WARNING
FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, AND INTESTINAL PERFORATION
" FATAL AND/OR SERIOUS HEPATOTOXICITY OCCURRED IN 14% OF ZYDELIG-TREATED PATIENTS. MONITOR HEPATIC FUNCTION PRIOR TO AND DURING TREATMENT. INTERRUPT AND THEN REDUCE OR DISCONTINUE ZYDELIG AS RECOMMENDED [SEE DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
" FATAL AND/OR SERIOUS AND SEVERE DIARRHEA OR COLITIS OCCURRED IN 14% OF ZYDELIG-TREATED PATIENTS. MONITOR FOR THE DEVELOPMENT OF SEVERE DIARRHEA OR COLITIS. INTERRUPT AND THEN REDUCE OR DISCONTINUE ZYDELIG AS RECOMMENDED [SEE DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
" FATAL AND SERIOUS PNEUMONITIS CAN OCCUR IN ZYDELIG-TREATED PATIENTS. MONITOR FOR PULMONARY SYMPTOMS AND BILATERAL INTERSTITIAL INFILTRATES. INTERRUPT OR DISCONTINUE ZYDELIG AS RECOMMENDED [SEE DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
" FATAL AND SERIOUS INTESTINAL PERFORATION CAN OCCUR IN ZYDELIG-TREATED PATIENTS ACROSS CLINICAL TRIALS. DISCONTINUE ZYDELIG FOR INTESTINAL PERFORATION [SEE WARNINGS AND PRECAUTIONS].
INDICATIONS
RELAPSED CHRONIC LYMPHOCYTIC LEUKEMIA
ZYDELIG IS INDICATED, IN COMBINATION WITH RITUXIMAB, FOR THE TREATMENT OF PATIENTS WITH RELAPSED CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) FOR WHOM RITUXIMAB ALONE WOULD BE CONSIDERED APPROPRIATE THERAPY DUE TO OTHER CO-MORBIDITIES.
RELAPSED FOLLICULAR B-CELL NON-HODGKIN LYMPHOMA
ZYDELIG IS INDICATED FOR THE TREATMENT OF PATIENTS WITH RELAPSED FOLLICULAR B-CELL NON-HODGKIN LYMPHOMA (FL) WHO HAVE RECEIVED AT LEAST TWO PRIOR SYSTEMIC THERAPIES.
ACCELERATED APPROVAL WAS GRANTED FOR THIS INDICATION BASED ON OVERALL RESPONSE RATE [SEE CLINICAL STUDIES]. AN IMPROVEMENT IN PATIENT SURVIVAL OR DISEASE RELATED SYMPTOMS HAS NOT BEEN ESTABLISHED. CONTINUED APPROVAL FOR THIS INDICATION MAY BE CONTINGENT UPON VERIFICATION OF CLINICAL BENEFIT IN CONFIRMATORY TRIALS.
RELAPSED SMALL LYMPHOCYTIC LYMPHOMA
ZYDELIG IS INDICATED FOR THE TREATMENT OF PATIENTS WITH RELAPSED SMALL LYMPHOCYTIC LYMPHOMA (SLL) WHO HAVE RECEIVED AT LEAST TWO PRIOR SYSTEMIC THERAPIES.
ACCELERATED APPROVAL WAS GRANTED FOR THIS INDICATION BASED ON OVERALL RESPONSE RATE [SEE CLINICAL STUDIES]. AN IMPROVEMENT IN PATIENT SURVIVAL OR DISEASE RELATED SYMPTOMS HAS NOT BEEN ESTABLISHED. CONTINUED APPROVAL FOR THIS INDICATION MAY BE CONTINGENT UPON VERIFICATION OF CLINICAL BENEFIT IN CONFIRMATORY TRIALS.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
150 MG TABLETS: PINK, OVAL-SHAPED, FILM-COATED TABLET DEBOSSED WITH "GSI" ON ONE SIDE AND "150" ON THE OTHER SIDE.
100 MG TABLETS: ORANGE, OVAL-SHAPED, FILM-COATED TABLET DEBOSSED WITH "GSI" ON ONE SIDE AND "100" ON THE OTHER SIDE.
STORAGE AND HANDLING
ZYDELIG TABLETS SUPPLIED AS FOLLOWS:
TABLET STRENGTH PACKAGE CONFIGURATION NDC NO. DESCRIPTION OF TABLET; DEBOSSED ON TABLET
150 MG HIGH DENSITY POLYETHYLENE(HDPE) BOTTLE WITH A POLYESTER FIBER COIL, CAPPED WITH A CHILD-RESISTANT CLOSURE. EACH BOTTLE CONTAINS 60 FILM-COATED TABLETS. 61958-1702-1 OVAL SHAPED; PINK; "150" ON ONE SIDE AND "GSI" ON THE OTHER SIDE
100 MG 61958-1701-1 OVAL-SHAPED; ORANGE; "100" ON ONE SIDE AND "GSI" ON THE OTHER SIDE
STORE BETWEEN 20-30 Β°C (68-86 Β°F) WITH EXCURSIONS PERMITTED 15-30 Β°C (59-86 Β°F).
" DISPENSE ONLY IN ORIGINAL CONTAINER.
" DO NOT USE IF SEAL OVER BOTTLE OPENING IS BROKEN OR MISSING.
MANUFACTURED AND DISTRIBUTED BY: GILEAD SCIENCES, INC. FOSTER CITY, CA 94404. ISSUED: JULY 2014
DOSAGE AND ADMINISTRATION
RECOMMENDED DOSE
THE RECOMMENDED MAXIMUM STARTING DOSE OF ZYDELIG IS 150 MG ADMINISTERED ORALLY TWICE DAILY.
ZYDELIG CAN BE TAKEN WITH OR WITHOUT FOOD. TABLETS SHOULD BE SWALLOWED WHOLE.
CONTINUE TREATMENT UNTIL DISEASE PROGRESSION OR UNACCEPTABLE TOXICITY. THE OPTIMAL AND SAFE DOSING REGIMEN FOR PATIENTS WHO RECEIVE TREATMENT LONGER THAN SEVERAL MONTHS IS UNKNOWN.
DOSE MODIFICATION
SEE THE TABLE BELOW FOR DOSE MODIFICATION INSTRUCTIONS FOR SPECIFIC TOXICITIES RELATED TO ZYDELIG. FOR OTHER SEVERE OR LIFE-THREATENING TOXICITIES RELATED TO ZYDELIG, WITHHOLD DRUG UNTIL TOXICITY IS RESOLVED. IF RESUMING ZYDELIG AFTER INTERRUPTION FOR OTHER SEVERE OR LIFE-THREATENING TOXICITIES, REDUCE THE DOSE TO 100 MG TWICE DAILY. RECURRENCE OF OTHER SEVERE OR LIFE-THREATENING ZYDELIG-RELATED TOXICITY UPON RECHALLENGE SHOULD RESULT IN PERMANENT DISCONTINUATION OF ZYDELIG.
TABLE 1 : DOSE MODIFICATIONS FOR TOXICITIES DUE TO ZYDELIG
SIDE EFFECTS
THE FOLLOWING SERIOUS ADVERSE REACTIONS HAVE BEEN ASSOCIATED WITH ZYDELIG IN CLINICAL TRIALS AND ARE DISCUSSED IN GREATER DETAIL IN OTHER SECTIONS OF THE PRESCRIBING INFORMATION.
" HEPATOTOXICITY [SEE WARNINGS AND PRECAUTIONS]
" SEVERE DIARRHEA OR COLITIS [SEE WARNINGS AND PRECAUTIONS]
" PNEUMONITIS [SEE W WARNINGS AND PRECAUTIONS]
" INTESTINAL PERFORATION [SEE WARNINGS AND PRECAUTIONS]
" SEVERE CUTANEOUS REACTIONS [SEE WARNINGS AND PRECAUTIONS]
" ANAPHYLAXIS [SEE WARNINGS AND PRECAUTIONS]
" NEUTROPENIA [SEE WARNINGS AND PRECAUTIONS]
CLINICAL TRIAL 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.
SUMMARY OF CLINICAL TRIALS IN CHRONIC LYMPHOCYTIC LEUKEMIA
THE SAFETY DATA REFLECT SUBJECT EXPOSURE TO ZYDELIG FROM STUDY 1, IN WHICH 218 SUBJECTS WITH RELAPSED CLL RECEIVED UP TO 8 DOSES OF RITUXIMAB WITH OR WITHOUT ZYDELIG 150 MG TWICE DAILY. THE MEDIAN DURATION OF EXPOSURE TO ZYDELIG WAS 5 MONTHS.
SERIOUS ADVERSE REACTIONS WERE REPORTED IN 54 (49%) SUBJECTS TREATED WITH ZYDELIG + RITUXIMAB. THE MOST FREQUENT ( ? 2%) SERIOUS ADVERSE REACTIONS REPORTED FOR SUBJECTS TREATED WITH ZYDELIG WERE PNEUMONIA (17%), PYREXIA (9%), SEPSIS (8%), FEBRILE NEUTROPENIA (5%) AND DIARRHEA (5%). ADVERSE REACTIONS THAT LED TO DISCONTINUATION OF ZYDELIG OCCURRED IN 11 (10%) SUBJECTS. THE MOST COMMON ADVERSE REACTIONS THAT LED TO TREATMENT DISCONTINUATIONS WERE HEPATOTOXICITY AND DIARRHEA/COLITIS.
THIRTY-NINE SUBJECTS (35%) HAD DOSE INTERRUPTIONS AND SIXTEEN SUBJECTS (15%) HAD DOSE REDUCTIONS DUE TO ADVERSE REACTIONS OR LABORATORY ABNORMALITIES. THE MOST COMMON REASONS FOR DOSE REDUCTIONS WERE ELEVATED TRANSAMINASES, DIARRHEA OR COLITIS, AND RASH.
TABLE 2 AND TABLE 3 SUMMARIZE COMMON ADVERSE REACTIONS AND LABORATORY ABNORMALITIES REPORTED FOR ZYDELIG + RITUXIMAB AND PLACEBO + RITUXIMAB ARMS.
TABLE 2 : ADVERSE REACTIONS REPORTED IN ? 5% OF CLL PATIENTS AND OCCURRED AT ? 2% HIGHER INCIDENCE IN SUBJECTS RECEIVING ZYDELIG
ADVERSE REACTION ZYDELIG + R
N=110 (%) PLACEBO + R
N=108 (%)
ANY GRADE GRADE ? 3 ANY GRADE GRADE ? 3
GASTROINTESTINAL DISORDERS
NAUSEA 28 (25) 0 23 (21) 0
VOMITING 14 (13) 0 9 (8) 0
DIARRHEAA 23 (21) 6 (5) 17 (16) 0
GASTROESOPHAGEAL REFLUX DISEASE 7 (6) 0 1 (1) 0
STOMATITIS 7 (6) 2 (2) 2 (2) 0
NERVOUS SYSTEM DISORDERS
HEADACHE 11 (10) 1 (1) 5 (5) 0
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
PYREXIA 38 (35) 3 (3) 18 (17) 1 (1)
CHILLS 23 (21) 2 (2) 17 (16) 0
PAIN 8 (7) 0 2 (2) 0
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
RASHB 20 (18) 4 (4) 7 (6) 1 (1)
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS
PNEUMONIAC 25 (23) 18 (16) 19 (18) 14 (13)
NASAL CONGESTION 6 (5) 0 2 (2) 0
INFECTIONS AND INFESTATIONS
SEPSISD 9 (8) 8 (7) 4 (4) 4 (4)
BRONCHITIS 7 (6) 1 (1) 3 (3) 1 (1)
SINUSITIS 9 (8) 0 4 (4) 0
URINARY TRACT INFECTION 6 (5) 0 3 (3) 2 (2)
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
ARTHRALGIA 8 (7) 1 (1) 4 (4) 1 (1)
A DIARRHEA INCLUDES THE FOLLOWING PREFERRED TERMS: DIARRHEA, COLITIS.
B RASH INCLUDES THE FOLLOWING PREFERRED TERMS: DERMATITIS EXFOLIATIVE, RASH, RASH MACULAR, RASH MACULO-PAPULAR, RASH PAPULAR, RASH PRURITIC, AND SKIN DISORDER.
C PNEUMONIA INCLUDES THE TERMS: PNEUMONIA, PNEUMONITIS, LUNG INFECTION, LUNG INFILTRATION, PNEUMOCYSTIS JIROVECI PNEUMONIA, PNEUMONIA LEGIONELLA, LUNG INFECTION PSEUDOMONAL, PNEUMONIA FUNGAL, RESPIRATORY TRACT INFECTION, LOWER RESPIRATORY TRACT INFECTION, AND LOWER RESPIRATORY TRACT INFECTION BACTERIAL.
D SEPSIS INCLUDES THE TERMS: SEPSIS, SEPTIC SHOCK, NEUTROPENIC SEPSIS, AND SEPSIS SYNDROME.
R: RITUXIMAB
TABLE 3 : TREATMENT-EMERGENT LABORATORY ABNORMALITIES REPORTED IN ? 10% OF CLL PATIENTS OCCURRING AT A ? 5% HIGHER INCIDENCE IN SUBJECTS RECEIVING ZYDELIG
LABORATORY PARAMETER ZYDELIG + R
N=110 (%) PLACEBO + R
N=108 (%)
ANY GRADE GRADE 3-4 ANY GRADE GRADE 3-4
HEMATOLOGY ABNORMALITIES
NEUTROPHIL COUNT DECREASED 66 (60) 41 (37) 55 (51) 29 (27)
LYMPHOCYTE COUNT DECREASED 22 (20) 10 (9) 13 (12) 4 (4)
LYMPHOCYTE COUNT INCREASED 27 (25) 20 (18) 10 (9) 5 (5)
SERUM CHEMISTRY ABNORMALITIES
ALT INCREASED 38 (35) 9 (8) 11 (10) 1 (1)
AST INCREASED 27 (25) 6 (5) 15 (14) 0
GGT INCREASED 29 (26) 2 (2) 15 (14) 3 (3)
TRIGLYCERIDES (HYPERTRIGLYCERIDEMIA) 62 (56) 3 (3) 37 (34) 0
HYPERGLYCEMIA 59 (54) 8 (7) 50 (46) 2 (2)
HYPOGLYCEMIA 12 (11) 0 5 (5) 0
HYPONATREMIA 22 (20) 2 (2) 16 (15) 7 (6)
GRADES WERE OBTAINED PER CTCAE VERSION 4.03.
R: RITUXIMAB
SUMMARY OF CLINICAL TRIALS IN INDOLENT NON-HODGKIN LYMPHOMA
THE SAFETY DATA REFLECT EXPOSURE TO ZYDELIG IN 146 ADULTS WITH INDOLENT NON-HODGKIN LYMPHOMA TREATED WITH ZYDELIG 150 MG TWICE DAILY IN CLINICAL TRIALS. THE MEDIAN DURATION OF EXPOSURE WAS 6.1 MONTHS (RANGE 0.3 TO 26.4 MONTHS).
SERIOUS ADVERSE REACTIONS WERE REPORTED IN 73 (50%) SUBJECTS. THE MOST FREQUENT SERIOUS ADVERSE REACTIONS THAT OCCURRED WERE PNEUMONIA (15%), DIARRHEA (11%), AND PYREXIA (9%).
ADVERSE REACTIONS RESULTED IN INTERRUPTION OR DISCONTINUATION FOR 78 (53%) SUBJECTS. THE MOST COMMON REASONS FOR INTERRUPTION OR DISCONTINUATIONS WERE DIARRHEA (11%), PNEUMONIA (11%), AND ELEVATED TRANSAMINASES (10%).
TABLE 4 PROVIDES THE ADVERSE REACTIONS OCCURRING IN AT LEAST 10% OF SUBJECTS RECEIVING ZYDELIG MONOTHERAPY, AND TABLE 5 PROVIDES THE TREATMENT-EMERGENT LABORATORY ABNORMALITIES.
TABLE 4 : ADVERSE REACTIONS ( ? 10% OF SUBJECTS) IN PATIENTS WITH INDOLENT NON-HODGKIN LYMPHOMA TREATED WITH ZYDELIG 150 MG BID
ADVERSE REACTION ZYDELIG MONOTHERAPY
N=146 (%)
ANY GRADE GRADE ? 3
GASTROINTESTINAL DISORDERS
DIARRHEAA 68 (47) 20 (14)
NAUSEA 42 (29) 2 (1)
ABDOMINAL PAINB 38 (26) 3 (2)
VOMITING 22 (15) 2 (1)
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
FATIGUE 44 (30) 2 (1)
PYREXIA 41 (28) 3 (2)
ASTHENIA 17 (12) 3 (2)
PERIPHERAL EDEMA 15 (10) 3 (2)
INFECTIONS AND INFESTATIONS
UPPER RESPIRATORY TRACT INFECTION 18 (12) 0
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS
PNEUMONIAC 37 (25) 23 (16)
COUGH 42 (29) 1 (1)
DYSPNEA 25 (17) 6 (4)
SKIN AND SUBCUTANEOUS DISORDERS
RASHD 31 (21) 4 (3)
NIGHT SWEATS 18 (12) 0
NERVOUS SYSTEM DISORDERS
HEADACHE 16 (11) 1 (1)
METABOLISM AND NUTRITION DISORDERS
DECREASED APPETITE 24 (16) 1 (1)
PSYCHIATRIC DISORDERS
INSOMNIA 17 (12) 0
A DIARRHEA INCLUDES THE FOLLOWING PREFERRED TERMS: DIARRHEA, COLITIS, ENTEROCOLITIS, AND GASTROINTESTINAL INFLAMMATION.
B ABDOMINAL PAIN INCLUDES THE FOLLOWING PREFERRED TERMS: ABDOMINAL PAIN, ABDOMINAL PAIN UPPER, ABDOMINAL PAIN LOWER, AND ABDOMINAL DISCOMFORT.
C PNEUMONIA INCLUDES THE TERMS: PNEUMONIA, PNEUMONITIS, INTERSTITIAL LUNG DISEASE, LUNG INFILTRATION, PNEUMONIA ASPIRATION, RESPIRATORY TRACT INFECTION, ATYPICAL PNEUMONIA, LUNG INFECTION, PNEUMOCYSTIS JIROVECI PNEUMONIA, BRONCHOPNEUMONIA, PNEUMONIA NECROTIZING, LOWER RESPIRATORY TRACT INFECTION, PNEUMONIA PNEUMOCOCCAL, PNEUMONIA STAPHYLOCOCCAL, PNEUMONIA STREPTOCOCCAL, PNEUMONIA CYTOMEGALOVIRAL, AND RESPIRATORY SYNCYTIAL VIRUS INFECTION.
D RASH INCLUDES THE FOLLOWING PREFERRED TERMS: DERMATITIS EXFOLIATIVE, RASH, RASH ERYTHEMATOUS, RASH MACULAR, RASH MACULO-PAPULAR, RASH PRURITIC, AND EXFOLIATIVE RASH.
TABLE 5 : TREATMENT-EMERGENT LABORATORY ABNORMALITIES IN PATIENTS WITH INDOLENT NON-HODGKIN LYMPHOMA TREATED WITH ZYDELIG 150 MG BID
LABORATORY ABNORMALITY ZYDELIG MONOTHERAPY
N=146 (%)
ANY GRADE GRADE 3 GRADE 4
SERUM CHEMISTRY ABNORMALITIES
ALT INCREASED 73 (50) 20 (14) 7 (5)
AST INCREASED 60 (41) 12 (8) 6 (4)
HEMATOLOGY ABNORMALITIES
NEUTROPHILS DECREASED 78 (53) 20 (14) 16 (11)
HEMOGLOBIN DECREASED 41 (28) 3 (2) 0
PLATELETS DECREASED 38 (26) 4 (3) 5 (3)
GRADES WERE OBTAINED PER CTCAE VERSION 4.03.
READ THE ZYDELIG (IDELALISIB TABLETS) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
IDELALISIB IS AN INHIBITOR OF PI3K? KINASE, WHICH IS EXPRESSED IN NORMAL AND MALIGNANT B-CELLS. IDELALISIB INDUCED APOPTOSIS AND INHIBITED PROLIFERATION IN CELL LINES DERIVED FROM MALIGNANT B-CELLS AND IN PRIMARY TUMOR CELLS. IDELALISIB INHIBITS SEVERAL CELL SIGNALING PATHWAYS, INCLUDING B-CELL RECEPTOR (BCR) SIGNALING AND THE CXCR4 AND CXCR5 SIGNALING, WHICH ARE INVOLVED IN TRAFFICKING AND HOMING OF B-CELLS TO THE LYMPH NODES AND BONE MARROW. TREATMENT OF LYMPHOMA CELLS WITH IDELALISIB RESULTED IN INHIBITION OF CHEMOTAXIS AND ADHESION, AND REDUCED CELL VIABILITY.
PHARMACODYNAMICS
ELECTROCARDIOGRAPHIC EFFECTS
THE EFFECT OF ZYDELIG (150 MG AND 400 MG) ON THE QT/QTC INTERVAL WAS EVALUATED IN A PLACEBO-AND POSITIVE-CONTROLLED (MOXIFLOXACIN 400 MG) CROSSOVER STUDY IN 46 HEALTHY SUBJECTS. AT A DOSE 2.7 TIMES THE MAXIMUM RECOMMENDED DOSE, ZYDELIG DID NOT PROLONG THE QT/QTC INTERVAL (I.E., NOT GREATER THAN OR EQUAL TO 10 MS).
PHARMACOKINETICS
ABSORPTION
FOLLOWING ORAL ADMINISTRATION OF A SINGLE DOSE OF ZYDELIG IN THE FASTED STATE, THE MEDIAN TMAX WAS OBSERVED AT 1.5 HOURS.
IDELALISIB EXPOSURE INCREASED IN A LESS THAN DOSE-PROPORTIONAL MANNER OVER A DOSE RANGE OF 50 MG TO 350 MG TWICE DAILY IN THE FASTED STATE.
RELATIVE TO FASTING CONDITIONS, THE ADMINISTRATION OF A SINGLE DOSE OF ZYDELIG WITH A HIGH-FAT MEAL INCREASED IDELALISIB AUC 1.4-FOLD. ZYDELIG CAN BE ADMINISTERED WITHOUT REGARD TO FOOD.
DISTRIBUTION
IDELALISIB IS GREATER THAN 84% BOUND TO HUMAN PLASMA PROTEINS WITH NO CONCENTRATION DEPENDENCE. THE MEAN BLOOD-TO-PLASMA RATIO WAS 0.7. THE POPULATION APPARENT CENTRAL VOLUME OF DISTRIBUTION AT STEADY STATE IS 23 L.
METABOLISM AND ELIMINATION
IDELALISIB IS METABOLIZED TO ITS MAJOR METABOLITE GS-563117 VIA ALDEHYDE OXIDASE AND CYP3A. GS-563117 IS INACTIVE AGAINST PI3K? IN VITRO. IDELALISIB UNDERGOES MINOR METABOLISM BY UGT1A4.
THE POPULATION APPARENT SYSTEMIC CLEARANCE AT STEADY-STATE IS 14.9 L/HR. THE POPULATION TERMINAL ELIMINATION HALF-LIFE OF IDELALISIB IS 8.2 HOURS. FOLLOWING A SINGLE DOSE OF 150 MG OF [14C] IDELALISIB, 78% AND 14% OF THE RADIOACTIVITY WAS EXCRETED IN FECES AND URINE, RESPECTIVELY. GS-563117 ACCOUNTED FOR 49% OF THE RADIOACTIVITY IN THE URINE AND 44% IN THE FECES.
SPECIFIC POPULATIONS
AGE, GENDER, RACE, AND WEIGHT
POPULATION PHARMACOKINETIC ANALYSES INDICATED THAT AGE, GENDER, RACE, AND WEIGHT HAD NO EFFECT ON IDELALISIB EXPOSURE.
PEDIATRIC PATIENTS
THE PHARMACOKINETICS OF IDELALISIB HAS NOT BEEN STUDIED IN PEDIATRIC PATIENTS.
PATIENTS WITH RENAL IMPAIRMENT
A PHARMACOKINETIC STUDY FOLLOWING A SINGLE DOSE OF 150 MG OF ZYDELIG WAS PERFORMED IN HEALTHY SUBJECTS AND SUBJECTS WITH SEVERE RENAL IMPAIRMENT (CLCR 15 TO 29 ML/MIN). CREATININE CLEARANCE HAD NO EFFECT ON IDELALISIB EXPOSURE. NO DOSE ADJUSTMENT IS NEEDED FOR PATIENTS WITH CLCR ? 15 ML/MIN.
PATIENTS WITH HEPATIC IMPAIRMENT
A PHARMACOKINETIC STUDY OF ZYDELIG WAS PERFORMED IN HEALTHY SUBJECTS AND SUBJECTS WITH HEPATIC IMPAIRMENT. THE GEOMETRIC MEAN AUC INCREASED UP TO 1.7-FOLD IN SUBJECTS WITH ALT OR AST OR BILIRUBIN VALUES GREATER THAN THE UPPER LIMIT OF NORMAL (ULN) COMPARED TO SUBJECTS WITH NORMAL AST OR ALT OR BILIRUBIN VALUES. LIMITED SAFETY AND EFFICACY DATA ARE AVAILABLE FOR PATIENTS WITH BASELINE AST OR ALT GREATER THAN 2.5 X ULN OR BILIRUBIN GREATER THAN 1.5 X ULN, AS THESE PATIENTS WERE EXCLUDED FROM STUDIES 1 AND 2. PATIENTS WITH BASELINE HEPATIC IMPAIRMENT SHOULD BE MONITORED FOR SIGNS OF ZYDELIG TOXICITY [SEE BOXED WARNING AND WARNINGS AND PRECAUTIONS]. FOLLOW DOSE MODIFICATIONS FOR ADVERSE REACTIONS [SEE DOSAGE AND ADMINISTRATION].
DRUG INTERACTIONS
IN VITRO STUDIES
IDELALISIB IS A SUBSTRATE FOR ALDEHYDE OXIDASE, CYP3A, AND UGT1A4 IN VITRO.
IDELALISIB INHIBITS CYP2C8, CYP2C19, CYP3A, AND UGT1A1 AND GS-563117 INHIBITS CYP2C8, CYP2C9, CYP2C19, CYP3A AND UGT1A1 IN VITRO. IDELALISIB AND GS-563117 ARE NOT LIKELY TO INHIBIT CYP1A, CYP2B6, AND CYP2D6.
IDELALISIB INDUCES CYP2B6 AND CYP3A4, BUT DOES NOT INDUCE CYP1A2 IN VITRO. GS-563117 DOES NOT INDUCE THESE ENZYMES.
IDELALISIB AND GS-563117 ARE SUBSTRATES OF P-GLYCOPROTEIN (P-GP) AND BCRP IN VITRO. IDELALISIB IS NOT A SUBSTRATE OF OATP1B1, OATP1B3, OAT1, OAT3, OR OCT2. GS-563117 IS NOT A SUBSTRATE OF OATP1B1 OR OATP1B3.
IDELALISIB INHIBITS P-GP, OATP1B1, AND OATP1B3, AND GS-563117 INHIBITS OATP1B1, OATP1B3 IN VITRO. IDELALISIB IS NOT LIKELY TO INHIBIT BCRP, OCT2, OAT1, OR OAT3, AND GS-563117 IS NOT LIKELY TO INHIBIT P-GP, BCRP, OCT2, OAT1, OR OAT3.
EFFECT OF OTHER DRUGS ON IDELALISIB
A SINGLE DOSE OF 150 MG OF ZYDELIG WAS ADMINISTERED ALONE AND AFTER RIFAMPIN (A STRONG CYP3A AND P-GP INDUCER) 600 MG ONCE DAILY FOR 8 DAYS IN HEALTHY SUBJECTS. RIFAMPIN DECREASED THE GEOMETRIC MEAN IDELALISIB AUC BY 75% AND THE GEOMETRIC MEAN CMAX BY 58%. AVOID COADMINISTRATION OF ZYDELIG WITH STRONG CYP3A AND P-GP INDUCERS.
A SINGLE DOSE OF 400 MG OF ZYDELIG WAS ADMINISTERED ALONE AND AFTER KETOCONAZOLE (A STRONG CYP3A AND P-GP INHIBITOR) 400 MG DAILY FOR 4 DAYS IN HEALTHY SUBJECTS. KETOCONAZOLE INCREASED THE GEOMETRIC MEAN IDELALISIB AUC BY 1.8-FOLD. NO CHANGES IN THE GEOMETRIC MEAN CMAX WERE OBSERVED. PATIENTS TAKING CONCOMITANT CYP3A INHIBITORS SHOULD BE MONITORED FOR SIGNS OF ZYDELIG TOXICITY [SEE WARNINGS AND PRECAUTIONS]. FOLLOW DOSE MODIFICATIONS FOR ADVERSE REACTIONS [SEE DOSAGE AND ADMINISTRATION].
EFFECT OF IDELALISIB ON OTHER DRUGS
A SINGLE ORAL DOSE OF MIDAZOLAM 5 MG WAS ADMINISTERED ALONE AND AFTER ZYDELIG 150 MG FOR 15 DOSES IN HEALTHY SUBJECTS. THE GEOMETRIC MEAN MIDAZOLAM CMAX INCREASED BY 2.4-FOLD AND THE GEOMETRIC MEAN MIDAZOLAM AUC INCREASED BY 5.4-FOLD. AVOID COADMINISTRATION OF ZYDELIG WITH CYP3A SUBSTRATES, AS ZYDELIG IS A STRONG CYP3A INHIBITOR.
A SINGLE DOSE OF 10 MG OF ROSUVASTATIN (OATP1B1 AND OATP1B3 SUBSTRATE) WAS ADMINISTERED ALONE AND AFTER ZYDELIG 150 MG FOR 12 DOSES IN HEALTHY SUBJECTS. NO CHANGES IN EXPOSURE TO ROSUVASTATIN WERE OBSERVED.
A SINGLE DOSE OF 0.5 MG OF DIGOXIN (P-GP SUBSTRATE) WAS ADMINISTERED ALONE AND AFTER ZYDELIG 150 MG FOR 19 DOSES IN HEALTHY SUBJECTS. NO CHANGES IN EXPOSURE TO DIGOXIN WERE OBSERVED.
ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY
TOXICITIES OBSERVED IN ANIMALS AND NOT REPORTED IN PATIENTS INCLUDE CARDIAC TOXICITY (CARDIOMYOPATHY, INFLAMMATION, AND INCREASED HEART WEIGHT) AND PANCREATIC FINDINGS (INFLAMMATION, HEMORRHAGE, AND LOW-INCIDENCE ACINAR DEGENERATION AND HYPERPLASIA). THESE FINDINGS WERE OBSERVED IN SPRAGUE-DAWLEY RATS IN TOXICOLOGY STUDIES AT EXPOSURES (AUCS) HIGHER THAN THOSE REPORTED IN PATIENTS AT THE RECOMMENDED DOSE OF 150 MG TWICE DAILY. CARDIAC INFLAMMATION WAS MAINLY SEEN IN A 28-DAY STUDY IN RATS, THE OTHER FINDINGS WERE OBSERVED IN THE 13-WEEK AND/OR 6-MONTH STUDIES.
CLINICAL STUDIES
RELAPSED CHRONIC LYMPHOCYTIC LEUKEMIA
ZYDELIG WAS EVALUATED IN A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY (STUDY 1) IN 220 SUBJECTS WITH RELAPSED CLL WHO REQUIRED TREATMENT AND WERE UNABLE TO TOLERATE STANDARD CHEMOIMMUNOTHERAPY DUE TO COEXISTING MEDICAL CONDITIONS, REDUCED RENAL FUNCTION AS MEASURED BY CREATININE CLEARANCE < 60 ML/MIN, OR NCI CTCAE GRADE ? 3 NEUTROPENIA OR GRADE ? 3 THROMBOCYTOPENIA RESULTING FROM MYELOTOXIC EFFECTS OF PRIOR THERAPY WITH CYTOTOXIC AGENTS. SUBJECTS WERE RANDOMIZED 1:1 TO RECEIVE 8 DOSES OF RITUXIMAB (FIRST DOSE AT 375 MG/MΒ², SUBSEQUENT DOSES AT 500 MG/MΒ² EVERY 2 WEEKS FOR 4 INFUSIONS AND EVERY 4 WEEKS FOR AN ADDITIONAL 4 INFUSIONS) IN COMBINATION WITH EITHER AN ORAL PLACEBO TWICE DAILY OR WITH ZYDELIG 150 MG TAKEN TWICE DAILY UNTIL DISEASE PROGRESSION OR UNACCEPTABLE TOXICITY.
IN STUDY 1, THE MEDIAN AGE WAS 71 (RANGE 47, 92) WITH 78% OVER 65, 66% WERE MALE, AND 90% WERE CAUCASIAN. THE MEDIAN TIME SINCE DIAGNOSIS WAS 8.5 YEARS. THE MEDIAN NUMBER OF PRIOR THERAPIES WAS 3. NEARLY ALL (96%) SUBJECTS HAD RECEIVED PRIOR ANTI-CD20 MONOCLONAL ANTIBODIES. THE MOST COMMON ( > 15%) PRIOR REGIMENS WERE: BENDAMUSTINE + RITUXIMAB (98 SUBJECTS, 45%), FLUDARABINE + CYCLOPHOSPHAMIDE + RITUXIMAB (75 SUBJECTS, 34%), SINGLE-AGENT RITUXIMAB (67 SUBJECTS, 31%), FLUDARABINE + RITUXIMAB (37 SUBJECTS, 17%), AND CHLORAMBUCIL (36 SUBJECTS, 16%).
THE PRIMARY ENDPOINT WAS PROGRESSION FREE SURVIVAL (PFS), AS ASSESSED BY AN INDEPENDENT REVIEW COMMITTEE (IRC). THE TRIAL WAS STOPPED FOR EFFICACY FOLLOWING THE FIRST PRE-SPECIFIED INTERIM ANALYSIS. RESULTS OF A SECOND INTERIM ANALYSIS CONTINUED TO SHOW A STATISTICALLY SIGNIFICANT IMPROVEMENT FOR ZYDELIG + RITUXIMAB OVER PLACEBO + RITUXIMAB FOR THE PRIMARY ENDPOINT OF PFS (HR: 0.18, 95% CI [0.10, 0.32], P < 0.0001). THE EFFICACY RESULTS ARE SHOWN IN TABLE 6 AND THE KAPLAN-MEIER CURVE FOR PFS IS SHOWN IN FIGURE 1.
TABLE 6 : EFFICACY RESULTS FROM STUDY 1
ZYDELIG + R
N=110 PLACEBO + R
N=110
PFS MEDIAN (MONTHS) (95% CI) NR(10.7, NR) 5.5(3.8, 7.1)
HAZARD RATIO (95% CI) 0.18 (0.10, 0.32)
P-VALUE < 0.0001 β
R: RITUXIMAB; PFS: PROGRESSION-FREE SURVIVAL; NR: NOT REACHED
β THE P VALUE FOR PFS WAS BASED ON STRATIFIED LOG-RANK TEST.
FIGURE 1 : KAPLAN-MEIER PLOT OF STUDY 1 IRC-ASSESSED PFS
RELAPSED FOLLICULAR B-CELL NON-HODGKIN LYMPHOMA
THE SAFETY AND EFFICACY OF ZYDELIG IN PATIENTS WITH FL WAS EVALUATED IN A SINGLE-ARM, MULTICENTER CLINICAL TRIAL WHICH INCLUDED 72 PATIENTS WITH FOLLICULAR B-CELL NON-HODGKIN LYMPHOMA WHO HAD RELAPSED WITHIN 6 MONTHS FOLLOWING RITUXIMAB AND AN ALKYLATING AGENT AND HAD RECEIVED AT LEAST 2 PRIOR TREATMENTS. THE MEDIAN AGE WAS 62 YEARS (RANGE 33 TO 84), 54% WERE MALE, AND 90% WERE CAUCASIAN. AT ENROLLMENT, 92% OF PATIENTS HAD A BASELINE ECOG PERFORMANCE STATUS OF 0 OR 1. THE MEDIAN TIME SINCE DIAGNOSIS WAS 4.7 YEARS AND THE MEDIAN NUMBER OF PRIOR TREATMENTS WAS 4 (RANGE 2 TO 12). THE MOST COMMON PRIOR COMBINATION REGIMENS WERE R-CHOP (49%), BR (50%), AND R-CVP (28%). AT BASELINE, 33% OF PATIENTS HAD EXTRANODAL INVOLVEMENT AND 26% HAD BONE MARROW INVOLVEMENT.
PATIENTS RECEIVED 150 MG OF ZYDELIG ORALLY TWICE DAILY UNTIL EVIDENCE OF DISEASE PROGRESSION OR UNACCEPTABLE TOXICITY. TUMOR RESPONSE WAS ASSESSED ACCORDING TO THE REVISED INTERNATIONAL WORKING GROUP RESPONSE CRITERIA FOR MALIGNANT LYMPHOMA. THE PRIMARY ENDPOINT WAS INDEPENDENT REVIEW COMMITTEE-ASSESSED OVERALL RESPONSE RATE (ORR). EFFICACY RESULTS ARE SUMMARIZED IN TABLE 7.
TABLE 7 : OVERALL RESPONSE RATE (ORR) AND DURATION OF RESPONSE (DOR) IN PATIENTS WITH RELAPSED FOLLICULAR LYMPHOMA
N=72
ORR 39(54%)
95% CI (42, 66%)
CR 6(8%)
PR 33 (46%)
MEDIAN* DOR, MONTHS (RANGE) MEDIAN NOT EVALUABLE (0.0+, 14.8+)
CI = CONFIDENCE INTERVAL; CR = COMPLETE RESPONSE; PR = PARTIAL RESPONSE
* KAPLAN-MEIER ESTIMATE
THE MEDIAN TIME TO RESPONSE WAS 1.9 MONTHS (RANGE 1.6-8.3).
RELAPSED SMALL LYMPHOCYTIC LYMPHOMA
THE SAFETY AND EFFICACY OF ZYDELIG IN PATIENTS WITH SLL WAS EVALUATED IN A SINGLE-ARM, MULTICENTER CLINICAL TRIAL WHICH INCLUDED 26 PATIENTS WITH SMALL LYMPHOCYTIC LYMPHOMA WHO HAD RELAPSED WITHIN 6 MONTHS FOLLOWING RITUXIMAB AND AN ALKYLATING AGENT AND HAD RECEIVED AT LEAST 2 PRIOR TREATMENTS. THE MEDIAN AGE WAS 65 YEARS (RANGE 50 TO 87), 73% WERE MALE, AND 81% WERE CAUCASIAN. AT ENROLLMENT, 96% OF PATIENTS HAD A BASELINE ECOG PERFORMANCE STATUS OF 0 OR 1. THE MEDIAN TIME SINCE DIAGNOSIS WAS 6.7 YEARS AND THE MEDIAN NUMBER OF PRIOR TREATMENTS WAS 4 (RANGE 2 TO 9). THE MOST COMMON PRIOR COMBINATION REGIMENS WERE BR (81%), FCR (62%) AND R-CHOP (35%). AT BASELINE, 27% OF PATIENTS HAD EXTRANODAL INVOLVEMENT.
SUBJECTS RECEIVED 150 MG OF ZYDELIG ORALLY TWICE DAILY UNTIL EVIDENCE OF DISEASE PROGRESSION OR UNACCEPTABLE TOXICITY. TUMOR RESPONSE WAS ASSESSED ACCORDING TO THE REVISED INTERNATIONAL WORKING GROUP RESPONSE CRITERIA FOR MALIGNANT LYMPHOMA. THE PRIMARY ENDPOINT WAS INDEPENDENT REVIEW COMMITTEE-ASSESSED OVERALL RESPONSE RATE (ORR). EFFICACY RESULTS ARE SUMMARIZED IN TABLE 8.
TABLE 8 : OVERALL RESPONSE RATE (ORR) AND DURATION OF RESPONSE (DOR) IN PATIENTS WITH RELAPSED SMALL LYMPHOCYTIC LYMPHOMA
N=26
ORR 15(58%)
95% CI (37, 77%)
CR 0
PR 15 (58%)
MEDIAN* DOR, MONTHS (RANGE) 11.9(0.0+, 14.7+)
CI = CONFIDENCE INTERVAL; CR = COMPLETE RESPONSE; PR = PARTIAL RESPONSE
* KAPLAN-MEIER ESTIMATE THE MEDIAN TIME TO RESPONSE WAS 1.9 MONTHS (RANGE 1.6-8.3).