INDICATIONS
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].
LIMITATIONS OF USE
" PATIENTS WHO ARE CYP2D6 ULTRA-RAPID METABOLIZERS (URMS) MAY NOT ACHIEVE ADEQUATE CONCENTRATIONS OF CERDELGA TO ACHIEVE A THERAPEUTIC EFFECT [SEE CLINICAL STUDIES].
" A SPECIFIC DOSAGE CANNOT BE RECOMMENDED FOR THOSE PATIENTS WHOSE CYP2D6 GENOTYPE CANNOT BE DETERMINED (INDETERMINATE METABOLIZERS) [SEE CLINICAL STUDIES].
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
CERDELGA IS SUPPLIED AS 84 MG HARD GELATIN CAPSULES, WITH A PEARL BLUE-GREEN OPAQUE CAP AND PEARL WHITE OPAQUE BODY IMPRINTED WITH "GZ02" IN BLACK. EACH CAPSULE CONTAINS 100 MG ELIGLUSTAT TARTRATE, WHICH IS EQUIVALENT TO 84 MG OF ELIGLUSTAT.
STORAGE AND HANDLING
CERDELGA IS SUPPLIED AS 84 MG HARD GELATIN CAPSULES, 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. ISSUED: AUGUST 2014
DOSAGE AND ADMINISTRATION
PATIENT SELECTION
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].
RECOMMENDED ADULT DOSAGE
THE RECOMMENDED DOSAGE OF CERDELGA IS 84 MG TWICE DAILY IN CYP2D6 EMS AND IMS. THE RECOMMENDED DOSAGE IN CYP2D6 PMS IS 84 MG ONCE DAILY; APPROPRIATE ADVERSE EVENT MONITORING IS RECOMMENDED [SEE ADVERSE REACTIONS]. THE PREDICTED EXPOSURES WITH 84 MG ONCE DAILY IN PATIENTS WHO ARE CYP2D6 PMS ARE EXPECTED TO BE SIMILAR TO EXPOSURES OBSERVED WITH 84 MG TWICE DAILY IN CYP2D6 IMS [SEE CLINICAL PHARMACOLOGY].
SOME INHIBITORS OF CYP2D6 AND CYP3A ARE CONTRAINDICATED WITH CERDELGA DEPENDING ON THE PATIENT'S METABOLIZER STATUS [SEE CONTRAINDICATIONS]. COADMINISTRATION OF CERDELGA WITH OTHER CYP2D6 AND CYP3A INHIBITORS MAY REQUIRE DOSAGE ADJUSTMENT DEPENDING ON THE PATIENT'S CYP2D6 METABOLIZER STATUS TO REDUCE THE RISK OF POTENTIALLY SIGNIFICANT ADVERSE REACTIONS [SEE TABLE 3 AND TABLE 4 IN DRUG INTERACTIONS].
REDUCE THE DOSAGE OF CERDELGA TO 84 MG ONCE DAILY FOR:
" CYP2D6 EMS AND IMS TAKING STRONG OR MODERATE CYP2D6 INHIBITORS
" CYP2D6 EMS TAKING STRONG OR MODERATE CYP3A INHIBITORS
IMPORTANT ADMINISTRATION INSTRUCTIONS
" SWALLOW CAPSULES WHOLE, PREFERABLY WITH WATER, AND DO NOT CRUSH, DISSOLVE, OR OPEN THE CAPSULES.
" CERDELGA CAN BE TAKEN WITH OR WITHOUT FOOD.
" AVOID THE CONSUMPTION OF GRAPEFRUIT OR GRAPEFRUIT JUICE WITH CERDELGA BECAUSE GRAPEFRUIT IS A STRONG CYP3A INHIBITOR [SEE DRUG INTERACTIONS].
" IF A DOSE OF CERDELGA IS MISSED, TAKE THE PRESCRIBED DOSE AT THE NEXT SCHEDULED TIME; DO NOT DOUBLE THE NEXT DOSE.
" FOR PATIENTS CURRENTLY TREATED WITH IMIGLUCERASE, VELAGLUCERASE ALFA, OR TALIGLUCERASE ALFA, CERDELGA MAY BE ADMINISTERED 24 HOURS AFTER THE LAST DOSE OF THE PREVIOUS ENZYME REPLACEMENT THERAPY (ERT).
SIDE EFFECTS
CLINICAL TRIALS EXPERIENCE
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. TABLE 1 PRESENTS THE PROFILE FROM THE 9-MONTH DOUBLE-BLIND, RANDOMIZED, PLACEBOCONTROLLED TRIAL OF 40 TREATMENT-NAÏVE 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 1: ADVERSE REACTIONS OCCURRING IN ? 10% OF TREATMENT-NAÏVE 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 2 PRESENTS THE PROFILE FROM THE 12-MONTH OPEN-LABEL, RANDOMIZED, IMIGLUCERASECONTROLLED 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 2: 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)
PATIENTS N (%) IMIGLUCERASE (N=53)
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 AN UNCONTROLLED STUDY, WITH UP TO 4 YEARS OF TREATMENT, IN 26 PATIENTS, THE TYPES AND INCIDENCES OF ADVERSE REACTIONS WERE SIMILAR TO TRIALS 1 AND 2.
READ THE CERDELGA (EIGLUSTAT CAPSULES) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
OVERDOSE
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].
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
GAUCHER DISEASE IS CAUSED BY A DEFICIENCY OF THE LYSOSOMAL ENZYME ACID ?-GLUCOSIDASE. ACID ?-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.
PHARMACODYNAMICS
ELECTROCARDIOGRAPHIC EVALUATION
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.
PHARMACOKINETICS
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.
ABSORPTION
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.
DISTRIBUTION
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).
METABOLISM AND ELIMINATION
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.
SPECIFIC POPULATIONS
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.
DRUG INTERACTIONS - EFFECT OF OTHER DRUGS ON CERDELGA
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).
CO-ADMINISTRATION OF CERDELGA WITH CYP2D6 INHIBITORS
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.
CO-ADMINISTRATION OF CERDELGA WITH CYP3A INHIBITORS
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.
CO-ADMINISTRATION OF CERDELGA WITH CYP2D6 AND CYP3A INHIBITORS
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.
EFFECT OF CYP3A INDUCERS ON ELIGLUSTAT PK
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.
EFFECT OF OATP (ORGANIC ANION TRANSPORTING POLYPEPTIDE) INHIBITORS ON ELIGLUSTAT PK
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.
EFFECT OF P-GP INHIBITORS ON ELIGLUSTAT PK
THE EFFECT OF P-GP INHIBITORS ON THE SYSTEMIC EXPOSURE OF ELIGLUSTAT HAS NOT BEEN STUDIED CLINICALLY.
EFFECT OF GASTRIC PH-MODIFYING AGENTS ON ELIGLUSTAT PK
GASTRIC PH-MODIFYING AGENTS (MAALOX®, TUMS®, PROTONIX®) DID NOT HAVE A CLINICALLY RELEVANT EFFECT ON ELIGLUSTAT EXPOSURE.
DRUG INTERACTIONS - EFFECT OF CERDELGA ON THE PK OF OTHER DRUGS
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. 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.
CLINICAL STUDIES
THE EFFICACY OF CERDELGA WAS EVALUATED IN THREE CLINICAL TRIALS IN PATIENTS WITH GAUCHER DISEASE TYPE 1.
CERDELGA IN TREATMENT-NAÏVE GD1 PATIENTS - TRIAL 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.
PATIENTS SWITCHING FROM ENZYME REPLACEMENT THERAPY TO CERDELGA -TRIAL 2
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.