INDICATIONS
GILENYA IS INDICATED FOR THE TREATMENT OF PATIENTS WITH RELAPSING FORMS OF MULTIPLE SCLEROSIS (MS) TO REDUCE THE FREQUENCY OF CLINICAL EXACERBATIONS AND TO DELAY THE ACCUMULATION OF PHYSICAL DISABILITY.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
GILENYA IS AVAILABLE AS 0.5 MG HARD CAPSULES WITH A WHITE OPAQUE BODY AND BRIGHT YELLOW CAP IMPRINTED WITH "FTY 0.5 MG" ON THE CAP AND 2 RADIAL BANDS IMPRINTED ON THE CAPSULE BODY WITH YELLOW INK.
STORAGE AND HANDLING
0.5 MG GILENYA CAPSULES ARE HARD GELATIN CAPSULES WITH A WHITE OPAQUE BODY AND BRIGHT YELLOW CAP IMPRINTED WITH "FTY 0.5 MG" ON THE CAP AND 2 RADIAL BANDS IMPRINTED ON THE CAPSULE BODY WITH YELLOW INK. GILENYA CAPSULES ARE SUPPLIED AS FOLLOWS:
BOTTLE OF 30 CAPSULES NDC 0078-0607-15
CARTON OF 28 CAPSULES CONTAINING 2 FOLDED BLISTER CARDS OF 14 CAPSULES PER BLISTER CARD NDC 0078-0607-51
CARTON OF 7 CAPSULES CONTAINING 1 BLISTER CARD OF 7 CAPSULES PER BLISTER CARD NDC 0078-0607-89
GILENYA CAPSULES SHOULD BE STORED AT 25°C (77°F); EXCURSIONS PERMITTED TO 15°C-30°C (59°F-86°F). PROTECT FROM MOISTURE.
MANUFACTURED BY: NOVARTIS PHARMA STEIN AG STEIN, SWITZERLAND. DISTRIBUTED BY: NOVARTIS PHARMACEUTICALS CORPORATION EAST HANOVER, NEW JERSEY 07936. REVISED: MAY 2015
DOSAGE AND ADMINISTRATION
RECOMMENDED DOSE
THE RECOMMENDED DOSE OF GILENYA IS 0.5 MG ORALLY ONCE-DAILY. FINGOLIMOD DOSES HIGHER THAN 0.5 MG ARE ASSOCIATED WITH A GREATER INCIDENCE OF ADVERSE REACTIONS WITHOUT ADDITIONAL BENEFIT. GILENYA CAN BE TAKEN WITH OR WITHOUT FOOD.
FIRST DOSE MONITORING
INITIATION OF GILENYA TREATMENT RESULTS IN A DECREASE IN HEART RATE [SEE WARNINGS AND PRECAUTIONS AND CLINICAL PHARMACOLOGY]. AFTER THE FIRST DOSE OF GILENYA, THE HEART RATE DECREASE STARTS WITHIN AN HOUR AND THE DAY 1 NADIR GENERALLY OCCURS WITHIN APPROXIMATELY 6 HOURS, ALTHOUGH THE NADIR CAN BE OBSERVED UP TO 24 HOURS AFTER THE FIRST DOSE IN SOME PATIENTS.
THE FIRST DOSE OF GILENYA SHOULD BE ADMINISTERED IN A SETTING IN WHICH RESOURCES TO APPROPRIATELY MANAGE SYMPTOMATIC BRADYCARDIA ARE AVAILABLE. IN ORDER TO ASSESS PATIENT RESPONSE TO THE FIRST DOSE OF FINGOLIMOD, OBSERVE ALL PATIENTS FOR 6 HOURS FOR SIGNS AND SYMPTOMS OF BRADYCARDIA WITH HOURLY PULSE AND BLOOD PRESSURE MEASUREMENT. OBTAIN IN ALL PATIENTS AN ELECTROCARDIOGRAM (ECG) PRIOR TO DOSING, AND AT THE END OF THE OBSERVATION PERIOD.
ADDITIONAL OBSERVATION SHOULD BE INSTITUTED UNTIL THE FINDING HAS RESOLVED IN THE FOLLOWING SITUATIONS:
" THE HEART RATE 6 HOURS POSTDOSE IS < 45 BPM
" THE HEART RATE 6 HOURS POSTDOSE IS AT THE LOWEST VALUE POSTDOSE (SUGGESTING THAT THE MAXIMUM PHARMACODYNAMIC EFFECT ON THE HEART MAY NOT HAVE OCCURRED)
" THE ECG 6 HOURS POSTDOSE SHOWS NEW ONSET SECOND DEGREE OR HIGHER ATRIOVENTRICULAR (AV) BLOCK
SHOULD POSTDOSE SYMPTOMATIC BRADYCARDIA OCCUR, INITIATE APPROPRIATE MANAGEMENT, BEGIN CONTINUOUS ECG MONITORING, AND CONTINUE OBSERVATION UNTIL THE SYMPTOMS HAVE RESOLVED.
SHOULD A PATIENT REQUIRE PHARMACOLOGIC INTERVENTION FOR SYMPTOMATIC BRADYCARDIA, CONTINUOUS OVERNIGHT ECG MONITORING IN A MEDICAL FACILITY SHOULD BE INSTITUTED, AND THE FIRST DOSE MONITORING STRATEGY SHOULD BE REPEATED AFTER THE SECOND DOSE OF GILENYA.
PATIENTS WITH SOME PREEXISTING CONDITIONS (E.G., ISCHEMIC HEART DISEASE, HISTORY OF MYOCARDIAL INFARCTION, CONGESTIVE HEART FAILURE, HISTORY OF CARDIAC ARREST, CEREBROVASCULAR DISEASE, UNCONTROLLED HYPERTENSION, HISTORY OF SYMPTOMATIC BRADYCARDIA, HISTORY OF RECURRENT SYNCOPE, SEVERE UNTREATED SLEEP APNEA, AV BLOCK, SINOATRIAL HEART BLOCK) MAY POORLY TOLERATE THE GILENYA-INDUCED BRADYCARDIA, OR EXPERIENCE SERIOUS RHYTHM DISTURBANCES AFTER THE FIRST DOSE OF GILENYA. PRIOR TO TREATMENT WITH GILENYA, THESE PATIENTS SHOULD HAVE A CARDIAC EVALUATION BY A PHYSICIAN APPROPRIATELY TRAINED TO CONDUCT SUCH EVALUATION, AND, IF TREATED WITH GILENYA, SHOULD BE MONITORED OVERNIGHT WITH CONTINUOUS ECG IN A MEDICAL FACILITY AFTER THE FIRST DOSE. GILENYA IS CONTRAINDICATED IN PATIENTS WHO IN THE LAST 6 MONTHS EXPERIENCED MYOCARDIAL INFARCTION, UNSTABLE ANGINA, STROKE, TRANSIENT ISCHEMIC ATTACK (TIA), DECOMPENSATED HEART FAILURE REQUIRING HOSPITALIZATION OR CLASS III/IV HEART FAILURE [SEE CONTRAINDICATIONS].
SINCE INITIATION OF GILENYA TREATMENT RESULTS IN DECREASED HEART RATE AND MAY PROLONG THE QT INTERVAL, PATIENTS WITH A PROLONGED QTC INTERVAL ( > 450 MSEC MALES, > 470 MSEC FEMALES) BEFORE DOSING OR DURING 6 HOUR OBSERVATION, OR AT ADDITIONAL RISK FOR QT PROLONGATION (E.G., HYPOKALEMIA, HYPOMAGNESEMIA, CONGENITAL LONG-QT SYNDROME), OR ON CONCURRENT THERAPY WITH QT PROLONGING DRUGS WITH A KNOWN RISK OF TORSADES DE POINTES (E.G., CITALOPRAM, CHLORPROMAZINE, HALOPERIDOL, METHADONE, ERYTHROMYCIN) SHOULD BE MONITORED OVERNIGHT WITH CONTINUOUS ECG IN A MEDICAL FACILITY [SEE DRUG INTERACTIONS].
EXPERIENCE WITH GILENYA IS LIMITED IN PATIENTS RECEIVING CONCURRENT THERAPY WITH DRUGS THAT SLOW HEART RATE OR ATRIOVENTRICULAR CONDUCTION (E.G., BETA BLOCKERS, HEART-RATE LOWERING CALCIUM CHANNEL BLOCKERS SUCH AS DILTIAZEM OR VERAPAMIL, OR DIGOXIN). BECAUSE THE INITIATION OF GILENYA TREATMENT IS ALSO ASSOCIATED WITH SLOWING OF THE HEART RATE, CONCOMITANT USE OF THESE DRUGS DURING GILENYA INITIATION MAY BE ASSOCIATED WITH SEVERE BRADYCARDIA OR HEART BLOCK. THE POSSIBILITY TO SWITCH TO DRUGS THAT DO NOT SLOW THE HEART RATE OR ATRIOVENTRICULAR CONDUCTION SHOULD BE EVALUATED BY THE PHYSICIAN PRESCRIBING THESE DRUGS BEFORE INITIATING GILENYA. PATIENTS WHO CANNOT SWITCH SHOULD HAVE OVERNIGHT CONTINUOUS ECG MONITORING AFTER THE FIRST DOSE [SEE DRUG INTERACTIONS].
CLINICAL DATA INDICATE EFFECTS OF GILENYA ON HEART RATE ARE MAXIMAL AFTER THE FIRST DOSE ALTHOUGH MILDER EFFECTS ON HEART RATE MAY PERSIST FOR, ON AVERAGE, 2 TO 4 WEEKS AFTER INITIATION OF THERAPY AT WHICH TIME HEART RATE GENERALLY RETURNS TO BASELINE. PHYSICIANS SHOULD CONTINUE TO BE ALERT TO PATIENT REPORTS OF CARDIAC SYMPTOMS.
REINITIATION OF THERAPY FOLLOWING DISCONTINUATION
IF GILENYA THERAPY IS DISCONTINUED FOR MORE THAN 14 DAYS, AFTER THE FIRST MONTH OF TREATMENT, THE EFFECTS ON HEART RATE AND AV CONDUCTION MAY RECUR ON REINTRODUCTION OF GILENYA TREATMENT AND THE SAME PRECAUTIONS (FIRST DOSE MONITORING) AS FOR INITIAL DOSING SHOULD APPLY. WITHIN THE FIRST 2 WEEKS OF TREATMENT, FIRST DOSE PROCEDURES ARE RECOMMENDED AFTER INTERRUPTION OF 1 DAY OR MORE; DURING WEEKS 3 AND 4 OF TREATMENT FIRST DOSE PROCEDURES ARE RECOMMENDED AFTER TREATMENT INTERRUPTION OF MORE THAN 7 DAYS.
SIDE EFFECTS
THE FOLLOWING SERIOUS ADVERSE REACTIONS ARE DESCRIBED ELSEWHERE IN LABELING:
" BRADYARRHYTHMIA AND ATRIOVENTRICULAR BLOCKS [SEE WARNINGS AND PRECAUTIONS]
" INFECTIONS [SEE WARNINGS AND PRECAUTIONS]
" MACULAR EDEMA [SEE WARNINGS AND PRECAUTIONS]
" POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME [SEE WARNINGS AND PRECAUTIONS]
" RESPIRATORY EFFECTS [SEE WARNINGS AND PRECAUTIONS]
" LIVER INJURY [SEE WARNINGS AND PRECAUTIONS]
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.
IN CLINICAL TRIALS (STUDIES 1, 2, AND 3), A TOTAL OF 1212 PATIENTS WITH RELAPSING FORMS OF MULTIPLE SCLEROSIS RECEIVED GILENYA 0.5 MG. THIS INCLUDED 783 PATIENTS WHO RECEIVED GILENYA 0.5 MG IN THE 2-YEAR PLACEBO-CONTROLLED TRIALS (STUDIES 1 AND 3) AND 429 PATIENTS WHO RECEIVED GILENYA 0.5 MG IN THE 1 YEAR ACTIVE-CONTROLLED TRIAL (STUDY 2). THE OVERALL EXPOSURE IN THE CONTROLLED TRIALS WAS EQUIVALENT TO 1716 PERSON-YEARS. APPROXIMATELY 1000 PATIENTS RECEIVED AT LEAST 2 YEARS OF TREATMENT WITH GILENYA 0.5 MG. IN ALL CLINICAL STUDIES, INCLUDING UNCONTROLLED EXTENSION STUDIES, THE EXPOSURE TO GILENYA 0.5 MG WAS APPROXIMATELY 4119 PERSON-YEARS.
IN PLACEBO-CONTROLLED TRIALS, THE MOST FREQUENT ADVERSE REACTIONS (INCIDENCE ? 10% AND > PLACEBO) FOR GILENYA 0.5 MG WERE HEADACHE, LIVER TRANSAMINASE ELEVATION, DIARRHEA, COUGH, INFLUENZA, SINUSITIS, BACK PAIN, ABDOMINAL PAIN, AND PAIN IN EXTREMITY. ADVERSE EVENTS THAT LED TO TREATMENT DISCONTINUATION AND OCCURRED IN MORE THAN 1% OF PATIENTS TAKING GILENYA 0.5 MG WERE SERUM TRANSAMINASE ELEVATIONS (4.7% COMPARED TO 1% ON PLACEBO) AND BASAL CELL CARCINOMA (1% COMPARED TO 0.5% ON PLACEBO).
TABLE 1 LISTS ADVERSE REACTIONS THAT OCCURRED IN ? 1% OF GILENYA-TREATED PATIENTS AND ? 1% HIGHER RATE THAN FOR PLACEBO.
TABLE 1 : ADVERSE REACTIONS REPORTED IN STUDIES 1 AND 3 (OCCURRING IN ? 1% OF PATIENTS AND REPORTED FOR GILENYA 0.5 MG AT ? 1% HIGHER RATE THAN FOR PLACEBO)
PRIMARY SYSTEM ORGAN CLASS PREFERRED TERM GILENYA 0.5 MG
N=783 % PLACEBO
N=773 %
INFECTIONS
INFLUENZA 11 8
SINUSITIS 11 8
BRONCHITIS 8 5
HERPES ZOSTER 2 1
TINEA VERSICOLOR 2 < 1
CARDIAC DISORDERS
BRADYCARDIA 3 1
NERVOUS SYSTEM DISORDERS
HEADACHE 25 24
MIGRAINE 6 4
GASTROINTESTINAL DISORDERS
NAUSEA 13 12
DIARRHEA 13 10
ABDOMINAL PAIN 11 10
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
ASTHENIA 2 1
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
BACK PAIN 10 9
PAIN IN EXTREMITY 10 7
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
ALOPECIA 3 2
ACTINIC KERATOSIS 2 1
INVESTIGATIONS
LIVER TRANSAMINASE ELEVATIONS (ALT/GGT/AST) 15 4
BLOOD TRIGLYCERIDES INCREASED 3 1
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS
COUGH 12 11
DYSPNEA 9 7
EYE DISORDERS
VISION BLURRED 4 2
VASCULAR DISORDERS
HYPERTENSION 8 4
BLOOD AND LYMPHATIC SYSTEM DISORDERS
LYMPHOPENIA 7 < 1
LEUKOPENIA 2 < 1
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCLUDING CYSTS AND POLYPS)
SKIN PAPILLOMA 3 2
BASAL CELL CARCINOMA 2 1
ADVERSE REACTIONS OF DIZZINESS, PNEUMONIA, ECZEMA AND PRURITUS WERE ALSO REPORTED IN STUDIES 1 AND 3 BUT DID NOT MEET THE REPORTING RATE CRITERIA FOR INCLUSION IN TABLE 1 (DIFFERENCE WAS LESS THAN 1%).
ADVERSE REACTIONS WITH GILENYA 0.5 MG IN STUDY 2, THE 1-YEAR ACTIVE-CONTROLLED (VERSUS INTERFERON BETA-1A) STUDY WERE GENERALLY SIMILAR TO THOSE IN STUDIES 1 AND 3.
VASCULAR EVENTS
VASCULAR EVENTS, INCLUDING ISCHEMIC AND HEMORRHAGIC STROKES, AND PERIPHERAL ARTERIAL OCCLUSIVE DISEASE WERE REPORTED IN PREMARKETING CLINICAL TRIALS IN PATIENTS WHO RECEIVED GILENYA DOSES (1.25-5 MG) HIGHER THAN RECOMMENDED FOR USE IN MS. SIMILAR EVENTS HAVE BEEN REPORTED WITH GILENYA 0.5 MG IN THE POSTMARKETING SETTING ALTHOUGH A CAUSAL RELATIONSHIP HAS NOT BEEN ESTABLISHED.
LYMPHOMAS
CASES OF LYMPHOMA HAVE OCCURRED IN PREMARKETING CLINICAL TRIALS AND IN THE POSTMARKETING SETTING. THE RELATIONSHIP TO GILENYA REMAINS UNCERTAIN.
READ THE GILENYA (FINGOLIMOD CAPSULES) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
OVERDOSE
GILENYA CAN INDUCE BRADYCARDIA AS WELL AS AV CONDUCTION BLOCKS (INCLUDING COMPLETE AV BLOCK). THE DECLINE IN HEART RATE USUALLY STARTS WITHIN 1 HOUR OF THE FIRST DOSE AND IS MAXIMAL WITHIN 6 HOURS IN MOST PATIENTS [SEE WARNINGS AND PRECAUTIONS]. IN CASE OF GILENYA OVERDOSAGE, OBSERVE PATIENTS OVERNIGHT WITH CONTINUOUS ECG MONITORING IN A MEDICAL FACILITY, AND OBTAIN REGULAR MEASUREMENTS OF BLOOD PRESSURE [SEE DOSAGE AND ADMINISTRATION].
NEITHER DIALYSIS NOR PLASMA EXCHANGE RESULTS IN REMOVAL OF FINGOLIMOD FROM THE BODY.
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
FINGOLIMOD IS METABOLIZED BY SPHINGOSINE KINASE TO THE ACTIVE METABOLITE, FINGOLIMOD-PHOSPHATE. FINGOLIMOD-PHOSPHATE IS A SPHINGOSINE 1-PHOSPHATE RECEPTOR MODULATOR, AND BINDS WITH HIGH AFFINITY TO SPHINGOSINE 1-PHOSPHATE RECEPTORS 1, 3, 4, AND 5. FINGOLIMOD-PHOSPHATE BLOCKS THE CAPACITY OF LYMPHOCYTES TO EGRESS FROM LYMPH NODES, REDUCING THE NUMBER OF LYMPHOCYTES IN PERIPHERAL BLOOD. THE MECHANISM BY WHICH FINGOLIMOD EXERTS THERAPEUTIC EFFECTS IN MULTIPLE SCLEROSIS IS UNKNOWN, BUT MAY INVOLVE REDUCTION OF LYMPHOCYTE MIGRATION INTO THE CENTRAL NERVOUS SYSTEM.
PHARMACODYNAMICS
HEART RATE AND RHYTHM
FINGOLIMOD CAUSES A TRANSIENT REDUCTION IN HEART RATE AND AV CONDUCTION AT TREATMENT INITIATION [SEE WARNINGS AND PRECAUTIONS].
HEART RATE PROGRESSIVELY INCREASES AFTER THE FIRST DAY, RETURNING TO BASELINE VALUES WITHIN 1 MONTH OF THE START OF CHRONIC TREATMENT.
AUTONOMIC RESPONSES OF THE HEART, INCLUDING DIURNAL VARIATION OF HEART RATE AND RESPONSE TO EXERCISE, ARE NOT AFFECTED BY FINGOLIMOD TREATMENT.
FINGOLIMOD TREATMENT IS NOT ASSOCIATED WITH A DECREASE IN CARDIAC OUTPUT.
POTENTIAL TO PROLONG THE QT INTERVAL
IN A THOROUGH QT INTERVAL STUDY OF DOSES OF 1.25 OR 2.5 MG FINGOLIMOD AT STEADY-STATE, WHEN A NEGATIVE CHRONOTROPIC EFFECT OF FINGOLIMOD WAS STILL PRESENT, FINGOLIMOD TREATMENT RESULTED IN A PROLONGATION OF QTC, WITH THE UPPER BOUNDARY OF THE 90% CONFIDENCE INTERVAL (CI) OF 14.0 MSEC. THERE IS NO CONSISTENT SIGNAL OF INCREASED INCIDENCE OF QTC OUTLIERS, EITHER ABSOLUTE OR CHANGE FROM BASELINE, ASSOCIATED WITH FINGOLIMOD TREATMENT. IN MS STUDIES, THERE WAS NO CLINICALLY RELEVANT PROLONGATION OF THE QT INTERVAL, BUT PATIENTS AT RISK FOR QT PROLONGATION WERE NOT INCLUDED IN CLINICAL STUDIES.
IMMUNE SYSTEM
EFFECTS ON IMMUNE CELL NUMBERS IN THE BLOOD
IN A STUDY IN WHICH 12 SUBJECTS RECEIVED GILENYA 0.5 MG DAILY, THE LYMPHOCYTE COUNT DECREASED TO APPROXIMATELY 60% OF BASELINE WITHIN 4 TO 6 HOURS AFTER THE FIRST DOSE. WITH CONTINUED DAILY DOSING, THE LYMPHOCYTE COUNT CONTINUED TO DECREASE OVER A 2-WEEK PERIOD, REACHING A NADIR COUNT OF APPROXIMATELY 500 CELLS/MCL OR APPROXIMATELY 30% OF BASELINE. IN A PLACEBO-CONTROLLED STUDY IN 1272 MS PATIENTS (OF WHOM 425 RECEIVED FINGOLIMOD 0.5 MG DAILY AND 418 RECEIVED PLACEBO), 18% (N=78) OF PATIENTS ON FINGOLIMOD 0.5 MG REACHED A NADIR OF < 200 CELLS/MCL ON AT LEAST 1 OCCASION. NO PATIENT ON PLACEBO REACHED A NADIR OF < 200 CELLS/MCL. LOW LYMPHOCYTE COUNTS ARE MAINTAINED WITH CHRONIC DAILY DOSING OF GILENYA 0.5 MG DAILY.
CHRONIC FINGOLIMOD DOSING LEADS TO A MILD DECREASE IN THE NEUTROPHIL COUNT TO APPROXIMATELY 80% OF BASELINE. MONOCYTES ARE UNAFFECTED BY FINGOLIMOD.
PERIPHERAL LYMPHOCYTE COUNT INCREASES ARE EVIDENT WITHIN DAYS OF STOPPING FINGOLIMOD TREATMENT AND TYPICALLY NORMAL COUNTS ARE REACHED WITHIN 1 TO 2 MONTHS.
EFFECT ON ANTIBODY RESPONSE
GILENYA REDUCES THE IMMUNE RESPONSE TO VACCINATION, AS EVALUATED IN 2 STUDIES.
IN THE FIRST STUDY, THE IMMUNOGENICITY OF KEYHOLE LIMPET HEMOCYANIN (KLH) AND PNEUMOCOCCAL POLYSACCHARIDE VACCINE (PPV-23) IMMUNIZATION WERE ASSESSED BY IGM AND IGG TITERS IN A STEADY-STATE, RANDOMIZED, PLACEBO-CONTROLLED STUDY IN HEALTHY VOLUNTEERS. COMPARED TO PLACEBO, ANTIGEN-SPECIFIC IGM TITERS WERE DECREASED BY 91% AND 25% IN RESPONSE TO KLH AND PPV-23, RESPECTIVELY, IN SUBJECTS ON GILENYA 0.5 MG. SIMILARLY, IGG TITERS WERE DECREASED BY 45% AND 50%, IN RESPONSE TO KLH AND PPV-23, RESPECTIVELY, IN SUBJECTS ON GILENYA 0.5 MG DAILY COMPARED TO PLACEBO. THE RESPONDER RATE FOR GILENYA 0.5 MG AS MEASURED BY THE NUMBER OF SUBJECTS WITH A > 4-FOLD INCREASE IN KLH IGG WAS COMPARABLE TO PLACEBO AND 25% LOWER FOR PPV-23 IGG, WHILE THE NUMBER OF SUBJECTS WITH A > 4 FOLD INCREASE IN KLH AND PPV-23 IGM WAS 75% AND 40% LOWER, RESPECTIVELY, COMPARED TO PLACEBO. THE CAPACITY TO MOUNT A SKIN DELAYED-TYPE HYPERSENSITIVITY REACTION TO CANDIDA AND TETANUS TOXOID WAS DECREASED BY APPROXIMATELY 30% IN SUBJECTS ON GILENYA 0.5 MG DAILY, COMPARED TO PLACEBO. IMMUNOLOGIC RESPONSES WERE FURTHER DECREASED WITH FINGOLIMOD 1.25 MG (A DOSE HIGHER THAN RECOMMENDED IN MS) [SEE WARNINGS AND PRECAUTIONS].
IN THE SECOND STUDY, THE IMMUNOGENICITY OF NORTHERN HEMISPHERE SEASONAL INFLUENZA AND TETANUS TOXOID VACCINATION WAS ASSESSED IN A 12-WEEK STEADY-STATE, RANDOMIZED, PLACEBO-CONTROLLED STUDY OF GILENYA 0.5 MG IN MULTIPLE SCLEROSIS PATIENTS (N=136). THE RESPONDER RATE 3 WEEKS AFTER VACCINATION, DEFINED AS SEROCONVERSION OR A ? 4-FOLD INCREASE IN ANTIBODY DIRECTED AGAINST AT LEAST 1 OF THE 3 INFLUENZA STRAINS, WAS 54% FOR GILENYA 0.5 MG AND 85% IN THE PLACEBO GROUP. THE RESPONDER RATE 3 WEEKS AFTER VACCINATION, DEFINED AS SEROCONVERSION OR A ? 4-FOLD INCREASE IN ANTIBODY DIRECTED AGAINST TETANUS TOXOID WAS 40% FOR GILENYA 0.5 MG AND 61% IN THE PLACEBO GROUP.
PULMONARY FUNCTION
SINGLE FINGOLIMOD DOSES ? 5 MG (10-FOLD THE RECOMMENDED DOSE) ARE ASSOCIATED WITH A DOSE-DEPENDENT INCREASE IN AIRWAY RESISTANCE. IN A 14-DAY STUDY OF 0.5, 1.25, OR 5 MG/DAY, FINGOLIMOD WAS NOT ASSOCIATED WITH IMPAIRED OXYGENATION OR OXYGEN DESATURATION WITH EXERCISE OR AN INCREASE IN AIRWAY RESPONSIVENESS TO METHACHOLINE. SUBJECTS ON FINGOLIMOD TREATMENT HAD A NORMAL BRONCHODILATOR RESPONSE TO INHALED BETA-AGONISTS.
IN A 14-DAY PLACEBO-CONTROLLED STUDY OF PATIENTS WITH MODERATE ASTHMA, NO EFFECT WAS SEEN FOR GILENYA 0.5 MG (RECOMMENDED DOSE IN MS). A 10% REDUCTION IN MEAN FEV1 AT 6 HOURS AFTER DOSING WAS OBSERVED IN PATIENTS RECEIVING FINGOLIMOD 1.25 MG (A DOSE HIGHER THAN RECOMMENDED FOR USE IN MS) ON DAY 10 OF TREATMENT. FINGOLIMOD 1.25 MG WAS ASSOCIATED WITH A 5-FOLD INCREASE IN THE USE OF RESCUE SHORT ACTING BETA-AGONISTS.
PHARMACOKINETICS
ABSORPTION
THE T MAX OF FINGOLIMOD IS 12-16 HOURS. THE APPARENT ABSOLUTE ORAL BIOAVAILABILITY IS 93%.
FOOD INTAKE DOES NOT ALTER C MAX OR EXPOSURE (AUC) OF FINGOLIMOD OR FINGOLIMOD-PHOSPHATE. THEREFORE GILENYA MAY BE TAKEN WITHOUT REGARD TO MEALS.
STEADY-STATE BLOOD CONCENTRATIONS ARE REACHED WITHIN 1 TO 2 MONTHS FOLLOWING ONCE-DAILY ADMINISTRATION AND STEADY-STATE LEVELS ARE APPROXIMATELY 10-FOLD GREATER THAN WITH THE INITIAL DOSE.
DISTRIBUTION
FINGOLIMOD HIGHLY (86%) DISTRIBUTES IN RED BLOOD CELLS. FINGOLIMOD-PHOSPHATE HAS A SMALLER UPTAKE IN BLOOD CELLS OF < 17%. FINGOLIMOD AND FINGOLIMOD-PHOSPHATE ARE > 99.7% PROTEIN BOUND. FINGOLIMOD AND FINGOLIMOD-PHOSPHATE PROTEIN BINDING IS NOT ALTERED BY RENAL OR HEPATIC IMPAIRMENT.
FINGOLIMOD IS EXTENSIVELY DISTRIBUTED TO BODY TISSUES WITH A VOLUME OF DISTRIBUTION OF ABOUT 1200±260 L.
METABOLISM
THE BIOTRANSFORMATION OF FINGOLIMOD IN HUMANS OCCURS BY 3 MAIN PATHWAYS: BY REVERSIBLE STEREOSELECTIVE PHOSPHORYLATION TO THE PHARMACOLOGICALLY ACTIVE (S)-ENANTIOMER OF FINGOLIMOD-PHOSPHATE, BY OXIDATIVE BIOTRANSFORMATION CATALYZED MAINLY BY THE CYTOCHROME P450 4F2 (CYP4F2) AND POSSIBLY OTHER CYP4F ISOENZYMES WITH SUBSEQUENT FATTY ACID-LIKE DEGRADATION TO INACTIVE METABOLITES, AND BY FORMATION OF PHARMACOLOGICALLY INACTIVE NON-POLAR CERAMIDE ANALOGS OF FINGOLIMOD.
INHIBITORS OR INDUCERS OF CYP4F2 AND POSSIBLY OTHER CYP4F ISOZYMES MIGHT ALTER THE EXPOSURE OF FINGOLIMOD OR FINGOLIMOD-PHOSPHATE. IN VITRO STUDIES IN HEPATOCYTES INDICATED THAT CYP3A4 MAY CONTRIBUTE TO FINGOLIMOD METABOLISM IN THE CASE OF STRONG INDUCTION OF CYP3A4.
FOLLOWING SINGLE ORAL ADMINISTRATION OF [14C] FINGOLIMOD, THE MAJOR FINGOLIMOD-RELATED COMPONENTS IN BLOOD, AS JUDGED FROM THEIR CONTRIBUTION TO THE AUC UP TO 816 HOURS POST-DOSE OF TOTAL RADIOLABELED COMPONENTS, ARE FINGOLIMOD ITSELF (23.3%), FINGOLIMOD-PHOSPHATE (10.3%), AND INACTIVE METABOLITES [M3 CARBOXYLIC ACID METABOLITE (8.3%), M29 CERAMIDE METABOLITE (8.9%), AND M30 CERAMIDE METABOLITE (7.3%)].
ELIMINATION
FINGOLIMOD BLOOD CLEARANCE IS 6.3±2.3 L/H, AND THE AVERAGE APPARENT TERMINAL HALF-LIFE (T ½ ) IS 6 TO 9 DAYS. BLOOD LEVELS OF FINGOLIMOD-PHOSPHATE DECLINE IN PARALLEL WITH THOSE OF FINGOLIMOD IN THE TERMINAL PHASE, YIELDING SIMILAR HALF-LIVES FOR BOTH.
AFTER ORAL ADMINISTRATION, ABOUT 81% OF THE DOSE IS SLOWLY EXCRETED IN THE URINE AS INACTIVE METABOLITES. FINGOLIMOD AND FINGOLIMOD-PHOSPHATE ARE NOT EXCRETED INTACT IN URINE BUT ARE THE MAJOR COMPONENTS IN THE FECES WITH AMOUNTS OF EACH REPRESENTING LESS THAN 2.5% OF THE DOSE.
SPECIFIC POPULATIONS
GERIATRIC PATIENTS
THE MECHANISM FOR ELIMINATION AND RESULTS FROM POPULATION PHARMACOKINETICS SUGGEST THAT DOSE ADJUSTMENT WOULD NOT BE NECESSARY IN ELDERLY PATIENTS. HOWEVER, CLINICAL EXPERIENCE IN PATIENTS AGED ABOVE 65 YEARS IS LIMITED.
GENDER
GENDER HAS NO CLINICALLY SIGNIFICANT INFLUENCE ON FINGOLIMOD AND FINGOLIMOD-PHOSPHATE PHARMACOKINETICS.
RACE
THE EFFECTS OF RACE ON FINGOLIMOD AND FINGOLIMOD-PHOSPHATE PHARMACOKINETICS CANNOT BE ADEQUATELY ASSESSED DUE TO A LOW NUMBER OF NON-WHITE PATIENTS IN THE CLINICAL PROGRAM.
RENAL IMPAIRMENT
IN PATIENTS WITH SEVERE RENAL IMPAIRMENT, FINGOLIMOD CMAX AND AUC ARE INCREASED BY 32% AND 43%, RESPECTIVELY, AND FINGOLIMOD-PHOSPHATE C MAX AND AUC ARE INCREASED BY 25% AND 14%, RESPECTIVELY, WITH NO CHANGE IN APPARENT ELIMINATION HALF-LIFE. BASED ON THESE FINDINGS, THE GILENYA 0.5 MG DOSE IS APPROPRIATE FOR USE IN PATIENTS WITH RENAL IMPAIRMENT. THE SYSTEMIC EXPOSURE OF 2 METABOLITES (M2 AND M3) IS INCREASED BY 3-AND 13-FOLD, RESPECTIVELY. THE TOXICITY OF THESE METABOLITES HAS NOT BEEN FULLY CHARACTERIZED.
A STUDY IN PATIENTS WITH MILD OR MODERATE RENAL IMPAIRMENT HAS NOT BEEN CONDUCTED.
HEPATIC IMPAIRMENT
IN SUBJECTS WITH MILD, MODERATE, OR SEVERE HEPATIC IMPAIRMENT (CHILD-PUGH CLASS A, B, AND C), NO CHANGE IN FINGOLIMOD CMAX WAS OBSERVED, BUT FINGOLIMOD AUC 0-? WAS INCREASED RESPECTIVELY BY 12%, 44%, AND 103%. IN PATIENTS WITH SEVERE HEPATIC IMPAIRMENT (CHILD-PUGH CLASS C), FINGOLIMOD-
PHOSPHATE C MAX WAS DECREASED BY 22% AND AUC0-96 HOURS WAS DECREASED BY 29%. THE PHARMACOKINETICS OF FINGOLIMOD-PHOSPHATE WAS NOT EVALUATED IN PATIENTS WITH MILD OR MODERATE HEPATIC IMPAIRMENT. THE APPARENT ELIMINATION HALF-LIFE OF FINGOLIMOD IS UNCHANGED IN SUBJECTS WITH MILD HEPATIC IMPAIRMENT, BUT IS PROLONGED BY ABOUT 50% IN PATIENTS WITH MODERATE OR SEVERE HEPATIC IMPAIRMENT.
PATIENTS WITH SEVERE HEPATIC IMPAIRMENT (CHILD-PUGH CLASS C) SHOULD BE CLOSELY MONITORED, AS THE RISK OF ADVERSE REACTIONS IS GREATER [SEE WARNINGS AND PRECAUTIONS].
NO DOSE ADJUSTMENT IS NEEDED IN PATIENTS WITH MILD OR MODERATE HEPATIC IMPAIRMENT (CHILD-PUGH CLASS A AND B).
DRUG INTERACTIONS
KETOCONAZOLE
THE COADMINISTRATION OF KETOCONAZOLE (A POTENT INHIBITOR OF CYP3A AND CYP4F) 200 MG TWICE-DAILY AT STEADY-STATE AND A SINGLE DOSE OF FINGOLIMOD 5 MG LED TO A 70% INCREASE IN AUC OF FINGOLIMOD AND FINGOLIMOD-PHOSPHATE. PATIENTS WHO USE GILENYA AND SYSTEMIC KETOCONAZOLE CONCOMITANTLY SHOULD BE CLOSELY MONITORED, AS THE RISK OF ADVERSE REACTIONS IS GREATER [SEE DRUG INTERACTIONS].
CARBAMAZEPINE
THE COADMINISTRATION OF CARBAMAZEPINE (A POTENT CYP450 ENZYME INDUCER) 600 MG TWICE-DAILY AT STEADY-STATE AND A SINGLE DOSE OF FINGOLIMOD 2 MG DECREASED BLOOD CONCENTRATIONS (AUC) OF FINGOLIMOD AND FINGOLIMOD-PHOSPHATE BY APPROXIMATELY 40%. THE CLINICAL IMPACT OF THIS DECREASE IS UNKNOWN.
OTHER STRONG CYP450 ENZYME INDUCERS, E.G., RIFAMPICIN, PHENYTOIN, PHENOBARBITAL, AND ST. JOHN'S WORT, MAY ALSO REDUCE AUC OF FINGOLIMOD AND FINGOLIMOD-PHOSPHATE. THE CLINICAL IMPACT OF THIS POTENTIAL DECREASE IS UNKNOWN.
POTENTIAL OF FINGOLIMOD AND FINGOLIMOD-PHOSPHATE TO INHIBIT THE METABOLISM OF COMEDICATIONS
IN VITRO INHIBITION STUDIES USING POOLED HUMAN LIVER MICROSOMES AND SPECIFIC METABOLIC PROBE SUBSTRATES DEMONSTRATE THAT FINGOLIMOD HAS LITTLE OR NO CAPACITY TO INHIBIT THE ACTIVITY OF THE FOLLOWING CYP ENZYMES: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, OR CYP4A9/11 (FINGOLIMOD ONLY), AND SIMILARLY FINGOLIMOD-PHOSPHATE HAS LITTLE OR NO CAPACITY TO INHIBIT THE ACTIVITY OF CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, OR CYP3A4 AT CONCENTRATIONS UP TO 3 ORDERS OF MAGNITUDE OF THERAPEUTIC CONCENTRATIONS. THEREFORE, FINGOLIMOD AND FINGOLIMOD-PHOSPHATE ARE UNLIKELY TO REDUCE THE CLEARANCE OF DRUGS THAT ARE MAINLY CLEARED THROUGH METABOLISM BY THE MAJOR CYP ISOENZYMES DESCRIBED ABOVE.
POTENTIAL OF FINGOLIMOD AND FINGOLIMOD-PHOSPHATE TO INDUCE ITS OWN AND/OR THE METABOLISM OF COMEDICATIONS
FINGOLIMOD WAS EXAMINED FOR ITS POTENTIAL TO INDUCE HUMAN CYP3A4, CYP1A2, CYP4F2, AND MDR1 (P-GLYCOPROTEIN) MRNA AND CYP3A, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, AND CYP4F2 ACTIVITY IN PRIMARY HUMAN HEPATOCYTES. FINGOLIMOD DID NOT INDUCE MRNA OR ACTIVITY OF THE DIFFERENT CYP ENZYMES AND MDR1 WITH RESPECT TO THE VEHICLE CONTROL; THEREFORE, NO CLINICALLY RELEVANT INDUCTION OF THE TESTED CYP ENZYMES OR MDR1 BY FINGOLIMOD ARE EXPECTED AT THERAPEUTIC CONCENTRATIONS. FINGOLIMOD-PHOSPHATE WAS ALSO EXAMINED FOR ITS POTENTIAL TO INDUCE MRNA AND/OR ACTIVITY OF HUMAN CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A, CYP4F2, CYP4F3B, AND CYP4F12. FINGOLIMOD-PHOSPHATE IS NOT EXPECTED TO HAVE CLINICALLY SIGNIFICANT INDUCTION EFFECTS ON THESE ENZYMES AT THERAPEUTIC DOSE OF FINGOLIMOD. IN VITRO EXPERIMENTS DID NOT PROVIDE AN INDICATION OF CYP INDUCTION BY FINGOLIMOD-PHOSPHATE.
TRANSPORTERS
BASED ON IN VITRO DATA, FINGOLIMOD AS WELL AS FINGOLIMOD-PHOSPHATE ARE NOT EXPECTED TO INHIBIT THE UPTAKE OF COMEDICATIONS AND/OR BIOLOGICS TRANSPORTED BY THE ORGANIC ANION TRANSPORTING POLYPEPTIDES OATP1B1, OATP1B3, OR THE SODIUM TAUROCHOLATE CO-TRANSPORTING POLYPEPTIDE (NTCP). SIMILARLY, THEY ARE NOT EXPECTED TO INHIBIT THE EFFLUX OF COMEDICATIONS AND/OR BIOLOGICS TRANSPORTED BY THE BREAST CANCER RESISTANCE PROTEIN (BCRP), THE BILE SALT EXPORT PUMP (BSEP), THE MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 2 (MRP2), OR P-GLYCOPROTEIN (P-GP) AT THERAPEUTIC CONCENTRATIONS.
ORAL CONTRACEPTIVES
THE COADMINISTRATION OF FINGOLIMOD 0.5 MG DAILY WITH ORAL CONTRACEPTIVES (ETHINYLESTRADIOL AND LEVONORGESTREL) DID NOT ELICIT ANY CLINICALLY SIGNIFICANT CHANGE IN ORAL CONTRACEPTIVES EXPOSURE. FINGOLIMOD AND FINGOLIMOD-PHOSPHATE EXPOSURE WERE CONSISTENT WITH THOSE FROM PREVIOUS STUDIES. NO INTERACTION STUDIES HAVE BEEN PERFORMED WITH ORAL CONTRACEPTIVES CONTAINING OTHER PROGESTAGENS; HOWEVER, AN EFFECT OF FINGOLIMOD ON THEIR EXPOSURE IS NOT EXPECTED.
CYCLOSPORINE
THE PHARMACOKINETICS OF SINGLE-DOSE FINGOLIMOD WAS NOT ALTERED DURING COADMINISTRATION WITH CYCLOSPORINE AT STEADY-STATE, NOR WAS CYCLOSPORINE STEADY-STATE PHARMACOKINETICS ALTERED BY FINGOLIMOD. THESE DATA INDICATE THAT GILENYA IS UNLIKELY TO REDUCE OR INCREASE THE CLEARANCE OF DRUGS CLEARED MAINLY BY CYP3A4. POTENT INHIBITION OF TRANSPORTERS MDR1 (P-GP), MRP2, AND OATP-1B1 DOES NOT INFLUENCE FINGOLIMOD DISPOSITION.
ISOPROTERENOL, ATROPINE, ATENOLOL, AND DILTIAZEM
SINGLE-DOSE FINGOLIMOD AND FINGOLIMOD-PHOSPHATE EXPOSURE WAS NOT ALTERED BY COADMINISTERED ISOPROTERENOL OR ATROPINE. LIKEWISE, THE SINGLE-DOSE PHARMACOKINETICS OF FINGOLIMOD AND FINGOLIMOD-PHOSPHATE AND THE STEADY-STATE PHARMACOKINETICS OF BOTH ATENOLOL AND DILTIAZEM WERE UNCHANGED DURING THE COADMINISTRATION OF THE LATTER 2 DRUGS INDIVIDUALLY WITH FINGOLIMOD
POPULATION PHARMACOKINETICS ANALYSIS
A POPULATION PHARMACOKINETICS EVALUATION PERFORMED IN MS PATIENTS DID NOT PROVIDE EVIDENCE FOR A SIGNIFICANT EFFECT OF FLUOXETINE AND PAROXETINE (STRONG CYP2D6 INHIBITORS) ON FINGOLIMOD OR FINGOLIMOD-PHOSPHATE PREDOSE CONCENTRATIONS. IN ADDITION, THE FOLLOWING COMMONLY COPRESCRIBED SUBSTANCES HAD NO CLINICALLY RELEVANT EFFECT ( < 20%) ON FINGOLIMOD OR FINGOLIMOD-PHOSPHATE PREDOSE CONCENTRATIONS: BACLOFEN, GABAPENTIN, OXYBUTYNIN, AMANTADINE, MODAFINIL, AMITRIPTYLINE, PREGABALIN, AND CORTICOSTEROIDS.
ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY
LUNG TOXICITY WAS OBSERVED IN 2 DIFFERENT STRAINS OF RATS AND IN DOGS AND MONKEYS. THE PRIMARY FINDINGS INCLUDED INCREASE IN LUNG WEIGHT, ASSOCIATED WITH SMOOTH MUSCLE HYPERTROPHY, HYPERDISTENSION OF THE ALVEOLI, AND/OR INCREASED COLLAGEN. INSUFFICIENT OR LACK OF PULMONARY COLLAPSE AT NECROPSY, GENERALLY CORRELATED WITH MICROSCOPIC CHANGES, WAS OBSERVED IN ALL SPECIES. IN RATS AND MONKEYS, LUNG TOXICITY WAS OBSERVED AT ALL ORAL DOSES TESTED IN CHRONIC STUDIES. THE LOWEST DOSES TESTED IN RATS (0.05 MG/KG/DAY IN THE 2-YEAR CARCINOGENICITY STUDY) AND MONKEYS (0.5 MG/KG/DAY IN THE 39-WEEK TOXICITY STUDY) ARE SIMILAR TO AND APPROXIMATELY 20 TIMES THE RHD ON A MG/M² BASIS, RESPECTIVELY.
IN THE 52-WEEK ORAL STUDY IN MONKEYS, RESPIRATORY DISTRESS ASSOCIATED WITH KETAMINE ADMINISTRATION WAS OBSERVED AT DOSES OF 3 AND 10 MG/KG/DAY; THE MOST AFFECTED ANIMAL BECAME HYPOXIC AND REQUIRED OXYGENATION. AS KETAMINE IS NOT GENERALLY ASSOCIATED WITH RESPIRATORY DEPRESSION, THIS EFFECT WAS ATTRIBUTED TO FINGOLIMOD. IN A SUBSEQUENT STUDY IN RATS, KETAMINE WAS SHOWN TO POTENTIATE THE BRONCHOCONSTRICTIVE EFFECTS OF FINGOLIMOD. THE RELEVANCE OF THESE FINDINGS TO HUMANS IS UNKNOWN.
CLINICAL STUDIES
THE EFFICACY OF GILENYA WAS DEMONSTRATED IN 2 STUDIES THAT EVALUATED ONCE-DAILY DOSES OF GILENYA 0.5 MG AND 1.25 MG IN PATIENTS WITH RELAPSING-REMITTING MS (RRMS). BOTH STUDIES INCLUDED PATIENTS WHO HAD EXPERIENCED AT LEAST 2 CLINICAL RELAPSES DURING THE 2 YEARS PRIOR TO RANDOMIZATION OR AT LEAST 1 CLINICAL RELAPSE DURING THE 1 YEAR PRIOR TO RANDOMIZATION, AND HAD AN EXPANDED DISABILITY STATUS SCALE (EDSS) SCORE FROM 0 TO 5.5. STUDY 1 WAS A 2-YEAR RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY IN PATIENTS WITH RRMS WHO HAD NOT RECEIVED ANY INTERFERON-BETA OR GLATIRAMER ACETATE FOR AT LEAST THE PREVIOUS 3 MONTHS AND HAD NOT RECEIVED ANY NATALIZUMAB FOR AT LEAST THE PREVIOUS 6 MONTHS. NEUROLOGICAL EVALUATIONS WERE PERFORMED AT SCREENING, EVERY 3 MONTHS AND AT TIME OF SUSPECTED RELAPSE. MRI EVALUATIONS WERE PERFORMED AT SCREENING, MONTH 6, MONTH 12, AND MONTH 24. THE PRIMARY ENDPOINT WAS THE ANNUALIZED RELAPSE RATE.
MEDIAN AGE WAS 37 YEARS, MEDIAN DISEASE DURATION WAS 6.7 YEARS AND MEDIAN EDSS SCORE AT BASELINE WAS 2.0. PATIENTS WERE RANDOMIZED TO RECEIVE GILENYA 0.5 MG (N=425), 1.25 MG (N=429), OR PLACEBO (N=418) FOR UP TO 24 MONTHS. MEDIAN TIME ON STUDY DRUG WAS 717 DAYS ON 0.5 MG, 715 DAYS ON 1.25 MG AND 719 DAYS ON PLACEBO.
THE ANNUALIZED RELAPSE RATE WAS SIGNIFICANTLY LOWER IN PATIENTS TREATED WITH GILENYA THAN IN PATIENTS WHO RECEIVED PLACEBO. THE SECONDARY ENDPOINT WAS THE TIME TO 3-MONTH CONFIRMED DISABILITY PROGRESSION AS MEASURED BY AT LEAST A 1POINT INCREASE FROM BASELINE IN EDSS (0.5 POINT INCREASE FOR PATIENTS WITH BASELINE EDSS OF 5.5) SUSTAINED FOR 3 MONTHS. TIME TO ONSET OF 3-MONTH CONFIRMED DISABILITY PROGRESSION WAS SIGNIFICANTLY DELAYED WITH GILENYA TREATMENT COMPARED TO PLACEBO. THE 1.25 MG DOSE RESULTED IN NO ADDITIONAL BENEFIT OVER THE GILENYA 0.5 MG DOSE. THE RESULTS FOR THIS STUDY ARE SHOWN IN TABLE 2 AND FIGURE 1.
TABLE 2 : CLINICAL AND MRI RESULTS OF STUDY 1
GILENYA 0.5 MG
N=425 PLACEBO
N=418 P-VALUE
CLINICAL ENDPOINTS
ANNUALIZED RELAPSE RATE (PRIMARY ENDPOINT) 0.18 0.40 < 0.001
PERCENTAGE OF PATIENTS WITHOUT RELAPSE 70% 46% < 0.001
HAZARD RATIO‡ OF DISABILITY PROGRESSION (95% CI) 0.70 (0.52, 0.96) 0.02
MRI ENDPOINT
MEAN (MEDIAN) NUMBER OF NEW OR NEWLY ENLARGING T2 LESIONS OVER 24 MONTHS 2.5 (0) 9.8 (5.0) < 0.001
MEAN (MEDIAN) NUMBER OF T1 GD-ENHANCING LESIONS AT MONTH 24 0.2 (0) 1.1 (0) < 0.001
ALL ANALYSES OF CLINICAL ENDPOINTS WERE INTENT-TO-TREAT. MRI ANALYSIS USED EVALUABLE DATASET.
‡HAZARD RATIO IS AN ESTIMATE OF THE RELATIVE RISK OF HAVING THE EVENT OF DISABILITY PROGRESSION ON GILENYA AS COMPARED TO PLACEBO.
FIGURE 1 : TIME TO 3-MONTH CONFIRMED DISABILITY PROGRESSION - STUDY 1 (ITT POPULATION)
STUDY 2 WAS A 1-YEAR RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, ACTIVE-CONTROLLED STUDY IN PATIENTS WITH RRMS WHO HAD NOT RECEIVED ANY NATALIZUMAB IN THE PREVIOUS 6 MONTHS. PRIOR THERAPY WITH INTERFERON-BETA OR GLATIRAMER ACETATE UP TO THE TIME OF RANDOMIZATION WAS PERMITTED.
NEUROLOGICAL EVALUATIONS WERE PERFORMED AT SCREENING, EVERY 3 MONTHS, AND AT THE TIME OF SUSPECTED RELAPSES. MRI EVALUATIONS WERE PERFORMED AT SCREENING AND AT MONTH 12. THE PRIMARY ENDPOINT WAS THE ANNUALIZED RELAPSE RATE.
MEDIAN AGE WAS 36 YEARS, MEDIAN DISEASE DURATION WAS 5.9 YEARS, AND MEDIAN EDSS SCORE AT BASELINE WAS 2.0. PATIENTS WERE RANDOMIZED TO RECEIVE GILENYA 0.5 MG (N=431), 1.25 MG (N=426), OR INTERFERON BETA-1A, 30 MCG VIA THE INTRAMUSCULAR ROUTE (IM) ONCE-WEEKLY (N=435) FOR UP TO 12 MONTHS. MEDIAN TIME ON STUDY DRUG WAS 365 DAYS ON GILENYA 0.5 MG, 354 DAYS ON 1.25 MG, AND 361 DAYS ON INTERFERON BETA-1A IM.
THE ANNUALIZED RELAPSE RATE WAS SIGNIFICANTLY LOWER IN PATIENTS TREATED WITH GILENYA 0.5 MG THAN IN PATIENTS WHO RECEIVED INTERFERON BETA-1A IM. THE KEY SECONDARY ENDPOINTS WERE NUMBER OF NEW AND NEWLY ENLARGING T2 LESIONS AND TIME TO ONSET OF 3-MONTH CONFIRMED DISABILITY PROGRESSION AS MEASURED BY AT LEAST A 1-POINT INCREASE FROM BASELINE IN EDSS (0.5 POINT INCREASE FOR THOSE WITH BASELINE EDSS OF 5.5) SUSTAINED FOR 3 MONTHS. THE NUMBER OF NEW AND NEWLY ENLARGING T2 LESIONS WAS SIGNIFICANTLY LOWER IN PATIENTS TREATED WITH GILENYA THAN IN PATIENTS WHO RECEIVED INTERFERON BETA-1A IM. THERE WAS NO SIGNIFICANT DIFFERENCE IN THE TIME TO 3-MONTH CONFIRMED DISABILITY PROGRESSION BETWEEN GILENYA AND INTERFERON BETA-1A-TREATED PATIENTS AT 1 YEAR. THE 1.25 MG DOSE RESULTED IN NO ADDITIONAL BENEFIT OVER THE GILENYA 0.5 MG DOSE. THE RESULTS FOR THIS STUDY ARE SHOWN IN TABLE 3.
TABLE 3 : CLINICAL AND MRI RESULTS OF STUDY 2
GILENYA 0.5 MG
N=429 INTERFERON BETA-1A IM 30 MCG
N=431 P-VALUE
CLINICAL ENDPOINTS
ANNUALIZED RELAPSE RATE (PRIMARY ENDPOINT) 0.16 0.33 < 0.001
PERCENTAGE OF PATIENTS WITHOUT RELAPSE 83% 70% < 0.001
HAZARD RATIO‡ OF DISABILITY PROGRESSION (95% CI) 0.71 (0.42, 1.21) 0.21
MRI ENDPOINT
MEAN (MEDIAN) NUMBER OF NEW OR NEWLY ENLARGING T2 LESIONS OVER 12 MONTHS 1.6 (0) 2.6 (1.0) 0.002
MEAN (MEDIAN) NUMBER OF T1 GD-ENHANCING LESIONS AT MONTH 12 0.2 (0) 0.5 (0) < 0.001
ALL ANALYSES OF CLINICAL ENDPOINTS WERE INTENT-TO-TREAT. MRI ANALYSIS USED EVALUABLE DATASET.
‡ HAZARD RATIO IS AN ESTIMATE OF THE RELATIVE RISK OF HAVING THE EVENT OF DISABILITY PROGRESSION ON GILENYA AS COMPARED TO CONTROL.
POOLED RESULTS OF STUDY 1 AND STUDY 2 SHOWED A CONSISTENT AND STATISTICALLY SIGNIFICANT REDUCTION OF ANNUALIZED RELAPSE RATE COMPARED TO COMPARATOR IN SUBGROUPS DEFINED BY GENDER, AGE, PRIOR MS THERAPY, AND DISEASE ACTIVITY.