP3A4 to a smaller extent. EXCRETION: After oral administration of 84 mg of radiolabeled eliglustat, 41.8% was excreted in the urine and 51.4% was excreted in feces, primarily as metabolites. TERMINAL HALF-LIFE: 6.5 hours in EMs and 8.9 hours in PMs. The capsules should be swallowed whole and should NOT be crushed, dissolved or opened.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established. In a single-dose escalation study in healthy subjects, a dose approximately equivalent to 21 times (59-fold higher than normal therapeutic concentrations) the recommended dose for Gaucher disease type 1 patients (approximately 1764 mg) produced hypotension, bradycardia, nausea, vomiting, and dizziness resulting in significant disequilibrium. THERAPEUTIC DOSE: ADULT: CYP2D6 EXTENSIVE and INTERMEDIATE METABOLIZERS: The recommended dose of eliglustat is 84 mg orally twice daily in CYP2D6 extensive metabolizers and intermediate metabolizers. CYP2D6 POOR METABOLIZERS: The recommended dose is 84 mg orally once daily in CYP2D6 poor metabolizers. PEDIATRIC: The safety and efficacy of eliglustat in pediatric patients have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Eliglustat, a glucosylceramide synthase inhibitor, is used orally for the long-term treatment of adult patients with Gaucher disease type 1 (GD1) who are CYP2D6 extensive metabolizers, intermediate metabolizers or poor metabolizers. It is a CYP2D6 and CYP3A substrate. Treatment results in the reduced production of glucosylceramide.
    B) PHARMACOLOGY: Eliglustat acts as a substrate reduction therapy. In Gaucher disease, patients are deficient in acid beta-glucosidase, a lysosomal enzyme. This deficiency leads to accumulation of glucosylceramide in lysosomal compartments of macrophages and formation of Gaucher cells (foam cells). Eliglustat inhibits glucosylceramide synthase, which thereby reduces glucosylceramide accumulation.
    C) EPIDEMIOLOGY: Exposure is rare. There are no reports of overdose.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: The most frequently reported adverse events occurring in greater than 10% of patients include fatigue, headache, nausea, back pain, pain in extremities and upper abdominal pain. OTHER EVENTS: Adverse events reported less frequently with eliglustat therapy are dizziness, asthenia, cough, dyspepsia, gastroesophageal reflux disease, constipation, palpitations and rash.
    2) ECG CHANGES: In patients with a history of cardiac disease, long QT syndromes, and in combination with Class IA (ie, quinidine, procainamide) and Class III (ie, amiodarone, sotalol) antiarrhythmic medications, the administration of eliglustat is not recommended because it may cause an increase in ECG intervals (ie, PR, QTc, and QRS intervals) at substantially increased plasma concentrations and a potential for cardiac dysrhythmias.
    3) DRUG-DRUG INTERACTIONS: Drugs that inhibit CYP2D6 and CYP3A may significantly increase plasma concentrations of eliglustat resulting in increases in PR, QTc and/or QRS intervals that could potentially lead to cardiac dysrhythmias.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited data. Clinical events are anticipated to be an extension of events reported with therapeutic use.
    2) MILD TO MODERATE TOXICITY: Gastrointestinal (ie, nausea, vomiting, diarrhea) and CNS (ie, headache) events are likely to occur.
    3) SEVERE TOXICITY: In a single-dose escalation study in healthy subjects, a dose approximately equivalent to 21 times (59-fold higher than normal therapeutic concentrations) the recommended dose for Gaucher disease type 1 patients (approximately 1764 mg) produced nausea, vomiting, hypotension, bradycardia, and dizziness resulting in significant disequilibrium.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PALPITATIONS
    1) WITH THERAPEUTIC USE
    a) In a 12-month open-label, randomized, controlled trial of 159 patients, palpitations developed in 5% of patients treated with eliglustat (n=106) compared to no reports in patients receiving imiglucerase (n=53) (Prod Info CERDELGA (TM) oral capsules, 2014).
    B) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) In patients with a history of cardiac disease (ie, congestive heart failure, recent acute myocardial infarction, bradycardia, heart block, ventricular arrhythmia), long QT syndromes, and in combination with Class IA (ie, quinidine, procainamide) and Class III (ie, amiodarone, sotalol) antiarrhythmic medications, the administration of eliglustat is not recommended because it may cause an increase in ECG intervals (ie, prolonged PR, QTc, and/or QRS intervals) at substantially increased plasma concentrations. In addition, drugs that inhibit CYP2D6 and CYP3A may increase exposure to eliglustat resulting in increases in PR, QTC and/or QRS intervals that could potentially lead to cardiac dysrhythmias (Prod Info CERDELGA (TM) oral capsules, 2014).
    C) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) In a single-dose escalation study in healthy subjects, a dose approximately equivalent to 21 times (59-fold higher than normal therapeutic concentrations) the recommended dose for Gaucher disease type 1 patients (approximately 1764 mg) produced hypotension, bradycardia, nausea, vomiting, and dizziness resulting in significant disequilibrium (Prod Info CERDELGA (TM) oral capsules, 2014).
    D) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) In a single-dose escalation study in healthy subjects, a dose approximately equivalent to 21 times (59-fold higher than normal therapeutic concentrations) the recommended dose for Gaucher disease type 1 patients (approximately 1764 mg) produced hypotension, bradycardia, nausea, vomiting, and dizziness resulting in significant disequilibrium (Prod Info CERDELGA (TM) oral capsules, 2014).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) COUGH
    1) WITH THERAPEUTIC USE
    a) In a 12-month open-label, randomized, controlled trial of 159 patients, cough developed in 7% of patients treated with eliglustat (n=106) compared to 4% of patients receiving imiglucerase (n=53) (Prod Info CERDELGA (TM) oral capsules, 2014).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache was one of the most common adverse events occurring in 10% or more of Gaucher disease type 1 patients treated with eliglustat (Prod Info CERDELGA (TM) oral capsules, 2014).
    b) In a 12-month open-label, randomized, controlled trial of 159 patients, headache developed in 13% of patients treated with eliglustat (n=106) compared to 2% of patients receiving imiglucerase (n=53) (Prod Info CERDELGA (TM) oral capsules, 2014).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In a 12-month open-label, randomized, controlled trial of 159 patients, dizziness developed in 8% of patients treated with eliglustat (n=106) compared to no reports in patients receiving imiglucerase (n=53) (Prod Info CERDELGA (TM) oral capsules, 2014).
    2) WITH POISONING/EXPOSURE
    a) In a single-dose escalation study in healthy subjects, a dose approximately equivalent to 21 times (59-fold higher than normal therapeutic concentrations) the recommended dose for Gaucher disease type 1 patients (approximately 1764 mg) produced dizziness resulting in significant disequilibrium, hypotension, bradycardia, nausea and vomiting (Prod Info CERDELGA (TM) oral capsules, 2014).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea was one of the most common adverse events occurring in 10% or more of Gaucher disease type 1 patients treated with eliglustat (Prod Info CERDELGA (TM) oral capsules, 2014).
    b) In a 12-month open-label, randomized, controlled trial of 159 patients, nausea developed in 12% of patients treated with eliglustat (n=106) compared to no reports in patients receiving imiglucerase (n=53) (Prod Info CERDELGA (TM) oral capsules, 2014).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea was one of the most common adverse events occurring in 10% or more of Gaucher disease type 1 patients treated with eliglustat (Prod Info CERDELGA (TM) oral capsules, 2014).
    b) In a 12-month open-label, randomized, controlled trial of 159 patients, diarrhea developed in 12% of patients treated with eliglustat (n=106) compared to 4% of patients receiving imiglucerase (n=53) (Prod Info CERDELGA (TM) oral capsules, 2014).
    C) VOMITING
    1) WITH POISONING/EXPOSURE
    a) In a single-dose escalation study in healthy subjects, a dose approximately equivalent to 21 times (59-fold higher than normal therapeutic concentrations) the recommended dose for Gaucher disease type 1 patients (approximately 1764 mg) produced nausea, vomiting, hypotension, bradycardia, and dizziness resulting in significant disequilibrium (Prod Info CERDELGA (TM) oral capsules, 2014).
    D) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Upper abdominal pain was one of the most common adverse events occurring in 10% or more of Gaucher disease type 1 patients treated with eliglustat (Prod Info CERDELGA (TM) oral capsules, 2014).
    b) In a 12-month open-label, randomized, controlled trial of 159 patients, upper abdominal pian developed in 10% of patients treated with eliglustat (n=106) compared to no reports in patients receiving imiglucerase (n=53) (Prod Info CERDELGA (TM) oral capsules, 2014).
    E) GASTROESOPHAGEAL REFLUX DISEASE
    1) WITH THERAPEUTIC USE
    a) In a 12-month open-label, randomized, controlled trial of 159 patients, gastroesophageal reflux disease developed in 7% of patients treated with eliglustat (n=106) compared to no reports in patients receiving imiglucerase (n=53) (Prod Info CERDELGA (TM) oral capsules, 2014).
    F) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) In a 12-month open-label, randomized, controlled trial of 159 patients, dyspepsia developed in 7% of patients treated with eliglustat (n=106) compared to 2% of patients receiving imiglucerase (n=53) (Prod Info CERDELGA (TM) oral capsules, 2014).
    G) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) In a 12-month open-label, randomized, controlled trial of 159 patients, constipation developed in 5% of patients treated with eliglustat (n=106) compared to no reports in patients receiving imiglucerase (n=53) (Prod Info CERDELGA (TM) oral capsules, 2014).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) In a 12-month open-label, randomized, controlled trial of 159 patients, rash developed in 5% of patients treated with eliglustat (n=106) compared to no reports in patients receiving imiglucerase (n=53) (Prod Info CERDELGA (TM) oral capsules, 2014).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BACKACHE
    1) WITH THERAPEUTIC USE
    a) Back pain was one of the most common adverse events occurring in 10% or more of Gaucher disease type 1 patients treated with eliglustat (Prod Info CERDELGA (TM) oral capsules, 2014).
    b) In a 12-month open-label, randomized, controlled trial of 159 patients, back pain developed in 12% of patients treated with eliglustat (n=106) compared to 6% of patients receiving imiglucerase (n=53) (Prod Info CERDELGA (TM) oral capsules, 2014).
    B) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Pain in the extremities was one of the most common adverse events occurring in 10% or more of Gaucher disease type 1 patients treated with eliglustat (Prod Info CERDELGA (TM) oral capsules, 2014).
    b) In a 12-month open-label, randomized, controlled trial of 159 patients, extremity pain developed in 11% of patients treated with eliglustat (n=106) compared to 2% of patients receiving imiglucerase (n=53) (Prod Info CERDELGA (TM) oral capsules, 2014).

Reproductive

    3.20.1) SUMMARY
    A) Eliglustat is classified as FDA pregnancy C. There are no adequate or well-controlled studies of eliglustat in pregnant women. In animal studies, the administration of eliglustat (approximately 6 times the recommended human dose based on body surface area) produced an increase in the number of late resorptions, fetal death, post implantation loss, reduced fetal weight, fetal skeletal variations and fetal skeletal malformations. It is not known whether eliglustat is excreted into human breast milk.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RATS: Rats given oral doses of 120 mg/kg/day (about 6 times the recommended human dose based on body surface area) produced fetal cerebral variations (dilated cerebral ventricles), fetal skeletal variations (poor bone ossification), and fetal skeletal malformations (abnormal number of ribs or lumbar vertebra). No significant adverse effects on prenatal or postnatal development occurred with rats given oral doses up to 100 mg/kg/day (about 5 times the recommended human dose based on body surface area) (Prod Info CERDELGA (TM) oral capsules, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Eliglustat is classified as FDA pregnancy C (Prod Info CERDELGA (TM) oral capsules, 2014).
    2) There are no adequate or well-controlled studies of eliglustat in pregnant women. Gaucher disease type 1 can increase the risk of spontaneous abortion in pregnant women, especially if the symptoms are not under control both preconception and during pregnancy. Pregnancy can exacerbate the symptoms associated with Gaucher disease type 1 and may produce new disease-related symptoms (Prod Info CERDELGA (TM) oral capsules, 2014).
    B) ANIMAL STUDIES
    1) RATS: Rats given oral doses of 120 mg/kg/day (about 6 times the recommended human dose based on body surface area) had an increased number of late resorptions, dead fetuses, post implantation loss, and reduced fetal body weight. No significant adverse effects on prenatal or postnatal development occurred with rats given oral doses up to 100 mg/kg/day (about 5 times the recommended human dose based on body surface area) (Prod Info CERDELGA (TM) oral capsules, 2014).
    2) RABBITS: No fetal harm occurred after rabbits were given oral doses up to 100 mg/kg/day (about 10 times the recommended human dose based on body surface area) (Prod Info CERDELGA (TM) oral capsules, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) BREAST MILK
    a) It is not known whether eliglustat is excreted into human breast milk. Because of the potential for serious adverse reactions in nursing infants, it is recommended to either discontinue nursing or discontinue eliglustat, considering the importance of the drug to the mother (Prod Info CERDELGA (TM) oral capsules, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) In rats, an increase in preimplantation loss occurred at 30 (1.5 times the recommended human oral dose based on body surface area) and 100 mg/kg/day (about 5 times the recommended human oral dose based on body surface area). In male rats, reversible adverse effects on sperm morphology, testes and slough cells in the epididymis occurred at 200 mg/kg/day (about 10 times the recommended human oral dose based on body surface area). Similar changes in sperm morphology were not observed in Cynomolgus monkeys administered 72 mg/kg/day (about 7 times the recommended human oral doses based on body surface area) (Prod Info CERDELGA (TM) oral capsules, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and neurologic function.
    B) Monitor fluid and electrolyte balance in patients with persistent vomiting and/or diarrhea or as indicated.
    C) Obtain a baseline ECG and institute continuous cardiac monitoring following a significant exposure or in patients with a history of cardiac disease (eg, CHF, myocardial infarction, bradycardia, heart block or dysrhythmias) or coadministration of drugs that are Class lA (procainamide, quinidine) or Class IIl (amiodarone, sotalol) antiarrhythmic medications, or drugs that inhibit CYP2D6 and CYP3A.
    D) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients that develop persistent signs or symptoms of hypotension and bradycardia, alterations in neurologic function, significant dehydration/electrolyte imbalance or other toxicity should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic adults with an inadvertent ingestion of 1 to 2 extra doses or an adult with mild gastrointestinal symptoms can be monitored at home. An asymptomatic child with an inadvertent ingestion (1 tablet) or mild gastrointestinal symptoms can be monitored at home with adult supervision.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or poison center for patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients that have more than mild gastrointestinal symptoms or had a deliberate ingestion should be referred to a healthcare facility for evaluation and treatment.

Monitoring

    A) Monitor vital signs and neurologic function.
    B) Monitor fluid and electrolyte balance in patients with persistent vomiting and/or diarrhea or as indicated.
    C) Obtain a baseline ECG and institute continuous cardiac monitoring following a significant exposure or in patients with a history of cardiac disease (eg, CHF, myocardial infarction, bradycardia, heart block or dysrhythmias) or coadministration of drugs that are Class lA (procainamide, quinidine) or Class IIl (amiodarone, sotalol) antiarrhythmic medications, or drugs that inhibit CYP2D6 and CYP3A.
    D) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Prehospital activated charcoal should be avoided, due to the potential development of vomiting following exposure.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Consider activated charcoal if the overdose is recent or other significant coingestants are suspected and the airway is protected.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY: Treatment is symptomatic and supportive. Overdose information is limited. Significant toxicity is not anticipated following a mild to moderate exposure. Monitor vital signs and neurologic function. Gastrointestinal events (ie, nausea, vomiting and/or diarrhea) are likely to occur. Monitor fluid and serum electrolytes as indicated. Replace fluids (oral or IV fluids) and electrolytes as necessary.
    2) MANAGEMENT OF SEVERE TOXICITY: Treatment is symptomatic and supportive. Correct any significant electrolyte abnormalities in patients with severe vomiting and/or diarrhea. HYPOTENSION: Treat moderate to severe hypotension with IV fluids, dopamine or norepinephrine as necessary. ECG CHANGES/POTENTIAL DYSRHYTHMIAS: Obtain a baseline ECG and institute continuous cardiac monitoring following a significant exposure or in patients at risk (ie, a history of cardiac disease including CHF, myocardial infarction, heart block, dysrhythmias, patients taking Class lA (ie, quinidine, procainamide ) or Class lll (ie, sotalol, amiodarone) antiarrhythmic medications, or patients with known drug-drug interactions (ie, CYP2D6 and CYP3A inhibitors).
    B) MONITORING OF PATIENT
    1) Monitor fluid and electrolyte balance in patients with persistent vomiting and/or diarrhea or as indicated.
    2) Monitor vital signs and neurologic function.
    3) Obtain a baseline ECG and institute continuous cardiac monitoring following a significant exposure or in patients with a history of cardiac disease (eg, CHF, myocardial infarction, bradycardia, heart block or dysrhythmias).
    4) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    D) VENTRICULAR ARRHYTHMIA
    1) Theoretically, eliglustat is likely to cause an increase in PR, QTc and QRS intervals at significantly elevated plasma concentrations; therefore, it is not recommended in patients with a history of cardiac disease, long QT syndromes, and in combination with Class IA (ie, quinidine, procainamide) and Class III (ie, amiodarone, sotalol) antiarrhythmic medications due to the increased risk of cardiac arrhythmias (Prod Info CERDELGA (TM) oral capsules, 2014). Obtain an ECG, institute continuous cardiac monitoring and administer oxygen as indicated. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Correct electrolyte abnormalities. Consider lidocaine for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution. Unstable rhythms require immediate cardioversion.
    2) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

Enhanced Elimination

    A) SUMMARY
    1) Eliglustat has a large volume of distribution (835 L) and moderately protein bound (76% to 83%) (Prod Info CERDELGA (TM) oral capsules, 2014); therefore, hemodialysis is UNLIKELY to be effective.

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established. In a single-dose escalation study in healthy subjects, a dose approximately equivalent to 21 times (59-fold higher than normal therapeutic concentrations) the recommended dose for Gaucher disease type 1 patients (approximately 1764 mg) produced hypotension, bradycardia, nausea, vomiting, and dizziness resulting in significant disequilibrium. THERAPEUTIC DOSE: ADULT: CYP2D6 EXTENSIVE and INTERMEDIATE METABOLIZERS: The recommended dose of eliglustat is 84 mg orally twice daily in CYP2D6 extensive metabolizers and intermediate metabolizers. CYP2D6 POOR METABOLIZERS: The recommended dose is 84 mg orally once daily in CYP2D6 poor metabolizers. PEDIATRIC: The safety and efficacy of eliglustat in pediatric patients have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) CYP2D6 EXTENSIVE and INTERMEDIATE METABOLIZERS: The recommended dose of eliglustat is 84 mg orally twice daily in CYP2D6 extensive metabolizers and intermediate metabolizers (Prod Info CERDELGA (TM) oral capsules, 2014).
    B) CYP2D6 POOR METABOLIZERS: The recommended dose is 84 mg orally once daily in CYP2D6 poor metabolizers (Prod Info CERDELGA (TM) oral capsules, 2014).
    7.2.2) PEDIATRIC
    A) The safety and efficacy of eliglustat in pediatric patients have not been established (Prod Info CERDELGA (TM) oral capsules, 2014).

Minimum Lethal Exposure

    A) A minimum lethal dose has not been established.

Maximum Tolerated Exposure

    A) A maximum tolerated dose has not been reported. In a single-dose escalation study in healthy subjects, a dose approximately equivalent to 21 times (59-fold higher than normal therapeutic concentrations) the recommended dose for Gaucher disease type 1 patients (approximately 1764 mg ) produced hypotension, bradycardia, nausea, vomiting, and dizziness resulting in significant disequilibrium (Prod Info CERDELGA (TM) oral capsules, 2014).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Eliglustat acts as substrate reduction therapy. In Gaucher disease type 1, patients are deficient in acid beta-glucosidase, a lysosomal enzyme. This deficiency leads to accumulation of glucosylceramide in lysosomal compartments of macrophages and formation of Gaucher cells (foam cells). Eliglustat inhibits glucosylceramide synthase, which reduces this accumulation (Prod Info CERDELGA (TM) oral capsules, 2014).

Physicochemical

Molecular Weight

    A) 479.59

References

General Bibliography

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    2) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    3) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    4) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    5) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    6) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    7) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    8) Neumar RW , Otto CW , Link MS , et al: Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S729-S767.
    9) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    10) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    11) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    12) Product Information: CERDELGA (TM) oral capsules, eliglustat oral capsules. Genzyme Ireland, Ltd, Waterford, Ireland, 2014.
    13) Product Information: Lidocaine HCl intravenous injection solution, lidocaine HCl intravenous injection solution. Hospira (per manufacturer), Lake Forest, IL, 2006.
    14) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    15) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    16) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    17) Vanden Hoek TL, Morrison LJ, Shuster M, et al: Part 12: cardiac arrest in special situations: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S829-S861.
    18) de Caen AR, Berg MD, Chameides L, et al: Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S526-S542.