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CERDELGA®
(eliglustat) Capsules
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 C23H36N2O4+½(C4H6O6) with the following chemical structure:
 |
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.
CERDELGA is indicated for the long-term treatment of adult patients with Gaucher disease type 1 (GD1) who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by an FDA-cleared test [see DOSAGE AND ADMINISTRATION].
Select patients with Gaucher disease type 1 based on their CYP2D6 metabolizer status. It is recommended patient genotypes be established using an FDA-cleared test for determining CYP2D6 genotype [see INDICATIONS AND USAGE].
The recommended dosage of CERDELGA in adults is based on the patient's CYP2D6 metabolizer status.
Table 1: Recommended Dosage Regimen by CYP2D6
Metabolizer Status
| CYP2D6 Metabolizer Status | CERDELGA Dosage |
| EMs | 84 mg twice daily |
| IMs | |
| PMs | 84 mg once daily |
Reduce dosage frequency of CERDELGA 84 mg to once daily in CYP2D6 EMs and IMs with or without hepatic impairment taking CYP2D6 or CYP3A inhibitors, as shown in Table 2 [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, Use In Specific Populations].
Table 2: Recommended Dosage of CERDELGA 84 mg Once
Daily based on CYP2D6 Metabolizer, Hepatic Impairment Status, and Concomitant
CYP Inhibitors
| CYP2D6 Metabolizer Status | Hepatic Impairment Status | Concomitant CYP Inhibitor |
| EMs | Without Hepatic Impairment |
|
| Mild (Child-Pugh Class A) Hepatic Impairment |
|
|
| IMs | Without Hepatic Impairment |
|
Capsules: 84 mg of eliglustat is in a capsule with a pearl blue-green opaque cap and pearl white opaque body imprinted with “GZ02” in black.
CERDELGA is supplied as 84 mg eliglustat in a capsule with a pearl blue-green opaque cap and pearl white opaque body imprinted with “GZ02” in black.
CERDELGA 84 mg capsules are supplied as:
NDC 58468-0220-1 – Carton containing 4 packs of capsules (56 capsules total). Each pack is composed of 1 blister card of 14 capsules and a cardboard wallet.
NDC 58468-0220-2 – Carton containing 1 pack of capsules (14 capsules total). Each pack is comprised of 1 blister card of 14 capsules and a cardboard wallet.
Store at 68°F-77°F (20°C-25°C) with excursions permitted between 59°F and 86°F (15°C to 30°C) [see USP Controlled Room Temperature].
Manufactured by: Genzyme Ireland, Ltd., IDA Industrial Park, Old Kilmeaden Road, Waterford, Ireland. Revised: Aug 2018
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The most common adverse reactions to CERDELGA (occurring in ≥10% of the 126 GD1 patients treated with CERDELGA across Trials 1 and 2 were fatigue, headache, nausea, diarrhea, back pain, pain in extremities, and upper abdominal pain.
The adverse reaction profile of CERDELGA is based on two controlled studies, Trials 1 and 2 [see Clinical Studies]. Table 3 presents the profile from the 9-month double-blind, randomized, placebo-controlled trial of 40 treatment-naive patients (Trial 1). Patients were between the ages of 16 and 63 on the date of the first dose of study drug, and included 20 males and 20 females.
Table 3: Adverse Reactions Occurring in ≥10%
of Treatment-Naive GD1 Patients and More Frequently than Placebo (Trial 1)
| Adverse Reaction | CERDELGA (N=20) |
Placebo (N=20) |
| Patients n (%) | Patients n (%) | |
| Arthralgia | 9 (45) | 2 (10) |
| Headache | 8 (40) | 6 (30) |
| Migraine | 2 (10) | 0 (0) |
| Flatulence | 2 (10) | 1 (5) |
| Nausea | 2 (10) | 1 (5) |
| Oropharyngeal pain | 2 (10) | 1 (5) |
Table 4 presents the profile from the 12-month open-label, randomized, imiglucerase-controlled trial of 159 treated patients switching from enzyme replacement therapy (ERT) (Trial 2). Patients were between the ages of 18 and 69 on the date of the first dose of CERDELGA, and included 87 females and 72 males.
Table 4: Adverse Reactions Occurring in ≥5%
of GD1 Patients Switching from Enzyme Replacement Therapy to CERDELGA and More
Frequently than Imiglucerase (Trial 2)*
| Adverse Reaction | CERDELGA (N=106) |
Imiglucerase (N=53) |
| Patients n (%) | Patients n (%) | |
| Fatigue | 15 (14) | 1 (2) |
| Headache | 14 (13) | 1 (2) |
| Nausea | 13 (12) | 0 (0) |
| Diarrhea | 13 (12) | 2 (4) |
| Back pain | 13 (12) | 3 (6) |
| Pain in extremity | 12 (11) | 1 (2) |
| Upper abdominal pain | 11(10) | 0 (0) |
| Dizziness | 9 (8) | 0 (0) |
| Asthenia | 9 (8) | 0 (0) |
| Cough | 7 (7) | 2 (4) |
| Dyspepsia | 7 (7) | 1 (2) |
| Gastroesophageal reflux disease | 7 (7) | 0 (0) |
| Constipation | 5 (5) | 0 (0) |
| Palpitations | 5 (5) | 0 (0) |
| Rash | 5 (5) | 0 (0) |
| * Trial 2 was not designed to support comparative claims for CERDELGA for the adverse reactions reported in this table. | ||
In a separate uncontrolled study, with up to 4 years of treatment in 26 naive GD1 patients, the types and incidences of adverse reactions were similar to Trials 1 and 2.
Coadministration of CERDELGA with:
See Table 5 for prevention and management of interactions with drugs affecting CERDELGA. Use of CERDELGA is contraindicated, to be avoided, or may require dosage adjustment depending on the concomitant drug and CYP2D6 metabolizer status [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, DRUG INTERACTIONS].
Table 5: Prevention and Management Strategies of Drug
Interactions Affecting CERDELGA Based on CYP2D6 Metabolizer Status and
Concomitant Interacting Drug
| Concomitant Drug(s) | CYP2D6 Metabolizer Status | ||
| EMs | IMs | PMs | |
| CYP2D6 Inhibitor | |||
| Strong | Reduce frequency of CERDELGA 84 mg to once daily | Continue CERDELGA 84 mg once daily3 | |
| Moderate | |||
| Weak | Continue CERDELGA 84 mg twice daily | ||
| CYP3A Inhibitor | |||
| Strong | Reduce frequency of CERDELGA 84 mg to once daily | Contraindicated | |
| Moderate | Avoid coadministration | ||
| Weak | Continue CERDELGA 84 mg twice daily | Avoid coadministration | |
| CYP2D6 Inhibitor Concomitantly with a strong CYP3A Inhibitor | |||
| Strong | Contraindicated | ||
| Moderate | |||
| CYP2D6 Inhibitor Concomitantly with a moderate CYP3A Inhibitor | |||
| Strong | Contraindicated | Avoid coadministrationa | |
| Moderate | |||
| CYP3A Inducer | |||
| Strong | Avoid coadministration | ||
| aNo effect of CYP2D6 inhibitor due to little or no CYP2D6 activity in CYP2D6 PMs. | |||
See Table 6 for clinically relevant interactions affecting P-gp or CYP2D6 substrates when coadministered with CERDELGA.
Table 6: Prevention and Management Strategies of Drug
Interactions Affecting Other Drugs
| Substrates for P-gp or CYP2D6 | ||
| Clinical Impact | Coadministration of CERDELGA may increase concentrations of drugs that are substrates for P-gp or CYP2D6 [see CLINICAL PHARMACOLOGY] and may increase the risk of toxicity of these drugs. | |
| Prevention or Management | Digoxin | Monitor serum digoxin concentrations before initiating CERDELGA. Reduce digoxin dose by 30% and continue monitoring. |
| Other P-gp substrates or CYP2D6 substrates | Monitor therapeutic drug concentrations, as indicated, or consider reducing the dosage of the concomitant drug and titrate to clinical effect. | |
Included as part of the PRECAUTIONS section.
CERDELGA is predicted to cause increases in ECG intervals (PR, QTc, and QRS) at substantially elevated eliglustat plasma concentrations and may increase the risk of cardiac arrhythmias.
Use of CERDELGA in patients with pre-existing cardiac conditions has not been studied during clinical trials. Avoid use of CERDELGA in patients with:
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Advise patients to discuss all the medications they are taking, including any herbal supplements or vitamins with their healthcare provider [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].
Advise patients to inform their healthcare provider of the following: history of congestive heart failure; recent acute myocardial infarction; bradycardia; heart block; ventricular arrhythmia; and long QT syndrome [see WARNINGS AND PRECAUTIONS].
Advise patients to inform their healthcare provider if they develop new symptoms such as palpitations, fainting, and dizziness.
[See DOSAGE AND ADMINISTRATION]
Advise patients:
Carcinogenic potential of CERDELGA was assessed in 2-year carcinogenicity studies in rats and mice. In Sprague-Dawley rats, eliglustat was administered by oral gavage at doses up to 75 mg/kg/day in males (about 3.6 times the recommended human daily dose of 84 mg twice daily, based on body surface area) and 50 mg/kg/day in females (about 2.4 times the recommended human daily dose based on body surface area). In CD-1 mice, eliglustat was administered to males and females at up to 75 mg/kg/day (about 1.8 times the recommended human daily dose based on body surface area) via dietary admixture. Eliglustat did not produce any treatmentrelated neoplasms in rats or mice.
Eliglustat was negative in the Ames test, chromosome aberration test in human peripheral blood lymphocytes, mouse lymphoma gene mutation assay and in vivo oral mouse micronucleus test.
In a fertility and early embryonic development study in rats, eliglustat increased pre-implantation loss at 30 (about 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 mature male rats, eliglustat showed reversible adverse effects on sperm morphology, testes (germ cell necrosis), and sloughed cells in the epididymis at 200 mg/kg/day (about 10 times the recommended human oral dose based on body surface area). Similar effects on sperm were not seen in mature cynomolgus monkeys at 72 mg/kg/day (about 7 times the recommended human oral dose based on body surface area).
Available data on CERDELGA use in pregnant women includes 20 pregnancies that occurred during the clinical development program and a small number of post-marketing case reports. These data are not sufficient to assess drug-associated risks major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies in pregnant rats administered oral eliglustat during organogenesis, a spectrum of various developmental abnormalities were observed at doses 6 times the recommended human dose. No adverse developmental outcomes were observed with oral administration of eliglustat to pregnant rabbits at dose levels 10 times the recommended human dose (see Data).
The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Disease-Associated Maternal And/Or Embryo/Fetal Risk
Women with Gaucher disease type 1 have an increased risk of spontaneous abortion, especially if disease symptoms are not treated and controlled pre-conception and during a pregnancy. Pregnancy may exacerbate existing Gaucher disease type 1 symptoms or result in new disease manifestations. Gaucher disease type 1 manifestations may lead to adverse pregnancy outcomes including, hepatosplenomegaly which can interfere with the normal growth of a pregnancy and thrombocytopenia which can lead to increased bleeding and possible hemorrhage.
Animal Data
Reproduction studies have been performed in pregnant rats at oral doses up to 120 mg/kg/day (about 6 times the recommended human dose based on body surface area) and in pregnant rabbits at oral doses up to 100 mg/kg/day (about 10 times the recommended human dose based on body surface area) following administration of eliglustat during the period of organogenesis (gestation days 6 to 17 in the rat and 6 to 18 in the rabbit).
In rats, at 120 mg/kg/day (about 6 times the recommended human dose based on body surface area), eliglustat increased the number of late resorptions, dead fetuses and post implantation loss, reduced fetal body weight, and caused fetal cerebral variations (dilated cerebral ventricles), fetal skeletal variations (poor bone ossification) and fetal skeletal malformations (abnormal number of ribs or lumbar vertebra). Eliglustat-related effects on fetal rats were observed in association with signs of maternal toxicity.
Eliglustat did not cause fetal harm in rabbits at oral doses up to 100 mg/kg/day (about 10 times the recommended human dose based on body surface area). Mild maternal toxicity was observed at the 100 mg/kg/day dose.
In a pre and postnatal development study in rats (dosed daily from gestation day 6 to postpartum day 21), eliglustat did not show any significant adverse effects on pre and postnatal development at doses up to 100 mg/kg/day (about 5 times the recommended human dose based on body surface area).
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.
In a milk excretion study in the rat, a single oral dose of 30 mg/kg [14C]-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.
Safety and effectiveness in pediatric patients have not been established.
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.
Use CERDELGA in patients with renal impairment based on the patient's CYP2D6 metabolizer status [see CLINICAL PHARMACOLOGY].
Use CERDELGA in patients with hepatic impairment based on CYP2D6 metabolizer status and concomitant use of CYP2D6 or CYP3A inhibitors [see CLINICAL PHARMACOLOGY].
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].
CERDELGA is contraindicated in the following patients based on CYP2D6 metabolizer status due to the risk of cardiac arrhythmias from prolongation of the PR, QTc, and/or QRS cardiac intervals.
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”. CERDELGA is a specific inhibitor of glucosylceramide synthase (IC50 = 10 ng/mL), and acts as a substrate reduction therapy for GD1. In clinical trials CERDELGA reduced spleen and liver size, and improved anemia and thrombocytopenia.
In this lysosomal storage disorder (LSD), clinical features are reflective of the accumulation of Gaucher cells in the 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 lead to clinically significant anemia and thrombocytopenia.
QTc interval prolongation was studied in a double-blind, single dose, placebo- and positive-controlled crossover study in 42 healthy subjects. Concentration-related increases were observed for the placebo-corrected change from baseline in the PR, QRS, and QTc intervals. Based on PK/PD modeling, eliglustat plasma concentrations of 500 ng/mL are predicted to cause 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 the highest geometric mean concentrations of 237 ng/mL following a single supratherapeutic dose tested in the thorough QT study, CERDELGA did not prolong the QT/QTc interval to any clinically relevant extent.
At a given dose, the systemic exposure (Cmax and AUC) depends on the CYP2D6 phenotype. In CYP2D6 EMs and IMs, the eliglustat pharmacokinetics is time-dependent and the systemic exposure increases in a more than dose proportional manner. 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 timeindependent. Compared to EMs, the systemic exposure following 84 mg twice daily at steady state is 7- to 9-fold higher in PMs.
In CYP2D6 EMs, median time to reach maximum plasma concentrations (tmax) occurs at 1.5 to 2 hours following multiple doses of CERDELGA 84 mg twice daily. The corresponding mean Cmax values range from 12.1 to 25.0 ng/mL in EMs. The mean AUCtau values range from 76.3 to 143 hr*ng/mL in EMs. The Cmax and AUCtau in one IM subject receiving multiple doses of CERDELGA 84 mg twice daily was 44.6 ng/mL and 306 hr*ng/mL, respectively. The oral bioavailability is low in EMs ( < 5%) following single dose of CERDELGA 84 mg due to significant first-pass metabolism.
In PMs, median tmax occurs at 3 hours following multiple doses of CERDELGA 84 mg twice daily. The corresponding mean Cmax and AUCtau values range from 113 to 137 ng/mL and 922 to 1057 hr*ng/mL, respectively.
Oral dosing of CERDELGA 84 mg once daily has not been studied in PMs. The predicted Cmax and AUC0-24hr in PMs using physiologically-based pharmacokinetic (PBPK) model with 84 mg once daily are 75 ng/mL and 956 hr*ng/mL, respectively.
Administration of CERDELGA with a high fat meal resulted in a 15% decrease in Cmax but no change in AUC. Food does not have a clinically relevant effect on eliglustat pharmacokinetics.
Eliglustat is moderately bound to human plasma proteins (76 to 83%). In the blood, it is mainly distributed in plasma and not red blood cells. After intravenous (IV) administration, the volume of distribution of eliglustat was 835 L in CYP2D6 EMs, suggesting wide distribution to tissues (CERDELGA is only for oral use).
CERDELGA is extensively metabolized with high clearance, mainly by CYP2D6 and to a lesser extent CYP3A4. Primary metabolic pathways of eliglustat involve sequential oxidation of the octanoyl moiety followed by oxidation of the 2,3-dihydro-1,4- benzodioxane moiety, or a combination of the two pathways, resulting in multiple oxidative metabolites. No active metabolites have been identified.
After oral administration of 84 mg [14C]-eliglustat, the majority of the administered dose is excreted in urine (41.8%) and feces (51.4%), mainly as metabolites. After 42 mg IV administration in healthy volunteers, mean (CV%) of eliglustat total body clearance was 88 L/h (8.8%) in CYP2D6 EMs (CERDELGA is only for oral use). Following multiple oral doses of CERDELGA 84 mg twice daily, eliglustat terminal elimination half-life(T½) was approximately 6.5 hours in EMs and 8.9 hours in PMs.
Based on population PK analysis, there was no effect of mild renal impairment on eliglustat PK. Furthermore, gender, body weight, age, and race had no clinically relevant impact on the pharmacokinetics of eliglustat.
In vitro, eliglustat is metabolized primarily by CYP2D6 and to a lesser extent by CYP3A4. Eliglustat is also a substrate of P-glycoprotein (P-gp).
Systemic exposure (Cmax and AUCtau) of eliglustat increased 7.0-fold and 8.4-fold, respectively, following co-administration of CERDELGA 84 mg twice daily with paroxetine (a strong CYP2D6 inhibitor) 30 mg once daily in EMs (N=30), respectively.
Simulations using PBPK models suggested that paroxetine may increase the Cmax and AUCtau of eliglustat 2.1- and 2.3-fold in IMs, respectively.
Compared to paroxetine, the effects of terbinafine (a moderate inhibitor of CYP2D6) on the exposure of eliglustat in EMs or IMs were predicted to be smaller. Simulations using PBPK models suggested that terbinafine may increase the Cmax and AUCtau of eliglustat 3.8- and 4.5-fold in EMs, respectively. Both Cmax and AUCtau increased 1.6-fold in IMs.
CYP2D6 EMs and IMS
Following co-administration of CERDELGA 84 mg twice daily with ketoconazole (a strong CYP3A inhibitor) 400 mg once daily, the systemic exposure (Cmax and AUCtau) of eliglustat increased 4.0-fold and 4.4-fold in EMs (N=31).
Simulations using PBPK models suggested that ketoconazole may increase the Cmax and AUCtau of eliglustat 4.4- and 5.4-fold in IMs, respectively.
Compared to ketoconazole, the effects of fluconazole (a moderate inhibitor of CYP3A) on the exposure of eliglustat in EMs or IMs were predicted to be smaller. Simulations using PBPK models suggested that fluconazole may increase the Cmax and AUCtau of eliglustat 2.8- and 3.2-fold in EMs, respectively, and 2.5- to 2.9-fold in IMs, respectively.
CYP2D6 PMS
The effect of CYP3A inhibitors on the systemic exposure of eliglustat in PMs has not been evaluated in clinical studies. Simulations using PBPK models suggest that ketoconazole may increase the Cmax and AUC0-24h of eliglustat 4.3- and 6.2-fold when coadministered with CERDELGA 84 mg once daily in PMs. Simulations using PBPK models suggested that fluconazole may increase the Cmax and AUC0-24h of eliglustat 2.4- and 3.0-fold, respectively, when co-administered with CERDELGA 84 mg once daily.
Simulations using PBPK models suggested that concomitant use of CERDELGA 84 mg twice daily with paroxetine and ketoconazole may increase the Cmax and AUCtau of eliglustat 16.7- and 24.2-fold in EMs, respectively. The predicted Cmax and AUCtau of eliglustat increased 7.5- to 9.8-fold in IMs, respectively.
Simulations using PBPK models suggested that concomitant use of CERDELGA 84 mg twice daily with terbinafine and fluconazole may increase the Cmax and AUCtau of eliglustat 10.2- and 13.6-fold in EMs. The predicted Cmax and AUCtau of eliglustat increased 4.2- to 5.0-fold in IMs, respectively.
Systemic exposures (Cmax and AUCtau) of eliglustat decreased by approximately 90% in EMs and IMs, following co-administration of CERDELGA 127 mg twice daily with rifampin (a strong CYP3A inducer) 600 mg PO once daily. The only approved dose of CERDELGA is 84 mg. Systemic exposures of eliglustat decreased by approximately 95% following co-administration of CERDELGA 84 mg twice daily with rifampin 600 mg PO once daily in PMs.
Systemic exposures of eliglustat were similar with or without co-administration of single 600 mg IV dose of rifampin (a potent OATP inhibitor) regardless of subjects' CYP2D6 phenotypes.
The effect of P-gp inhibitors on the systemic exposure of eliglustat has not been studied clinically.
Gastric pH-modifying agents (Maalox®, Tums®, Protonix®) did not have a clinically relevant effect on eliglustat exposure.
Eliglustat is an inhibitor of P-gp and CYP2D6.
Following multiple doses of CERDELGA 127 mg twice daily, systemic exposures (Cmax and AUC) to metoprolol (a CYP2D6 substrate) increased compared to metoprolol administration alone. Mean Cmax and AUC increased by 1.7- and 2.3-fold, respectively, in EMs and by 1.2- and 1.6-fold, respectively in IMs. The only approved dose of CERDELGA is 84 mg.
Following multiple doses of CERDELGA 127 mg twice daily in EMs and IMs or 84 mg twice daily in PMs, systemic exposures (Cmax and AUC) to digoxin (a P-gp substrate, with narrow therapeutic index) increased compared to digoxin administration alone. Â Mean Cmax and AUC increased by 1.7- and 1.5-fold, respectively. The only approved dose of CERDELGA is 84 mg.
In vitro, eliglustat is a weak inhibitor of CYP3A. Repeated doses of CERDELGA 84 mg twice daily did not change the exposures to norethindrone (1.0 mg) and ethinyl estradiol (0.035 mg). Therefore, CERDELGA is not expected to impact the efficacy or safety of oral contraceptives containing norethindrone and ethinyl estradiol.
The efficacy of CERDELGA was evaluated in three clinical trials in patients with Gaucher disease type 1.
Trial 1 was a randomized, double-blind, placebo-controlled, multicenter clinical study evaluating the efficacy and safety of CERDELGA in 40 treatment-naïve GD1 patients 16 years of age or older (median age 30.4 years) with pre-existing splenomegaly and hematological abnormalities. Patients were required to have received no treatment with substrate reduction therapy within 6 months or ERT within 9 months prior to randomization; all but 5 patients in the study had no prior therapy. Patients were stratified according to baseline spleen volume ( ≤ 20 or > 20 multiples of normal [MN]) and randomized in a 1:1 ratio to receive CERDELGA or placebo for the duration of the 9-month blinded primary analysis period. The CERDELGA treatment group was comprised of IM (5%), EM (90%) and URM (5%) patients. Patients randomized to CERDELGA treatment received a starting dose of 42 mg twice daily, with a dose increase to 84 mg twice daily possible at Week 4 based on the plasma trough concentration at Week 2. The majority of patients (17 [85%]) received a dose escalation to 84 mg twice daily at Week 4, and 3 (15%) continued to receive 42 mg twice daily for the duration of the 9-month blinded primary analysis period.
The primary endpoint was the percentage change in spleen volume (in MN) from baseline to 9 months as compared to placebo. Secondary endpoints were absolute change in hemoglobin level, percentage change in liver volume (in MN), and percentage change in platelet count from baseline to 9 months compared to placebo.
At baseline, mean spleen volumes were 12.5 and 13.9 MN in the placebo and CERDELGA groups, respectively, and mean liver volumes were 1.4 MN for both groups. Mean hemoglobin levels were 12.8 and 12.1 g/dL, and platelet counts were 78.5 and 75.1 x 109/L, respectively.
During the 9-month primary analysis period, CERDELGA demonstrated statistically significant improvements in all primary and secondary endpoints compared to placebo, as shown in Table 6.
Table 6: Change from Baseline to Month 9 in
Treatment-Naïve Patients with GD1 Receiving Treatment with CERDELGA in Trial 1
| Placebo (n=20) |
CERDELGA (n=20) |
Difference (CERDELGA -Placebo) [95% CI] | p value* | |
| Percentage Change in Spleen Volume MN (%) | 2.3 | -27.8 | -30.0 [-36.8, -23.2] |
< 0.0001 |
| Absolute Change in Spleen Volume (MN) | 0.3 | -3.7 | -4.1 [-5.3, -2.9] |
NA |
| Absolute Change in Hemoglobin Level (g/dL) | -0.5 | 0.7 | 1.2 [0.6, 1.9] |
0.0006 |
| Percentage Change in Liver Volume MN (%) | 1.4 | -5.2 | -6.6 [-11.4, -1.9] |
0.0072 |
| Absolute Change in Liver Volume (MN) | 0.0 | -0.1 | -0.1 [-0.2, 0.0] |
NA |
| Percentage Change in Platelet Count (%) | -9.1 | 32.0 | 41.1 [24.0, 58.2] |
< 0.0001 |
| Absolute Change in Platelet Count (x 109/L) | -7.2 | 24.1 | 31.3 [18.8, 43.8] |
NA |
| MN = Multiples of Normal, CI = confidence interval, NA =
Not applicable *Estimates and p-value are based on ANCOVA model that includes treatment group, baseline spleen severity group ( ≤ 20MN, > 20MN) and baseline parameter value. |
||||
In an uncontrolled study of treatment naïve GD1 patients, improvements in spleen and liver volume, hemoglobin level, and platelet count continued through the 4 year treatment period.
Trial 2 was a randomized, open-label, active-controlled, non-inferiority, multicenter clinical study evaluating the efficacy and safety of CERDELGA compared with imiglucerase in 159 treated GD1 patients (median age 37.4 years) previously treated with enzyme replacement therapy ( ≥ 3 years of enzyme replacement therapy, dosed at 30-130 U/kg/month in at least 6 of the prior 9 months) who met pre-specified therapeutic goals at baseline. Pre-specified baseline therapeutic goals included: no bone crisis and free of symptomatic bone disease within the last year; mean hemoglobin level of ≥ 11 g/dL in females and ≥ 12 g/dL in males; mean platelet count ≥ 100,000/mm³ ; spleen volume < 10 times normal and liver volume < 1.5 times normal.
Patients were randomized 2:1 to receive CERDELGA or imiglucerase for the duration of the 12-month primary analysis period. Seventy-five percent of patients randomized to CERDELGA were previously treated with imiglucerase; 21% with velaglucerase alfa and 4% were unreported. Patients randomized to CERDELGA treatment received a starting dose of 42 mg twice daily, with dose increases to 84 mg twice daily and 127 mg twice daily possible at Weeks 4 and 8 based on plasma trough concentrations of CERDELGA at Weeks 2 and 6, respectively. The percentage of patients receiving the 3 possible CERDELGA doses was: 42 mg twice daily (20%), 84 mg twice daily (32%) and 127 mg twice daily (48%). The CERDELGA treatment group was comprised of PM (4%), IM (10%), EM (80%) and URM (4%) patients.
At baseline, mean spleen volumes were 2.6 and 3.2 MN in the imiglucerase and CERDELGA groups, respectively, and liver volumes were 0.9 MN in both groups. Mean hemoglobin levels were 13.8 and 13.6 g/dL, and platelet counts were 192 and 207 x 109/L, respectively.
The primary composite endpoint required stability in all four component domains (hemoglobin level, platelet count, liver volume, and spleen volume) based on changes between baseline and 12 months. Stability was defined by the following pre-specified thresholds of change: hemoglobin level < 1.5 g/dL decrease, platelet count < 25% decrease, liver volume < 20% increase and spleen volume < 25% increase. The percentages of patients meeting the criteria for stability in the individual components of the composite endpoint were assessed as secondary efficacy endpoints.
CERDELGA met the criteria to be declared non-inferior to imiglucerase in maintaining patient stability. After 12 months of treatment, the percentage of patients meeting the primary composite endpoint was 84.8% for the CERDELGA group compared to 93.6% for the imiglucerase group. The lower bound of the 95% CI of the 8.8% difference, -17.6%, was within the pre-specified non-inferiority margin of -25%. At Month 12, the percentages of CERDELGA and imiglucerase patients respectively, who met stability criteria for the individual components of the composite endpoint were: hemoglobin level, 94.9% and 100%; platelet count, 92.9% and 100%; spleen volume, 95.8% and 100%; and liver volume, 96.0% and 93.6%. Of the patients who did not meet stability criteria for the individual components, 12 of 15 CERDELGA patients and 3 of 3 imiglucerase patients remained within therapeutic goals for GD1.
Mean changes from baseline in the hematological and visceral parameters through 12 months of treatment are shown in Table 7. There were no clinically meaningful differences between groups for any of the four parameters.
Table 7: Mean Changes from Baseline to Month 12 in
Patients with GD1 Switching to CERDELGA in Trial 2
| Imiglucerase (N=47) Mean [95% CI] |
CERDELGA (N=99) Mean [95% CI] |
|
| Percentage Change in Spleen Volume MN (%)* | -3.0 [-6.4, 0.4] | -6.2 [-9.5, -2.8] |
| Absolute Change in Spleen Volume (MN)* | -0.1 [-0.2, 0.0] | -0.2 [-0.3, -0.1] |
| Absolute Change in Hemoglobin Level (g/dL) | 0.0 [-0.2, 0.2] | -0.2 [-0.4, -0.1] |
| Percentage Change in Liver Volume MN (%) | 3.6 [0.6, 6.6] | 1.8 [-0.2, 3.7] |
| Absolute Change in Liver Volume (MN) | 0.0 [0.0, 0.1] | 0.0 [0.0, 0.0] |
| Percentage Change in Platelet Count (%) | 2.9 [-0.6, 6.4] | 3.8 [0.0, 7.6] |
| Absolute Change in Platelet Count (x 109/L) | 6.0 [-0.9, 13.0] | 9.5 [1.4, 17.6] |
| Patients Stable for 52 Weeks, n (%) (Composite Primary Endpoint) | 44 (93.6) | 84 (84.8) |
| MN = Multiples of Normal, CI = confidence interval * Excludes patients with a total splenectomy. |
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CERDELGA™
(sir-DEL-guh)
(eliglustat) capsules
What is the most important information I should know about CERDELGA?
CERDELGA can affect the way other medicines work and other medicines can affect how CERDELGA works. Using CERDELGA with other medicines or herbal supplements may cause an increased risk of side effects.
Especially tell your doctor if you take:
If you take any medicines for the conditions listed above, your doctor may need to prescribe a different medicine, change your dose of other medicines, or change your dose of CERDELGA. Tell your doctor about any new medicines before you start taking them.
What is CERDELGA?
CERDELGA is a prescription medicine used for the long-term treatment of Gaucher disease type 1 (GD1) in adults.
CERDELGA is not used in certain people with Gaucher disease type 1. Your doctor will perform a test to make sure that CERDELGA is right for you.
It is not known if CERDELGA is safe and effective in children.
What should I tell my doctor before taking CERDELGA?
Before taking CERDELGA, tell your doctor about all of your medical conditions, including if you:
Tell your doctor about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. See “What is the most important information I should know about CERDELGA?”
How should I take CERDELGA?
What should I avoid while taking CERDELGA?
Avoid eating or drinking grapefruit products while taking CERDELGA. Grapefruit products can increase the amount of CERDELGA in your body.
What are the possible side effects of CERDELGA?
See “What is the most important information I should know about CERDELGA?”
The most common side effects of CERDELGA include: tiredness, headache, nausea, diarrhea, and pain in the arms, legs, back, or stomach (abdomen).
Tell your doctor if you have any side effect that bothers you or that does not go away. Â These are not all the possible side effects of CERDELGA.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store CERDELGA?
General information about the safe and effective use of CERDELGA.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use CERDELGA for a condition for which it was not prescribed. Do not give CERDELGA to other people, even if they have the same symptoms you have. It may harm them.
If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about CERDELGA that is written for health professionals. For more information, go to www.cerdelga.com or call 1-800-745-4447.
What are the ingredients in CERDELGA?
Active ingredient: eliglustat
Inactive ingredients: microcrystalline cellulose, lactose monohydrate, hypromellose, glyceryl behenate, gelatin, candurin silver fine, yellow iron oxide, and FD&C blue 2
This Medication Guide has been approved by the U.S. Food and Drug Administration.
