Hypersensitivity to fingolimod or its excipients (4)

Transcription

1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights d nt include all the infrmatin needed t use GILENYA safely and effectively. See full prescribing infrmatin fr GILENYA. GILENYA (finglimd) capsules, fr ral use Initial U.S. Apprval: RECENT MAJOR CHANGES Warnings and Precautins (5.2, 5.3, 5.10) 12/ INDICATIONS AND USAGE GILENYA is a sphingsine 1-phsphate receptr mdulatr indicated fr treatment f patients with relapsing frms f multiple sclersis (MS) t reduce the frequency f clinical exacerbatins and t delay the accumulatin f physical disability. (1) DOSAGE AND ADMINISTRATION Recmmended dse: 0.5 mg rally nce-daily, with r withut fd (2.1) First Dse Mnitring (including re-initiatin after discntinuatin >14 days): Observe all patients fr bradycardia fr at least 6 hurs; mnitr pulse and bld pressure hurly. Electrcardigrams (ECGs) prir t dsing and at end f bservatin perid required. (2.2) Mnitr until reslutin if heart rate <45 bpm, atriventricular (AV) blck, r if lwest pstdse heart rate is at the end f the bservatin perid. (2.2) Mnitr symptmatic bradycardia with ECG until reslved. Cntinue vernight if interventin is required; repeat first-dse mnitring fr secnd dse. (2.2) Observe patients vernight if at higher risk f symptmatic bradycardia, heart blck, prlnged QTc interval, r if taking drugs with knwn risk f trsades de pintes. (2.2, 7.1) DOSAGE FORMS AND STRENGTHS mg hard capsules (3) CONTRAINDICATIONS Recent mycardial infarctin, unstable angina, strke, transient ischemic attack, decmpensated heart failure with hspitalizatin, r Class III/IV heart failure (4) Histry f Mbitz Type II 2nd degree r 3rd degree AV blck r sick sinus syndrme, unless patient has a pacemaker (4) Baseline QTc interval 500 msec (4) Treatment with Class Ia r Class III anti-arrhythmic drugs (4) Hypersensitivity t finglimd r its excipients (4) WARNINGS AND PRECAUTIONS Infectins: GILENYA may increase the risk. Obtain a CBC befre initiating treatment. Mnitr fr infectin during treatment and fr 2 mnths after discntinuatin. D nt start in patients with active infectins. (5.2) Prgressive multifcal leukencephalpathy (PML); Withhld GILENYA at the first sign r symptm suggestive f PML. (5.3) Macular edema: Examine the fundus befre and 3 4 mnths after treatment start. Diabetes mellitus and uveitis increase the risk. (5.4) Psterir reversible encephalpathy syndrme (PRES): If suspected, discntinue GILENYA. (5.5) Respiratry effects: Evaluate when clinically indicated. (5.6) Liver injury: Obtain liver enzyme results befre initiatin. Clsely mnitr patients with severe hepatic impairment. Discntinue if significant liver injury ccurs. (5.7, 8.6, 12.3) Fetal risk: Wmen f childbearing ptential shuld use effective cntraceptin during and fr 2 mnths after stpping GILENYA. (5.8) Increased bld pressure (BP): Mnitr BP during treatment. (5.9) Cutaneus malignancies: suspicius skin lesins shuld be evaluated. (5.10) ADVERSE REACTIONS Mst cmmn adverse reactins (incidence 10% and > placeb): Headache, liver transaminase elevatin, diarrhea, cugh, influenza, sinusitis, back pain, abdminal pain, and pain in extremity (6.1) T reprt SUSPECTED ADVERSE REACTIONS, cntact Nvartis Pharmaceuticals Crpratin at r FDA at FDA-1088 r DRUG INTERACTIONS Systemic ketcnazle: Mnitr during cncmitant use. (7.2, 12.3) Vaccines: Avid live attenuated vaccines during, and fr 2 mnths after stpping GILENYA treatment. (5.2, 7.3) See 17 fr PATIENT COUNSELING INFORMATION and Medicatin Guide Revised: 12/2017 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recmmended Dsage 2.2 First -Dse Mnitring 2.3 Reinitiatin f Therapy Fllwing Discntinuatin 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Bradyarrhythmia and Atriventricular Blcks 5.2 Infectins 5.3 Prgressive Multifcal Leukencephalpathy 5.4 Macular Edema 5.5 Psterir Reversible Encephalpathy Syndrme 5.6 Respiratry Effects 5.7 Liver Injury 5.8 Fetal Risk 5.9 Increased Bld Pressure 5.10 Cutaneus Malignancies 5.11 Immune System Effects Fllwing GILENYA Discntinuatin 5.12 Hypersensitivity Reactins 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 QT Prlnging Drugs 7.2 Ketcnazle 7.3 Vaccines 7.4 Antineplastic, Immunsuppressive, r Immune-Mdulating Therapies 7.5 Drugs That Slw Heart Rate r Atriventricular Cnductin (e.g., beta blckers r diltiazem) 7.6 Labratry Test Interactin 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labr and Delivery 8.3 Nursing Mthers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism f Actin 12.2 Pharmacdynamics 12.3 Pharmackinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcingenesis, Mutagenesis, Impairment f Fertility 13.2 Animal Txiclgy and/r Pharmaclgy 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sectins r subsectins mitted frm the full prescribing infrmatin are nt listed.

2 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GILENYA is indicated fr the treatment f patients with relapsing frms f multiple sclersis (MS) t reduce the frequency f clinical exacerbatins and t delay the accumulatin f physical disability. 2 DOSAGE AND ADMINISTRATION 2.1 Recmmended Dsage The recmmended dsage f GILENYA is 0.5 mg rally nce-daily. Finglimd dses higher than 0.5 mg are assciated with a greater incidence f adverse reactins withut additinal benefit. GILENYA can be taken with r withut fd. Patients wh initiate GILENYA and thse wh re-initiate treatment after discntinuatin fr lnger than 14 days require first -dse mnitring [see Dsage and Administratin (2.2, 2.3)]. 2.2 First -Dse Mnitring Initiatin f GILENYA treatment results in a decrease in heart rate [see Warnings and Precautins (5.1) and Clinical Pharmaclgy (12.2)]. After the first dse f GILENYA, the heart rate decrease starts within an hur and the Day 1 nadir generally ccurs within apprximately 6 hurs, althugh the nadir can be bserved up t 24 hurs after the first dse in sme patients. The first dse f GILENYA shuld be administered in a setting in which resurces t apprpriately manage symptmatic bradycardia are available. In rder t assess patient respnse t the first dse f finglimd, bserve all patients fr 6 hurs fr signs and symptms f bradycardia with hurly pulse and bld pressure measurement. Obtain in all patients an electrcardigram (ECG) prir t dsing, and at the end f the bservatin perid. Additinal bservatin shuld be instituted until the finding has reslved in the fllwing situatins: The heart rate 6 hurs pstdse is <45 bpm The heart rate 6 hurs pstdse is at the lwest value pstdse (suggesting that the maximum pharmacdynamic effect n the heart may nt have ccurred) The ECG 6 hurs pstdse shws new nset secnd degree r higher atriventricular (AV) blck Shuld pstdse symptmatic bradycardia ccur, initiate apprpriate management, begin cntinuus ECG mnitring, and cntinue bservatin until the symptms have reslved. Shuld a patient require pharmaclgic interventin fr symptmatic bradycardia, cntinuus vernight ECG mnitring in a medical facility shuld be instituted, and the first dse mnitring strategy shuld be repeated after the secnd dse f GILENYA. Patients with sme preexisting cnditins (e.g., ischemic heart disease, histry f mycardial infarctin, cngestive heart failure, histry f cardiac arrest, cerebrvascular disease, uncntrlled hypertensin, histry f symptmatic bradycardia, histry f recurrent syncpe, severe untreated sleep apnea, AV blck, sinatrial heart blck) may prly tlerate the GILENYA-induced bradycardia, r experience serius rhythm disturbances after the first dse f GILENYA. Prir t treatment with GILENYA, these patients shuld have a cardiac evaluatin by a physician apprpriately trained t cnduct such evaluatin, and, if treated with GILENYA, shuld be mnitred vernight with cntinuus ECG in a medical facility after the first dse. GILENYA is cntraindicated in patients wh in the last 6 mnths experienced mycardial infarctin, unstable angina, strke, transient ischemic attack (TIA), decmpensated heart failure requiring hspitalizatin r Class III/IV heart failure [see Cntraindicatins (4)]. Since initiatin f GILENYA treatment results in decreased heart rate and may prlng the QT interval, patients with a prlnged QTc interval (>450 msec males, >470 msec females) befre dsing r during 6 hur bservatin, r at additinal risk fr QT prlngatin (e.g., hypkalemia, hypmagnesemia, cngenital lng-qt syndrme), r n cncurrent therapy with QT prlnging drugs with a knwn risk f trsades de pintes (e.g., citalpram, chlrprmazine, halperidl, methadne, erythrmycin) shuld be mnitred vernight with cntinuus ECG in a medical facility [see Drug Interactins (7.1)]. Experience with GILENYA is limited in patients receiving cncurrent therapy with drugs that slw heart rate r atriventricular cnductin (e.g., beta blckers, heart-rate lwering calcium channel blckers such as diltiazem r verapamil, r digxin). Because the initiatin f GILENYA treatment is als assciated with slwing f the heart rate,

3 cncmitant use f these drugs during GILENYA initiatin may be assciated with severe bradycardia r heart blck. The pssibility t switch t drugs that d nt slw the heart rate r atriventricular cnductin shuld be evaluated by the physician prescribing these drugs befre initiating GILENYA. Patients wh cannt switch shuld have vernight cntinuus ECG mnitring after the first dse [see Drug Interactins (7.1)]. Clinical data indicate effects f GILENYA n heart rate are maximal after the first dse althugh milder effects n heart rate may persist fr, n average, 2 t 4 weeks after initiatin f therapy at which time heart rate generally returns t baseline. Physicians shuld cntinue t be alert t patient reprts f cardiac symptms. 2.3 Reinitiatin f Therapy Fllwing Discntinuatin If GILENYA therapy is discntinued fr mre than 14 days, after the first mnth f treatment, the effects n heart rate and AV cnductin may recur n reintrductin f GILENYA treatment and the same precautins (first dse mnitring) as fr initial dsing shuld apply. Within the first 2 weeks f treatment, first dse prcedures are recmmended after interruptin f 1 day r mre; during weeks 3 and 4 f treatment first dse prcedures are recmmended after treatment interruptin f mre than 7 days. 3 DOSAGE FORMS AND STRENGTHS GILENYA is available as 0.5 mg hard capsules with a white paque bdy and bright yellw cap imprinted with FTY 0.5 mg n the cap and 2 radial bands imprinted n the capsule bdy with yellw ink. 4 CONTRAINDICATIONS Patients wh in the last 6 mnths experienced mycardial infarctin, unstable angina, strke, TIA, decmpensated heart failure requiring hspitalizatin r Class III/IV heart failure Histry r presence f Mbitz Type II secnd-degree r third-degree atriventricular (AV) blck r sick sinus syndrme, unless patient has a functining pacemaker Baseline QTc interval 500 msec Treatment with Class Ia r Class III anti-arrhythmic drugs Patients wh have had a hypersensitivity reactin t finglimd r any f the excipients in GILENYA. Observed reactins include rash, urticaria and angiedema upn treatment initiatin [see Warnings and Precautins (5.12)]. 5 WARNINGS AND PRECAUTIONS 5.1 Bradyarrhythmia and Atriventricular Blcks Because f a risk fr bradyarrhythmia and atriventricular (AV) blcks, patients shuld be mnitred during GILENYA treatment initiatin [see Dsage and Administratin (2.2)]. Reductin in Heart Rate After the first dse f GILENYA, the heart rate decrease starts within an hur. On Day 1, the maximum decline in heart rate generally ccurs within 6 hurs and recvers, althugh nt t baseline levels, by 8 t 10 hurs pstdse. Because f physilgical diurnal variatin, there is a secnd perid f heart rate decrease within 24 hurs after the first dse. In sme patients, heart rate decrease during the secnd perid is mre prnunced than the decrease bserved in the first 6 hurs. Heart rates belw 40 beats per minute were rarely bserved. In cntrlled clinical trials, adverse reactins f symptmatic bradycardia fllwing the first dse were reprted in 0.6% f patients receiving GILENYA 0.5 mg and in 0.1% f patients n placeb. Patients wh experienced bradycardia were generally asymptmatic, but sme patients experienced hyptensin, dizziness, fatigue, palpitatins, and/r chest pain that usually reslved within the first 24 hurs n treatment. Fllwing the secnd dse, a further decrease in heart rate may ccur when cmpared t the heart rate prir t the secnd dse, but this change is f a smaller magnitude than that bserved fllwing the first dse. With cntinued dsing, the heart rate returns t baseline within 1 mnth f chrnic treatment. Atriventricular Blcks Initiatin f GILENYA treatment has resulted in transient AV cnductin delays. In cntrlled clinical trials, first-degree AV blck after the first dse ccurred in 4.7% f patients receiving GILENYA and 1.6% f patients n placeb. In a study f 697 patients with available 24-hur Hlter mnitring data after their first dse (N=351 receiving GILENYA and

4 N=346 n placeb), secnd-degree AV blcks (Mbitz Types I [Wenckebach] r 2:1 AV blcks) ccurred in 4% (N=14) f patients receiving GILENYA and 2% (N=7) f patients n placeb. Of the 14 patients receiving GILENYA, 7 patients had 2:1 AV blck (5 patients within the first 6 hurs pstdse and 2 patients after 6 hurs pstdse). All secnd degree AV blcks n placeb were Mbitz Type I and ccurred after the first 12 hurs pstdse. The cnductin abnrmalities were usually transient and asymptmatic, and reslved within the first 24 hurs n treatment, but they ccasinally required treatment with atrpine r isprterenl. Pstmarketing Experience In the pstmarketing setting, third-degree AV blck and AV blck with junctinal escape have been bserved during the first-dse 6-hur bservatin perid with GILENYA. Islated delayed nset events, including transient asystle and unexplained death, have ccurred within 24 hurs f the first dse. These events were cnfunded by cncmitant medicatins and/r preexisting disease, and the relatinship t GILENYA is uncertain. Cases f syncpe were als reprted after the first dse f GILENYA. 5.2 Infectins Risk f Infectins GILENYA causes a dse-dependent reductin in peripheral lymphcyte cunt t 20% 30% f baseline values because f reversible sequestratin f lymphcytes in lymphid tissues. GILENYA may therefre increase the risk f infectins, sme serius in nature [see Clinical Pharmaclgy (12.2)]. Life-threatening and fatal infectins have ccurred in assciatin with GILENYA. Befre initiating treatment with GILENYA, a recent CBC (i.e., within 6 mnths r after discntinuatin f prir therapy) shuld be available. Cnsider suspending treatment with GILENYA if a patient develps a serius infectin, and reassess the benefits and risks prir t reinitiatin f therapy. Because the eliminatin f finglimd after discntinuatin may take up t 2 mnths, cntinue mnitring fr infectins thrughut this perid. Instruct patients receiving GILENYA t reprt symptms f infectins t a physician. Patients with active acute r chrnic infectins shuld nt start treatment until the infectin(s) is reslved. In MS placeb-cntrlled trials, the verall rate f infectins (72%) with GILENYA was similar t placeb. Hwever, brnchitis, herpes zster, influenza, sinusitis, and pneumnia were mre cmmn in GILENYA-treated patients. Serius infectins ccurred at a rate f 2.3% in the GILENYA grup versus 1.6% in the placeb grup. In the pstmarketing setting, serius infectins with pprtunistic pathgens including viruses (e.g., Jhn Cunningham virus (JCV), herpes simplex viruses 1 and 2, varicella-zster virus), fungi (e.g., cryptccci), and bacteria (e.g., atypical mycbacteria) have been reprted with GILENYA. Patients with symptms and signs cnsistent with any f these infectins shuld underg prmpt diagnstic evaluatin and apprpriate treatment. Herpes Viral Infectins In placeb-cntrlled trials, the rate f herpetic infectins was 9% in patients receiving GILENYA 0.5 mg and 7% n placeb. Tw patients died f herpetic infectins during cntrlled trials. One death was due t disseminated primary herpes zster and the ther t herpes simplex encephalitis. In bth cases, the patients were taking a 1.25 mg dse f finglimd (higher than the recmmended 0.5 mg dse) and had received high-dse crticsterid therapy t treat suspected MS relapses. Serius, life-threatening events f disseminated varicella zster and herpes simplex infectins, including cases f encephalitis and multirgan failure, have ccurred with GILENYA in the pstmarketing setting. Include disseminated herpetic infectins in the differential diagnsis f patients wh are receiving GILENYA and present with an atypical MS relapse r multirgan failure. Cases f Kapsi s sarcma have been reprted in the pstmarketing setting. Kapsi s sarcma is an angiprliferative disrder that is assciated with infectin with human herpes virus 8 (HHV-8). Patients with symptms r signs cnsistent with Kapsi s sarcma shuld be referred fr prmpt diagnstic evaluatin and management. Cryptcccal infectins Cryptcccal infectins, including cases f fatal cryptcccal meningitis and disseminated cryptcccal infectins, have been reprted with GILENYA in the pstmarketing setting. Cryptcccal infectins have generally ccurred after

5 apprximately 2 years f GILENYA treatment, but may ccur earlier. The relatinship between the risk f cryptcccal infectin and the duratin f treatment is unknwn. Patients with symptms and signs cnsistent with a cryptcccal infectin shuld underg prmpt diagnstic evaluatin and treatment. Prir and Cncmitant Treatment with Antineplastic, Immunsuppressive, r Immune-Mdulating Therapies In clinical studies, patients wh received GILENYA did nt receive cncmitant treatment with antineplastic, nncrticsterid immunsuppressive, r immune-mdulating therapies used fr treatment f MS. Cncmitant use f GILENYA with any f these therapies, and als with crticsterids, wuld be expected t increase the risk f immunsuppressin [see Drug Interactins (7.4)]. When switching t GILENYA frm immune-mdulating r immunsuppressive medicatins, cnsider the duratin f their effects and their mde f actin t avid unintended additive immunsuppressive effects. Varicella Zster Virus Antibdy Testing/Vaccinatin Patients withut a healthcare prfessinal cnfirmed histry f chickenpx r withut dcumentatin f a full curse f vaccinatin against varicella zster virus (VZV) shuld be tested fr antibdies t VZV befre initiating GILENYA. VZV vaccinatin f antibdy-negative patients is recmmended prir t cmmencing treatment with GILENYA, fllwing which initiatin f treatment with GILENYA shuld be pstpned fr 1 mnth t allw the full effect f vaccinatin t ccur. 5.3 Prgressive Multifcal Leukencephalpathy Cases f prgressive multifcal leukencephalpathy (PML) have ccurred in patients with MS wh received GILENYA in the pstmarketing setting. PML is an pprtunistic viral infectin f the brain caused by the JC virus (JCV) that typically nly ccurs in patients wh are immuncmprmised, and that usually leads t death r severe disability. PML has ccurred in patients wh had nt been treated previusly with natalizumab, which has a knwn assciatin with PML, were nt taking any ther immunsuppressive r immunmdulatry medicatins cncmitantly, and did nt have any nging systemic medical cnditins resulting in cmprmised immune system functin. The majrity f cases have ccurred in patients treated with GILENYA fr at least 2 years. The relatinship between the risk f PML and the duratin f treatment is unknwn. At the first sign r symptm suggestive f PML, withhld GILENYA and perfrm an apprpriate diagnstic evaluatin. Typical symptms assciated with PML are diverse, prgress ver days t weeks, and include prgressive weakness n ne side f the bdy r clumsiness f limbs, disturbance f visin, and changes in thinking, memry, and rientatin leading t cnfusin and persnality changes. MRI findings may be apparent befre clinical signs r symptms. Cases f PML, diagnsed based n MRI findings and the detectin f JCV DNA in the cerebrspinal fluid in the absence f clinical signs r symptms specific t PML, have been reprted in patients treated with MS medicatins assciated with PML, including GILENYA. Many f these patients subsequently became symptmatic with PML. Therefre, mnitring with MRI fr signs that may be cnsistent with PML may be useful, and any suspicius findings shuld lead t further investigatin t allw fr an early diagnsis f PML, if present. Lwer PML-related mrtality and mrbidity have been reprted fllwing discntinuatin f anther MS medicatin assciated with PML in patients with PML wh were initially asymptmatic cmpared t patients with PML wh had characteristic clinical signs and symptms at diagnsis. It is nt knwn whether these differences are due t early detectin and discntinuatin f MS treatment r due t differences in disease in these patients. 5.4 Macular Edema Finglimd increases the risk f macular edema. Perfrm an examinatin f the fundus including the macula in all patients befre starting treatment, again 3 4 mnths after starting treatment, and again at any time after a patient reprts visual disturbances while n GILENYA therapy. A dse-dependent increase in the risk f macular edema ccurred in the GILENYA clinical develpment prgram. In 2-year, duble-blind, placeb-cntrlled studies in patients with multiple sclersis, macular edema with r withut visual symptms ccurred in 1.5% f patients (11/799) treated with finglimd 1.25 mg, 0.5% f patients (4/783) treated with GILENYA 0.5 mg and 0.4% f patients (3/773) treated with placeb. Macular edema ccurred predminantly during the first 3 t 4 mnths f therapy. These clinical trials excluded patients with diabetes mellitus, a knwn risk factr fr macular edema (see belw Macular Edema in Patients with Histry f Uveitis r Diabetes Mellitus). Symptms f

6 macular edema included blurred visin and decreased visual acuity. Rutine phthalmlgical examinatin detected macular edema in sme patients with n visual symptms. Macular edema generally partially r cmpletely reslved with r withut treatment after drug discntinuatin. Sme patients had residual visual acuity lss even after reslutin f macular edema. Macular edema has als been reprted in patients taking GILENYA in the pstmarketing setting, usually within the first 6 mnths f treatment. Cntinuatin f GILENYA in patients wh develp macular edema has nt been evaluated. A decisin n whether r nt t discntinue GILENYA therapy shuld include an assessment f the ptential benefits and risks fr the individual patient. The risk f recurrence after rechallenge has nt been evaluated. Macular Edema in Patients with Histry f Uveitis r Diabetes Mellitus Patients with a histry f uveitis and patients with diabetes mellitus are at increased risk f macular edema during GILENYA therapy. The incidence f macular edema is als increased in MS patients with a histry f uveitis. In the cmbined clinical trial experience with all dses f finglimd, the rate f macular edema was apprximately 20% in MS patients with a histry f uveitis versus 0.6% in thse withut a histry f uveitis. GILENYA has nt been tested in MS patients with diabetes mellitus. In additin t the examinatin f the fundus including the macula prir t treatment and at 3 4 mnths after starting treatment, MS patients with diabetes mellitus r a histry f uveitis shuld have regular fllwup examinatins. 5.5 Psterir Reversible Encephalpathy Syndrme There have been rare cases f psterir reversible encephalpathy syndrme (PRES) reprted in patients receiving GILENYA. Symptms reprted included sudden nset f severe headache, altered mental status, visual disturbances, and seizure. Symptms f PRES are usually reversible but may evlve int ischemic strke r cerebral hemrrhage. Delay in diagnsis and treatment may lead t permanent neurlgical sequelae. If PRES is suspected, GILENYA shuld be discntinued. 5.6 Respiratry Effects Dse-dependent reductins in frced expiratry vlume ver 1 secnd (FEV1) and diffusin lung capacity fr carbn mnxide (DLCO) were bserved in patients treated with GILENYA as early as 1 mnth after treatment initiatin. In 2- year placeb-cntrlled trials, the reductin frm baseline in the percent f predicted values fr FEV1 at the time f last assessment n drug was 2.8% fr GILENYA 0.5 mg and 1.0% fr placeb. Fr DLCO, the reductin frm baseline in percent f predicted values at the time f last assessment n drug was 3.3% fr GILENYA 0.5 mg and 0.5% fr placeb. The changes in FEV1 appear t be reversible after treatment discntinuatin. There is insufficient infrmatin t determine the reversibility f the decrease f DLCO after drug discntinuatin. In MS placeb-cntrlled trials, dyspnea was reprted in 9% f patients receiving GILENYA 0.5 mg and 7% f patients receiving placeb. Several patients discntinued GILENYA because f unexplained dyspnea during the extensin (uncntrlled) studies. GILENYA has nt been tested in MS patients with cmprmised respiratry functin. Spirmetric evaluatin f respiratry functin and evaluatin f DLCO shuld be perfrmed during therapy with GILENYA if clinically indicated. 5.7 Liver Injury Elevatins f liver enzymes may ccur in patients receiving GILENYA. Recent (i.e., within last 6 mnths) transaminase and bilirubin levels shuld be available befre initiatin f GILENYA therapy. In 2-year placeb-cntrlled clinical trials, elevatin f liver transaminases t 3-fld the upper limit f nrmal (ULN) r greater ccurred in 14% f patients treated with GILENYA 0.5 mg and 3% f patients n placeb. Elevatins 5-fld the ULN r greater ccurred in 4.5% f patients n GILENYA and 1% f patients n placeb. The majrity f elevatins ccurred within 6 t 9 mnths. In clinical trials, GILENYA was discntinued if the elevatin exceeded 5 times the ULN. Serum transaminase levels returned t nrmal within apprximately 2 mnths after discntinuatin f GILENYA. Recurrence f liver transaminase elevatins ccurred with rechallenge in sme patients. Cases f liver injury with hepatcellular and/r chlestatic hepatitis have been reprted with GILENYA in the pstmarketing setting. Liver enzymes and bilirubin shuld be mnitred in patients wh develp symptms suggestive f hepatic dysfunctin, such as unexplained nausea, vmiting, abdminal pain, fatigue, anrexia, r jaundice and/r dark urine. GILENYA shuld

7 be discntinued if significant liver injury is cnfirmed. Patients with preexisting liver disease may be at increased risk f develping elevated liver enzymes when taking GILENYA. Because GILENYA expsure is dubled in patients with severe hepatic impairment, these patients shuld be clsely mnitred, as the risk f adverse reactins is greater [see Use in Specific Ppulatins (8.6), Clinical Pharmaclgy (12.3)]. 5.8 Fetal Risk Based n animal studies, GILENYA may cause fetal harm. Because it takes apprximately 2 mnths t eliminate GILENYA frm the bdy, wmen f childbearing ptential shuld use effective cntraceptin t avid pregnancy during and fr 2 mnths after stpping GILENYA treatment. 5.9 Increased Bld Pressure In MS cntrlled clinical trials, patients treated with GILENYA 0.5 mg had an average increase ver placeb f apprximately 3 mmhg in systlic pressure, and apprximately 2 mmhg in diastlic pressure, first detected after apprximately 1 mnth f treatment initiatin, and persisting with cntinued treatment. Hypertensin was reprted as an adverse reactin in 8% f patients n GILENYA 0.5 mg and in 4% f patients n placeb. Bld pressure shuld be mnitred during treatment with GILENYA Cutaneus Malignancies The risk f basal cell carcinma (BCC) and melanma is increased in patients treated with GILENYA. In tw-year placeb-cntrlled trials, the incidence f BCC was 2% in patients n GILENYA 0.5 mg and 1% in patients n placeb [see Adverse Reactins (6.1)]. Melanma has been reprted with GILENYA in the pstmarketing setting. Peridic skin examinatin is recmmended fr all patients, particularly thse with risk factrs fr skin cancer. Prviders and patients are advised t mnitr fr suspicius skin lesins. If a suspicius skin lesin is bserved, it shuld be prmptly evaluated. As usual fr patients with increased risk fr skin cancer, expsure t sunlight and ultravilet light shuld be limited by wearing prtective clthing and using a sunscreen with a high prtectin factr Immune System Effects Fllwing GILENYA Discntinuatin Finglimd remains in the bld and has pharmacdynamic effects, including decreased lymphcyte cunts, fr up t 2 mnths fllwing the last dse f GILENYA. Lymphcyte cunts generally return t the nrmal range within 1 2 mnths f stpping therapy [see Clinical Pharmaclgy (12.2)]. Because f the cntinuing pharmacdynamic effects f finglimd, initiating ther drugs during this perid warrants the same cnsideratins needed fr cncmitant administratin (e.g., risk f additive immunsuppressant effects) [see Drug Interactins (7.4)] Hypersensitivity Reactins Hypersensitivity reactins, including rash, urticaria, and angiedema have been reprted with GILENYA in the pstmarketing setting. GILENYA is cntraindicated in patients with histry f hypersensitivity t finglimd r any f its excipients [see Cntraindicatins (4)]. 6 ADVERSE REACTIONS The fllwing serius adverse reactins are described elsewhere in labeling: Bradyarrhythmia and Atriventricular Blcks [see Warnings and Precautins (5.1)] Infectins [see Warnings and Precautins (5.2)] Prgressive multifcal leukencephalpathy [see Warnings and Precautins (5.3)] Macular Edema [see Warnings and Precautins (5.4)] Psterir Reversible Encephalpathy Syndrme [see Warnings and Precautins (5.5)] Respiratry Effects [see Warnings and Precautins (5.6)] Liver Injury [see Warnings and Precautins (5.7)] Fetal Risk [see Warnings and Precautins (5.8)] Increased Bld Pressure [see Warnings and Precautins (5.9)] Cutaneus Malignancies [see Warnings and Precautins (5.10)] Immune System Effects Fllwing GILENYA Discntinuatin [see Warnings and Precautins (5.11)] Hypersensitivity Reactins [see Warnings and Precautins (5.12)]

8 6.1 Clinical Trials Experience Because clinical trials are cnducted under widely varying cnditins, adverse reactin rates bserved in the clinical trials f a drug cannt be directly cmpared t rates in the clinical trials f anther drug and may nt reflect the rates bserved in practice. In clinical trials (Studies 1, 2, and 3), a ttal f 1212 patients with relapsing frms f multiple sclersis received GILENYA 0.5 mg. This included 783 patients wh received GILENYA 0.5 mg in the 2-year placeb-cntrlled trials (Studies 1 and 3) and 429 patients wh received GILENYA 0.5 mg in the 1 year active-cntrlled trial (Study 2). The verall expsure in the cntrlled trials was equivalent t 1716 persn-years. Apprximately 1000 patients received at least 2 years f treatment with GILENYA 0.5 mg. In all clinical studies, including uncntrlled extensin studies, the expsure t GILENYA 0.5 mg was apprximately 4119 persn-years. In placeb-cntrlled trials, the mst frequent adverse reactins (incidence 10% and >placeb) fr GILENYA 0.5 mg were headache, liver transaminase elevatin, diarrhea, cugh, influenza, sinusitis, back pain, abdminal pain, and pain in extremity. Adverse events that led t treatment discntinuatin and ccurred in mre than 1% f patients taking GILENYA 0.5 mg were serum transaminase elevatins (4.7% cmpared t 1% n placeb) and basal cell carcinma (1% cmpared t 0.5% n placeb). Table 1 lists adverse reactins that ccurred in 1% f GILENYA-treated patients and 1% higher rate than fr placeb. Table 1 Adverse Reactins Reprted in Studies 1 and 3 (Occurring in 1% f Patients and Reprted fr GILENYA 0.5 mg at 1% Higher Rate than fr Placeb) Primary System Organ Class Preferred Term GILENYA 0.5 mg N=783 % Placeb N=773 % Infectins Influenza 11 8 Sinusitis 11 8 Brnchitis 8 5 Herpes zster 2 1 Tinea versiclr 2 <1 Cardiac Disrders Bradycardia 3 1 Nervus system disrders Headache Migraine 6 4 Gastrintestinal disrders Nausea Diarrhea Abdminal pain General disrders and administratin site cnditins Asthenia 2 1 Musculskeletal and cnnective tissue disrders Back pain 10 9 Pain in extremity 10 7 Skin and subcutaneus tissue disrders Alpecia 3 2 Actinic keratsis 2 1

9 Investigatins Liver transaminase elevatins (ALT/GGT/AST) 15 4 Bld triglycerides increased 3 1 Respiratry, thracic, and mediastinal disrders Cugh Dyspnea 9 7 Eye disrders Visin blurred 4 2 Vascular disrders Hypertensin 8 4 Bld and lymphatic system disrders Lymphpenia 7 <1 Leukpenia 2 <1 Neplasms benign, malignant and unspecified (including cysts and plyps) Skin papillma Basal cell carcinma Adverse reactins f dizziness, pneumnia, eczema and pruritus were als reprted in Studies 1 and 3 but did nt meet the reprting rate criteria fr inclusin in Table 1 (difference was less than 1%). Adverse reactins with GILENYA 0.5 mg in Study 2, the 1-year active-cntrlled (versus interfern beta-1a) study were generally similar t thse in Studies 1 and 3. Vascular Events Vascular events, including ischemic and hemrrhagic strkes, and peripheral arterial cclusive disease were reprted in premarketing clinical trials in patients wh received GILENYA dses ( mg) higher than recmmended fr use in MS. Similar events have been reprted with GILENYA in the pstmarketing setting althugh a causal relatinship has nt been established. Lymphma Cases f lymphma, including bth T-cell and B-cell types and CNS lymphma, have ccurred in patients receiving GILENYA. The reprting rate f nn-hdgkin lymphma with GILENYA is greater than that expected in the general ppulatin adjusted by age, gender, and regin. The relatinship f lymphma t GILENYA remains uncertain. 7 DRUG INTERACTIONS 7.1 QT Prlnging Drugs GILENYA has nt been studied in patients treated with drugs that prlng the QT interval. Drugs that prlng the QT interval have been assciated with cases f trsades de pintes in patients with bradycardia. Since initiatin f GILENYA treatment results in decreased heart rate and may prlng the QT interval, patients n QT prlnging drugs with a knwn risk f trsades de pintes (e.g., citalpram, chlrprmazine, halperidl, methadne, erythrmycin) shuld be mnitred vernight with cntinuus ECG in a medical facility [see Dsage and Administratin (2.2) and Warnings and Precautins (5.1)]. 7.2 Ketcnazle The bld levels f finglimd and finglimd-phsphate are increased by 1.7-fld when used cncmitantly with ketcnazle. Patients wh use GILENYA and systemic ketcnazle cncmitantly shuld be clsely mnitred, as the risk f adverse reactins is greater.

10 7.3 Vaccines GILENYA reduces the immune respnse t vaccinatin. Vaccinatin may be less effective during and fr up t 2 mnths after discntinuatin f treatment with GILENYA [see Clinical Pharmaclgy (12.2)]. Avid the use f live attenuated vaccines during and fr 2 mnths after treatment with GILENYA because f the risk f infectin. 7.4 Antineplastic, Immunsuppressive, r Immune-Mdulating Therapies Antineplastic, immune-mdulating, r immunsuppressive therapies, (including crticsterids) are expected t increase the risk f immunsuppressin, and the risk f additive immune system effects must be cnsidered if these therapies are cadministered with GILENYA. When switching frm drugs with prlnged immune effects, such as natalizumab, teriflunmide r mitxantrne, the duratin and mde f actin f these drugs must be cnsidered t avid unintended additive immunsuppressive effects when initiating GILENYA [see Warnings and Precautins (5.2)]. 7.5 Drugs That Slw Heart Rate r Atriventricular Cnductin (e.g., beta blckers r diltiazem) Experience with GILENYA in patients receiving cncurrent therapy with drugs that slw the heart rate r atriventricular cnductin (e.g., beta blckers, digxin, r heart rate-slwing calcium channel blckers such as diltiazem r verapamil) is limited. Because initiatin f GILENYA treatment may result in an additinal decrease in heart rate, cncmitant use f these drugs during GILENYA initiatin may be assciated with severe bradycardia r heart blck. Seek advice frm the prescribing physician regarding the pssibility t switch t drugs that d nt slw the heart rate r atriventricular cnductin befre initiating GILENYA. Patients wh cannt switch, shuld have vernight cntinuus ECG mnitring after the first dse [see Dsage and Administratin (2.2) and Warnings and Precautins (5.1)]. 7.6 Labratry Test Interactin Because GILENYA reduces bld lymphcyte cunts via redistributin in secndary lymphid rgans, peripheral bld lymphcyte cunts cannt be utilized t evaluate the lymphcyte subset status f a patient treated with GILENYA. A recent CBC shuld be available befre initiating treatment with GILENYA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Categry C There are n adequate and well-cntrlled studies in pregnant wmen. In ral studies cnducted in rats and rabbits, finglimd demnstrated develpmental txicity, including teratgenicity (rats) and embrylethality, when given t pregnant animals. In rats, the highest n-effect dse was less than the recmmended human dse (RHD) f 0.5 mg/day n a bdy surface area (mg/m 2 ) basis. The mst cmmn fetal visceral malfrmatins in rats included persistent truncus arterisus and ventricular septal defect. The receptr affected by finglimd (sphingsine 1-phsphate receptr) is knwn t be invlved in vascular frmatin during embrygenesis. Because it takes apprximately 2 mnths t eliminate finglimd frm the bdy, ptential risks t the fetus may persist after treatment ends [see Warnings and Precautins (5.8, 5.11)]. GILENYA shuld be used during pregnancy nly if the ptential benefit justifies the ptential risk t the fetus. Pregnancy Registry A pregnancy registry has been established t cllect infrmatin abut the effect f GILENYA use during pregnancy. Physicians are encuraged t enrll pregnant patients, r pregnant wmen may register themselves in the GILENYA pregnancy registry by calling Quintiles at , sending an t gpr@quintiles.cm r visiting Animal Data When finglimd was rally administered t pregnant rats during the perid f rgangenesis (0, 0.03, 0.1, and 0.3 mg/kg/day r 0, 1, 3, and 10 mg/kg/day), increased incidences f fetal malfrmatins and embry-fetal deaths were bserved at all but the lwest dse tested (0.03 mg/kg/day), which is less than the RHD n a mg/m 2 basis. Oral administratin t pregnant rabbits during rgangenesis (0, 0.5, 1.5, and 5 mg/kg/day) resulted in increased incidences f embry-fetal mrtality and fetal grwth retardatin at the mid and high dses. The n-effect dse fr these effects in rabbits (0.5 mg/kg/day) is apprximately 20 times the RHD n a mg/m 2 basis.

11 When finglimd was rally administered t female rats during pregnancy and lactatin (0, 0.05, 0.15, and 0.5 mg/kg/day), pup survival was decreased at all dses and a neurbehaviral (learning) deficit was seen in ffspring at the high dse. The lw-effect dse f 0.05 mg/kg/day is similar t the RHD n a mg/m 2 basis. 8.2 Labr and Delivery The effects f GILENYA n labr and delivery are unknwn. 8.3 Nursing Mthers Finglimd is excreted in the milk f treated rats. It is nt knwn whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because f the ptential fr serius adverse reactins in nursing infants frm GILENYA, a decisin shuld be made whether t discntinue nursing r t discntinue the drug, taking int accunt the imprtance f the drug t the mther. 8.4 Pediatric Use The safety and effectiveness f GILENYA in pediatric patients with MS belw the age f 18 years have nt been established. In a study in which finglimd (0.3, 1.5, r 7.5 mg/kg/day) was rally administered t yung rats frm weaning thrugh sexual maturity, changes in bne mineral density and persistent neurbehaviral impairment (altered auditry startle) were bserved at all dses. Delayed sexual maturatin was nted in females at the highest dse tested and in males at all dses. The bne changes bserved in finglimd-treated juvenile rats are cnsistent with a reprted rle f S1P in the regulatin f bne mineral hmestasis. When finglimd (0.5 r 5 mg/kg/day) was rally administered t rats frm the nenatal perid thrugh sexual maturity, a marked decrease in T-cell dependent antibdy respnse was bserved at bth dses. This effect had nt fully recvered by 6-8 weeks after the end f treatment. 8.5 Geriatric Use Clinical MS studies f GILENYA did nt include sufficient numbers f patients aged 65 years and ver t determine whether they respnd differently than yunger patients. GILENYA shuld be used with cautin in patients aged 65 years and ver, reflecting the greater frequency f decreased hepatic, r renal, functin and f cncmitant disease r ther drug therapy. 8.6 Hepatic Impairment Because finglimd, but nt finglimd-phsphate, expsure is dubled in patients with severe hepatic impairment, patients with severe hepatic impairment shuld be clsely mnitred, as the risk f adverse reactins may be greater [see Warnings and Precautins (5.7) and Clinical Pharmaclgy (12.3)]. N dse adjustment is needed in patients with mild r mderate hepatic impairment. 8.7 Renal Impairment The bld level f sme GILENYA metablites is increased (up t 13-fld) in patients with severe renal impairment [see Clinical Pharmaclgy (12.3)]. The txicity f these metablites has nt been fully explred. The bld level f these metablites has nt been assessed in patients with mild r mderate renal impairment. 10 OVERDOSAGE GILENYA can induce bradycardia as well as AV cnductin blcks (including cmplete AV blck). The decline in heart rate usually starts within 1 hur f the first dse and is maximal within 6 hurs in mst patients [see Warnings and Precautins (5.1)]. In case f GILENYA verdsage, bserve patients vernight with cntinuus ECG mnitring in a medical facility, and btain regular measurements f bld pressure [see Dsage and Administratin (2.2)]. Neither dialysis nr plasma exchange results in remval f finglimd frm the bdy. 11 DESCRIPTION Finglimd is a sphingsine 1-phsphate receptr mdulatr. Chemically, finglimd is 2-amin-2-[2-(4-ctylphenyl)ethyl]prpan-1,3-dil hydrchlride. Its structure is shwn belw:

12 Finglimd hydrchlride is a white t practically white pwder that is freely sluble in water and alchl and sluble in prpylene glycl. It has a mlecular weight f GILENYA is prvided as 0.5 mg hard gelatin capsules fr ral use. Each capsule cntains 0.56 mg f finglimd hydrchlride, equivalent t 0.5 mg f finglimd. Each GILENYA 0.5 mg capsule cntains the fllwing inactive ingredients: gelatin, magnesium stearate, mannitl, titanium dixide, yellw irn xide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism f Actin Finglimd is metablized by sphingsine kinase t the active metablite, finglimd-phsphate. Finglimd-phsphate is a sphingsine 1-phsphate receptr mdulatr, and binds with high affinity t sphingsine 1-phsphate receptrs 1, 3, 4, and 5. Finglimd-phsphate blcks the capacity f lymphcytes t egress frm lymph ndes, reducing the number f lymphcytes in peripheral bld. The mechanism by which finglimd exerts therapeutic effects in multiple sclersis is unknwn, but may invlve reductin f lymphcyte migratin int the central nervus system Pharmacdynamics Heart Rate and Rhythm Finglimd causes a transient reductin in heart rate and AV cnductin at treatment initiatin [see Warnings and Precautins (5.1)]. Heart rate prgressively increases after the first day, returning t baseline values within 1 mnth f the start f chrnic treatment. Autnmic respnses f the heart, including diurnal variatin f heart rate and respnse t exercise, are nt affected by finglimd treatment. Finglimd treatment is nt assciated with a decrease in cardiac utput. Ptential t Prlng the QT Interval In a thrugh QT interval study f dses f 1.25 r 2.5 mg finglimd at steady-state, when a negative chrntrpic effect f finglimd was still present, finglimd treatment resulted in a prlngatin f QTc, with the upper bundary f the 90% cnfidence interval (CI) f 14.0 msec. There is n cnsistent signal f increased incidence f QTc utliers, either abslute r change frm baseline, assciated with finglimd treatment. In MS studies, there was n clinically relevant prlngatin f the QT interval, but patients at risk fr QT prlngatin were nt included in clinical studies. Immune System Effects n Immune Cell Numbers in the Bld In a study in which 12 subjects received GILENYA 0.5 mg daily, the lymphcyte cunt decreased t apprximately 60% f baseline within 4 t 6 hurs after the first dse. With cntinued daily dsing, the lymphcyte cunt cntinued t decrease ver a 2-week perid, reaching a nadir cunt f apprximately 500 cells/mcl r apprximately 30% f baseline. In a placeb-cntrlled study in 1272 MS patients (f whm 425 received finglimd 0.5 mg daily and 418 received placeb), 18% (N=78) f patients n finglimd 0.5 mg reached a nadir f <200 cells/mcl n at least 1 ccasin. N patient n placeb reached a nadir f <200 cells/mcl. Lw lymphcyte cunts are maintained with chrnic daily dsing f GILENYA 0.5 mg daily. Chrnic finglimd dsing leads t a mild decrease in the neutrphil cunt t apprximately 80% f baseline. Mncytes are unaffected by finglimd.

13 Peripheral lymphcyte cunt increases are evident within days f stpping finglimd treatment and typically nrmal cunts are reached within 1 t 2 mnths. Effect n Antibdy Respnse GILENYA reduces the immune respnse t vaccinatin, as evaluated in 2 studies. In the first study, the immungenicity f keyhle limpet hemcyanin (KLH) and pneumcccal plysaccharide vaccine (PPV-23) immunizatin were assessed by IgM and IgG titers in a steady-state, randmized, placeb-cntrlled study in healthy vlunteers. Cmpared t placeb, antigen-specific IgM titers were decreased by 91% and 25% in respnse t KLH and PPV-23, respectively, in subjects n GILENYA 0.5 mg. Similarly, IgG titers were decreased by 45% and 50%, in respnse t KLH and PPV-23, respectively, in subjects n GILENYA 0.5 mg daily cmpared t placeb. The respnder rate fr GILENYA 0.5 mg as measured by the number f subjects with a >4-fld increase in KLH IgG was cmparable t placeb and 25% lwer fr PPV-23 IgG, while the number f subjects with a >4 fld increase in KLH and PPV-23 IgM was 75% and 40% lwer, respectively, cmpared t placeb. The capacity t munt a skin delayed-type hypersensitivity reactin t Candida and tetanus txid was decreased by apprximately 30% in subjects n GILENYA 0.5 mg daily, cmpared t placeb. Immunlgic respnses were further decreased with finglimd 1.25 mg (a dse higher than recmmended in MS) [see Warnings and Precautins (5.2)]. In the secnd study, the immungenicity f Nrthern hemisphere seasnal influenza and tetanus txid vaccinatin was assessed in a 12-week steady-state, randmized, placeb-cntrlled study f GILENYA 0.5 mg in multiple sclersis patients (n=136). The respnder rate 3 weeks after vaccinatin, defined as sercnversin r a 4-fld increase in antibdy directed against at least 1 f the 3 influenza strains, was 54% fr GILENYA 0.5 mg and 85% in the placeb grup. The respnder rate 3 weeks after vaccinatin, defined as sercnversin r a 4-fld increase in antibdy directed against tetanus txid was 40% fr GILENYA 0.5 mg and 61% in the placeb grup. Pulmnary Functin Single finglimd dses 5 mg (10-fld the recmmended dse) are assciated with a dse-dependent increase in airway resistance. In a 14-day study f 0.5, 1.25, r 5 mg/day, finglimd was nt assciated with impaired xygenatin r xygen desaturatin with exercise r an increase in airway respnsiveness t methachline. Subjects n finglimd treatment had a nrmal brnchdilatr respnse t inhaled beta-agnists. In a 14-day placeb-cntrlled study f patients with mderate asthma, n effect was seen fr GILENYA 0.5 mg (recmmended dse in MS). A 10% reductin in mean FEV1 at 6 hurs after dsing was bserved in patients receiving finglimd 1.25 mg (a dse higher than recmmended fr use in MS) n Day 10 f treatment. Finglimd 1.25 mg was assciated with a 5-fld increase in the use f rescue shrt acting beta-agnists Pharmackinetics Absrptin The T max f finglimd is hurs. The apparent abslute ral biavailability is 93%. Fd intake des nt alter C max r expsure (AUC) f finglimd r finglimd-phsphate. Therefre GILENYA may be taken withut regard t meals. Steady-state bld cncentratins are reached within 1 t 2 mnths fllwing nce-daily administratin and steady-state levels are apprximately 10-fld greater than with the initial dse. Distributin Finglimd highly (86%) distributes in red bld cells. Finglimd-phsphate has a smaller uptake in bld cells f <17%. Finglimd and finglimd-phsphate are >99.7% prtein bund. Finglimd and finglimd-phsphate prtein binding is nt altered by renal r hepatic impairment. Finglimd is extensively distributed t bdy tissues with a vlume f distributin f abut L. Metablism The bitransfrmatin f finglimd in humans ccurs by 3 main pathways: by reversible stereselective phsphrylatin t the pharmaclgically active (S)-enantimer f finglimd-phsphate, by xidative bitransfrmatin catalyzed mainly by the cytchrme P450 4F2 (CYP4F2) and pssibly ther CYP4F isenzymes with subsequent fatty acid-like

14 degradatin t inactive metablites, and by frmatin f pharmaclgically inactive nn-plar ceramide analgs f finglimd. Inhibitrs r inducers f CYP4F2 and pssibly ther CYP4F iszymes might alter the expsure f finglimd r finglimd-phsphate. In vitr studies in hepatcytes indicated that CYP3A4 may cntribute t finglimd metablism in the case f strng inductin f CYP3A4. Fllwing single ral administratin f [ 14 C] finglimd, the majr finglimd-related cmpnents in bld, as judged frm their cntributin t the AUC up t 816 hurs pst-dse f ttal radilabeled cmpnents, are finglimd itself (23.3%), finglimd-phsphate (10.3%), and inactive metablites [M3 carbxylic acid metablite (8.3%), M29 ceramide metablite (8.9%), and M30 ceramide metablite (7.3%)]. Eliminatin Finglimd bld clearance is L/h, and the average apparent terminal half-life (t 1/2) is 6 t 9 days. Bld levels f finglimd-phsphate decline in parallel with thse f finglimd in the terminal phase, yielding similar half-lives fr bth. After ral administratin, abut 81% f the dse is slwly excreted in the urine as inactive metablites. Finglimd and finglimd-phsphate are nt excreted intact in urine but are the majr cmpnents in the feces with amunts f each representing less than 2.5% f the dse. Specific Ppulatins Geriatric Patients The mechanism fr eliminatin and results frm ppulatin pharmackinetics suggest that dse adjustment wuld nt be necessary in elderly patients. Hwever, clinical experience in patients aged abve 65 years is limited. Gender Gender has n clinically significant influence n finglimd and finglimd-phsphate pharmackinetics. Race The effects f race n finglimd and finglimd-phsphate pharmackinetics cannt be adequately assessed due t a lw number f nn-white patients in the clinical prgram. Renal Impairment In patients with severe renal impairment, finglimd C max and AUC are increased by 32% and 43%, respectively, and finglimd-phsphate C max and AUC are increased by 25% and 14%, respectively, with n change in apparent eliminatin half-life. Based n these findings, the GILENYA 0.5 mg dse is apprpriate fr use in patients with renal impairment. The systemic expsure f 2 metablites (M2 and M3) is increased by 3- and 13-fld, respectively. The txicity f these metablites has nt been fully characterized. A study in patients with mild r mderate renal impairment has nt been cnducted. Hepatic Impairment In subjects with mild, mderate, r severe hepatic impairment (Child-Pugh class A, B, and C), n change in finglimd C max was bserved, but finglimd AUC 0- was increased respectively by 12%, 44%, and 103%. In patients with severe hepatic impairment (Child-Pugh class C), finglimd-phsphate C max was decreased by 22% and AUC 0-96 hurs was decreased by 29%. The pharmackinetics f finglimd-phsphate was nt evaluated in patients with mild r mderate hepatic impairment. The apparent eliminatin half-life f finglimd is unchanged in subjects with mild hepatic impairment, but is prlnged by abut 50% in patients with mderate r severe hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) shuld be clsely mnitred, as the risk f adverse reactins is greater [see Warnings and Precautins (5.7)]. N dse adjustment is needed in patients with mild r mderate hepatic impairment (Child-Pugh class A and B). Drug Interactins Ketcnazle