Cerdelga (Page 3 of 5)

8.2 Lactation

Risk Summary

There are no human data available on the presence of eliglustat in human milk, the effects on the breastfed infant, or the effects on milk production. Eliglustat and its metabolites were present in the milk of lactating rats [see Data]. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CERDELGA and any potential adverse effects on the breastfed child from CERDELGA or from the underlying maternal condition.

Data

In a milk excretion study in the rat, a single oral dose of 30 mg/kg [14 C]-labeled eliglustat was administered to lactating female rats at day 11 postpartum. Approximately 0.23% of the administered radioactivity was excreted into the milk within 24 hours of dose administration. The concentration in the milk at 24 hours post dose was 16.3-fold higher than the plasma concentration.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of CERDELGA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Clinical experience has not identified differences in responses between the elderly and younger patients.

8.6 Renal Impairment

Use CERDELGA in patients with renal impairment based on the patient’s CYP2D6 metabolizer status [see Clinical Pharmacology (12.3)].

EMs

  • Avoid CERDELGA in patients with end-stage renal disease (ESRD) (estimated creatinine clearance (eCLcr) less than 15 mL/min not on dialysis or requiring dialysis).
  • No dosage adjustment is recommended in patients with mild, moderate, or severe renal impairment (eCLcr at least 15 mL/min).

IMs and PMs

  • Avoid CERDELGA in patients with any degree of renal impairment.

8.7 Hepatic Impairment

Use CERDELGA in patients with hepatic impairment based on CYP2D6 metabolizer status and concomitant use of CYP2D6 or CYP3A inhibitors [see Clinical Pharmacology (12.3)].

EMs

  • CERDELGA is contraindicated in patients with [see Contraindications (4)]:
    • severe (Child-Pugh Class C) hepatic impairment
    • moderate (Child-Pugh Class B) hepatic impairment
    • mild (Child-Pugh Class A) hepatic impairment taking a strong or moderate CYP2D6 inhibitor
  • Reduce dosage frequency of CERDELGA 84 mg to once daily [see Dosage and Administration (2.3)] in patients with mild hepatic impairment taking:
    • a weak CYP2D6 inhibitor
    • a strong, moderate, or weak CYP3A inhibitor
  • No dosage adjustment is recommended in patients with mild hepatic impairment, unless otherwise specified above.

IMs and PMs

  • CERDELGA is contraindicated in patients with any degree of hepatic impairment [see Contraindications (4)].

10 OVERDOSAGE

The highest eliglustat plasma concentration experienced to date occurred in a single-dose, dose escalation study in healthy subjects, in a subject taking a dose equivalent to approximately 21 times the recommended dose for GD1 patients. At the time of the highest plasma concentration (59-fold higher than normal therapeutic conditions), the subject experienced dizziness marked by disequilibrium, hypotension, bradycardia, nausea, and vomiting.

In the event of acute overdose, the patient should be carefully observed and given symptomatic and supportive treatment.

Hemodialysis is unlikely to be beneficial given that eliglustat has a large volume of distribution [see Clinical Pharmacology (12.3)].

11 DESCRIPTION

CERDELGA (eliglustat) capsules contain eliglustat tartrate, which is a small molecule inhibitor of glucosylceramide synthase that resembles the ceramide substrate for the enzyme, with the chemical name N-((1R ,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)octanamide (2R ,3R)-2,3-dihydroxysuccinate. Its molecular weight is 479.59, and the empirical formula is C23 H36 N2 O4 +½(C4 H6 O6 ) with the following chemical structure:

Chemical Structure
(click image for full-size original)

Each capsule of CERDELGA for oral use contains 84 mg of eliglustat (equivalent to 100 mg of eliglustat tartrate). The inactive ingredients are candurin silver fine, FD&C blue 2, gelatin, glyceryl behenate, hypromellose, lactose monohydrate, microcrystalline cellulose, and yellow iron oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Gaucher disease is caused by a deficiency of the lysosomal enzyme acid β-glucosidase. Acid β-glucosidase catalyzes the conversion of the sphingolipid glucocerebroside into glucose and ceramide. The enzymatic deficiency causes an accumulation of glucosylceramide (GL-1) primarily in the lysosomal compartment of macrophages, giving rise to foam cells or “Gaucher cells.”

The clinical features of this lysosomal storage disorder (LSD) are reflective of the accumulation of Gaucher cells in the reticuloendothelial system (liver, spleen, bone marrow, and other organs). The accumulation of Gaucher cells in the liver, spleen, and bone marrow leads to organomegaly and skeletal disease. Presence of Gaucher cells in the bone marrow and spleen leads to clinically significant anemia and thrombocytopenia.

CERDELGA is a specific inhibitor of glucosylceramide synthase (IC50 =10 ng/mL) and acts as a substrate reduction therapy for GD1 by reducing the production of GL-1. By reducing GL-1 production, CERDELGA alleviates the accumulation of GL-1 in the target organs.

12.2 Pharmacodynamics

Effects on spleen and liver volume, hemoglobin, and platelets increased with increasing steady-state average trough concentrations of eliglustat ranging up to 14 ng/mL in treatment naive patients in Trial 1. In patients previously treated with enzyme-replacement therapy in Trial 2 [see Clinical Studies (14.2)] , no clinically relevant exposure-response relationship was observed.

Cardiac Electrophysiology

Concentration-related increases were observed for the placebo-corrected change from baseline in the PR, QRS, and QTc intervals. At the mean peak concentration of 237 ng/mL at a dose of 800 mg eliglustat tartrate (8 times the recommended dose), CERDELGA did not prolong the QT/QTc interval to any clinically relevant extent. However, pharmacokinetic/pharmacodynamic modeling predicts mean (upper bound of the 95% one-sided confidence interval) increases in the PR, QRS, and QTcF intervals of 22 (26), 7 (10), and 13 (19) msec, respectively, at eliglustat plasma concentration of 500 ng/mL [see Warnings and Precautions (5.1)].

12.3 Pharmacokinetics

Absorption

The oral bioavailability of eliglustat was less than 5% in CYP2D6 EMs following a single 84 mg dose of CERDELGA.

In CYP2D6 EMs, the eliglustat pharmacokinetics is time-dependent and the systemic exposure increases in a more than dose-proportional manner over the dose range of 42 to 294 mg (0.5 to 3.5 times the recommended dosage). In addition, after multiple oral doses of 84 mg twice daily in EMs, eliglustat systemic exposure (AUC0–12 ) increased up to about 2-fold at steady state compared to after the first dose (AUC0–∞ ). The pharmacokinetics of eliglustat in CYP2D6 PMs is expected to be linear and time-independent. Compared to EMs, the systemic exposure following 84 mg twice daily at steady state is 7-fold to 9-fold higher in PMs.

Dosing of CERDELGA 84 mg once daily has not been studied in PMs. The predicted Cmax and AUC0–24hr in PMs using a physiologically based pharmacokinetic (PBPK) model with 84 mg once daily were 75 ng/mL and 956 hr∙ng/mL, respectively.

Table 7 describes the pharmacokinetic parameters for eliglustat in healthy subjects following multiple doses of 84 mg CERDELGA twice daily.

Table 7: Pharmacokinetic Parameters for Eliglustat following Multiple Doses of 84 mg CERDELGA Twice Daily
Parameter CYP2D6 Metabolizer Status
EMs(n=96) IMs(n=1) PMs *(n=9)
*
84 mg twice daily is not the recommended dosage in PMs [see Dosage and Administration (2.2)].
Range of the mean (CV%) values from multiple studies.
Range of the median time to reach maximum plasma concentration (Tmax ) from multiple studies.
Cmax (ng/mL) 12.1 (42%) to 25.0 (141%) 44.6 113 (32%) to 137 (40%)
AUCtau (ng∙hr/mL) 76.3 (37%) to 143 (160%) 306 922 (33%) to 1057 (38%)
Median Tmax (hr) [min to max] 1.5 [0.5 to 3.0] to 2 [1.5 to 2.1] 2 3 [2 to 4]

Administration of CERDELGA with a high fat meal (approximately 1000 calories with 50% calories from fat) resulted in a 15% decrease in Cmax (not clinically significant) but no change in AUC.

Distribution

Following intravenous administration, the volume of distribution of eliglustat was 835 L in EMs. Plasma protein binding of eliglustat ranges from 76% to 83%.

Elimination

Eliglustat terminal elimination half-life was approximately 6.5 hours in CYP2D6 EMs, and 8.9 hours in PMs. Following intravenous administration of 42 mg (0.5 times the recommended oral dose) in healthy subjects, the mean (range) of eliglustat total body clearance was 88 L/h (80 to 105 L/h) in EMs.

Metabolism

CERDELGA is primarily metabolized by CYP2D6 and to a lesser extent by CYP3A4.

Excretion

After oral administration of radiolabeled eliglustat, the majority of the administered dose is excreted in urine (42%) and feces (51%), mainly as metabolites.

Specific Populations

No clinically significant differences in the pharmacokinetics of eliglustat were observed based on age (18 to 71 years), sex, race (mostly were Caucasian, including those of Ashkenazi Jewish descent; however, it included the following populations: African American, American Indians, Hispanics, and Asians), or body weight (41 to 136 kg).

Patients with renal impairment

Eliglustat pharmacokinetics was similar in CYP2D6 EMs with severe renal impairment and healthy CYP2D6 EMs. Eliglustat pharmacokinetics in EMs with ESRD and in IMs or PMs with any degree of renal impairment is unknown [see Use in Specific Populations (8.6)].

Patients with hepatic impairment

Table 8 describes the effect of mild and moderate hepatic impairment on the pharmacokinetics of eliglustat in CYP2D6 EMs compared to EMs with normal hepatic function following a single 84 mg dose. The effect of hepatic impairment is highly variable with the coefficients of variation (CVs%) of 135% and 110% for Cmax and 171% and 121% for AUC in CYP2D6 EMs with mild and moderate hepatic impairment, respectively.

Table 8: Effect of Hepatic Impairment on Eliglustat Pharmacokinetics following a Single Dose of 84 mg CERDELGA in CYP2D6 EMs
Mild Hepatic Impairment (n=6) Moderate Hepatic Impairment (n=7)
Cmax ↑ 1.2-fold ↑ 2.8-fold
AUC ↑ 1.2-fold ↑ 5.2-fold

Steady-state pharmacokinetics of eliglustat in CYP2D6 IMs and PMs with mild and moderate hepatic impairment is unknown. The effect of severe hepatic impairment in subjects with any CYP2D6 phenotype is unknown [see Use in Specific Populations (8.7)].

Drug Interaction Studies

Effect of other drugs on CERDELGA

Table 9 describes the effect of drug interactions on the pharmacokinetics of eliglustat [see Drug Interactions (7.1)].

Table 9: Drug Interactions Affecting Eliglustat Concentrations
Concomitant Drug(s) CYP2D6 Metabolizer Status
EMs IMs PMs
Cmax AUCtau Cmax AUCtau Cmax AUCtau
↑ = Increased; ↓ = Decreased
*
Predicted pharmacokinetic parameters based on PBPK models.
Due to little or no CYP2D6 activity in CYP2D6 PMs.
Following coadministration with CERDELGA 84 mg once daily.
§
Following coadministration with CERDELGA 127 mg twice daily (1.5 times the recommended dosage).
CYP2D6 Inhibitor
Paroxetine(strong) ↑ 7.0-fold ↑ 8.4-fold ↑ 2.1-fold * ↑ 2.3-fold * No increase expected
Terbinafine(moderate) ↑ 3.8-fold * ↑ 4.5-fold * ↑ 1.6-fold *
CYP3A Inhibitor
Ketoconazole(strong) ↑ 4.0-fold ↑ 4.4-fold ↑ 4.4-fold * ↑ 5.4-fold * ↑ 4.3-fold *, ↑ 6.2-fold *,
Fluconazole(moderate) ↑ 2.8-fold * ↑ 3.2-fold * ↑ 2.5-fold * ↑ 2.9-fold * ↑ 2.4-fold *, ↑ 3.0-fold *,
CYP2D6 Inhibitors Concomitantly with CYP3A Inhibitors
Paroxetine with ketoconazole ↑ 16.7-fold * ↑ 24.2-fold * ↑ 7.5-fold * ↑ 9.8-fold * Expected similar increase as with CYP3A inhibitors alone
Terbinafine with fluconazole ↑ 10.2-fold * ↑ 13.6-fold * ↑ 4.2-fold * ↑ 5.0-fold *
CYP3A Inducers
Rifampin(strong) ↓ 90%§ ↓ 95%

No clinically significant pharmacokinetic changes were observed for eliglustat when coadministered with intravenous rifampin (an OATP inhibitor), or gastric pH modifying drugs (e.g., aluminum hydroxide, magnesium hydroxide, calcium carbonate, pantoprazole).

In vitro , eliglustat is a substrate of P-glycoprotein (P-gp). The effect of P-gp inhibitors on eliglustat pharmacokinetics is unknown.

Effect of CERDELGA on other drugs

CYP2D6 substrates

Following multiple doses of CERDELGA 127 mg twice daily (1.5 times the recommended dosage), metoprolol (a CYP2D6 substrate) mean Cmax and AUC increased by 1.7-fold and 2.3-fold in CYP2D6 EMs, respectively, and by 1.2-fold and 1.6-fold in IMs, respectively [see Drug Interactions (7.2)].

P-gp substrates

Following multiple doses of CERDELGA 127 mg twice daily (1.5 times the recommended dosage) in CYP2D6 EMs and IMs, or 84 mg twice daily in PMs, digoxin (a P-gp substrate) mean Cmax increased by 1.7-fold and AUC increased by 1.5-fold [see Drug Interactions (7.2)].

Oral contraceptives

Repeated doses of CERDELGA 84 mg twice daily did not change the exposures to norethindrone (1.0 mg) and ethinyl estradiol (0.035 mg).

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