TASCENSO ODT

1 INDICATIONS AND USAGE TASCENSO ODT is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in patients 10 years of age and older. TASCENSO ODT is a sphingosine 1-phosphate receptor modulator indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in patients 10 years of age and older. ( 1 )

2 DOSAGE AND ADMINISTRATION Assessments are required prior to initiating TASCENSO ODT ( 2.1 ) Recommended dosage for adults and pediatric patients (10 years of age and older) weighing more than 40 kg: 0.5 mg orally once daily, with or without food. ( 2.2 , 2.3 ) Recommended dosage for pediatric patients (10 years of age and older) weighing less than or equal to 40 kg: 0.25 mg orally once daily, with or without food ( 2.2 , 2.3 ). Administer TASCENSO ODT with or without water. Place tablet directly on the tongue and allow it to dissolve before swallowing. ( 2.2 ) First-Dose Monitoring (including reinitiation after discontinuation greater than 14 days and dose increases): Observe all patients for bradycardia for at least 6 hours; monitor pulse and blood pressure hourly. Electrocardiograms (ECGs) prior to dosing and at end of observation period required. ( 2.4 ) Monitor until resolution if heart rate < 45 beats per minute (bpm) in adults, < 55 bpm in patients aged 12 years and above, or < 60 bpm in pediatric patients aged 10 to below 12 years, atrioventricular (AV) block, or if lowest postdose heart rate is at the end of the observation period. ( 2.4 ) Monitor symptomatic bradycardia with ECG until resolved. Continue overnight if intervention is required; repeat first-dose monitoring for second dose. ( 2.4 ) Observe patients overnight if at higher risk of symptomatic bradycardia, heart block, prolonged QTc interval, or if taking drugs with known risk of torsades de pointes. ( 2.4 , 7.1 ) 2.1 Assessment Prior to Initiating TASCENSO ODT Cardiac Evaluation Obtain a cardiac evaluation in patients with certain preexisting conditions [see Dosage and Administration (2.4) and Warnings and Precautions (5.1) ]. Prior to starting treatment, determine whether patients are taking drugs that could slow heart rate or atrioventricular (AV) conduction [see Dosage and Administration (2.4) , Drug Interactions (7.5) ] . Complete Blood Count (CBC) Review results of a recent CBC [see Warnings and Precautions (5.2) , Drug Interactions (7.6) ]. Serum Transaminases (ALT and AST) and Total Bilirubin Levels Prior to starting treatment with TASCENSO ODT (i.e., within 6 months), review serum transaminases [alanine transaminase (ALT) and aspartate transferase (AST)] and total bilirubin levels [see Warnings and Precautions (5.5) ] . Ophthalmic Assessment Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with TASCENSO ODT [see Warnings and Precautions ( 5.4 )]. Skin Examination Obtain a baseline skin examination prior to or shortly after initiation of TASCENSO ODT. If a suspicious skin lesion is observed, it should be promptly evaluated [see Warnings and Precautions ( 5.12 )]. Prior Medications If patients are taking antineoplastic, immunosuppressive, or immune-modulating therapies, or if there is a history of prior use of these drugs, consider possible unintended additive immunosuppressive effects prior to initiating treatment with TASCENSO ODT [see Warnings and Precautions (5.2) , Drug Interactions (7.4) ]. Vaccinations Prior to initiating TASCENSO ODT, test patients for antibodies to varicella zoster virus (VZV). VZV vaccination of antibody- negative patients is recommended prior to commencing treatment with TASCENSO ODT [see Warnings and Precautions (5.2) ] . It is recommended that pediatric patients if possible, complete all other immunizations in accordance with current immunization guidelines prior to initiating TASCENSO ODT. 2.2 Important Administration Instructions Patients who initiate TASCENSO ODT, and those who reinitiate treatment after discontinuation for longer than 14 days, require first- dose monitoring. This monitoring is also recommended when the dose is increased in pediatric patients. Patients who are currently treated with another fingolimod product and underwent first-dose monitoring at initiation may be switched to TASCENSO ODT at the same daily dose without a need to repeat first-dose monitori…

5 WARNINGS AND PRECAUTIONS Bradyarrhythmia and Atrioventricular Blocks : Because of a risk for bradyarrhythmia and AV blocks, monitor during initiation of treatment ( 2.4 , 5.1 ) Infections : TASCENSO ODT may increase the risk. Obtain a complete blood count (CBC) before initiating TASCENSO ODT (i.e., within 6 months). Monitor for infection during treatment and for 2 months after discontinuation. Do not start in patients with active infections. ( 5.2 ) Progressive Multifocal Leukoencephalopathy (PML) : Withhold TASCENSO ODT at the first sign or symptom suggestive of PML. ( 5.3 ) Macular Edema : Increases the risk of macular edema. Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with TASCENSO ODT. Conduct an evaluation of the fundus, including the macula, 3 to 4 months after treatment start, periodically while on therapy, and any time there is a change in vision. Consider discontinuing TASCENSO ODT if macular edema develops. Diabetes mellitus and uveitis increase the risk. ( 5.4 ) Liver Injury : Obtain liver enzyme results before initiation and periodically during treatment. Closely monitor patients with severe hepatic impairment. Discontinue if there is evidence of liver injury without other cause. ( 5.5 , 8.6 , 12.3 ) Posterior Reversible Encephalopathy Syndrome (PRES) : If suspected, discontinue TASCENSO ODT. ( 5.6 ) Respiratory Effects : Evaluate when clinically indicated. ( 5.7 ) Fetal Risk : May cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use an effective method of contraception during treatment and for 2 months after stopping TASCENSO ODT. ( 5.8 , 8.1 , 8.3 ) Severe Increase in Disability After Stopping TASCENSO ODT: Monitor for development of severe increase in disability following discontinuation and begin appropriate treatment as needed. ( 5.9 ) Tumefactive MS : Consider when severe MS relapse occurs during treatment or after discontinuation. Obtain imaging and begin treatment as needed. ( 5.10 ) Increased Blood Pressure (BP) : Monitor BP during treatment. ( 5.11 ) Malignancies : Skin examination prior to or shortly after the start of treatment and periodically thereafter is recommended. Suspicious skin lesions should be evaluated. ( 5.12 ) 5.1 Bradyarrhythmia and Atrioventricular Blocks Because of a risk for bradyarrhythmia and AV blocks, patients should be monitored during TASCENSO ODT treatment initiation [see Dosage and Administration (2.4) ] . Reduction in Heart Rate After the first dose of TASCENSO ODT, the heart rate decrease starts within an hour. On Day 1, the maximum decline in heart rate generally occurs within 6 hours and recovers, although not to baseline levels, by 8 to 10 hours postdose. Because of physiological diurnal variation, there is a second period of heart rate decrease within 24 hours after the first dose. In some patients, heart rate decrease during the second period is more pronounced than the decrease observed in the first 6 hours. Heart rates below 40 beats per minute (bpm) in adults, and below 50 bpm in pediatric patients occurred rarely. In controlled clinical trials in adult patients, adverse reactions of symptomatic bradycardia following the first dose were reported in 0.6% of patients receiving fingolimod 0.5 mg and in 0.1% of patients on placebo. Patients who experienced bradycardia were generally asymptomatic, but some patients experienced hypotension, dizziness, fatigue, palpitations, and/or chest pain that usually resolved within the first 24 hours on treatment. 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 TASCENSO ODT-induced bradycardia, or experience serious rhythm …

4 CONTRAINDICATIONS TASCENSO ODT is contraindicated in patients who have: In the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization or Class III/IV heart failure. A history or presence of Mobitz Type II second-degree or third-degree AV block or sick sinus syndrome, unless patient has a functioning pacemaker [see Warnings and Precautions (5.1) ] A baseline QTc interval ≥ 500 msec Cardiac arrhythmias requiring anti-arrhythmic treatment with Class Ia or Class III anti-arrhythmic drugs Had a hypersensitivity reaction to fingolimod or any of the excipients in TASCENSO ODT. Observed reactions include rash, urticaria, and angioedema [see Warnings and Precautions (5.14) ]. Concomitant use with other products containing fingolimod Recent myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure with hospitalization, or Class III/IV heart failure. ( 4 ) History of Mobitz Type II 2 nd degree or 3 rd degree AV block or sick sinus syndrome, unless patient has a pacemaker. ( 4 ) Baseline QTc interval ≥ 500 msec. ( 4 ) Cardiac arrhythmias requiring anti-arrhythmic treatment with Class Ia or Class III anti-arrhythmic drugs. ( 4 ) Hypersensitivity to fingolimod or its excipients. ( 4 ) Concomitant use with other products containing fingolimod. ( 4 )

7 DRUG INTERACTIONS Systemic Ketoconazole : Monitor during concomitant use. ( 7.2 , 12.3 ) Vaccines : Avoid live attenuated vaccines during, and for 2 months after stopping TASCENSO ODT treatment. ( 5.3 , 7.3 ) 7.1 QT Prolonging Drugs TASCENSO ODT has not been studied in patients treated with drugs that prolong the QT interval. Drugs that prolong the QT interval have been associated with cases of torsades de pointes in patients with bradycardia. Since initiation of TASCENSO ODT treatment results in decreased heart rate and may prolong the QT interval, patients on 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 Dosage and Administration (2.4) , Warnings and Precautions (5.1) ]. 7.2 Ketoconazole The blood levels of fingolimod and fingolimod-phosphate are increased by 1.7-fold when used concomitantly with ketoconazole. Patients who use TASCENSO ODT and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is greater. 7.3 Vaccines TASCENSO ODT reduces the immune response to vaccination. Vaccination may be less effective during and for up to 2 months after discontinuation of treatment with TASCENSO ODT [see Clinical Pharmacology (12.2) ] . Avoid the use of live attenuated vaccines during and for 2 months after treatment with TASCENSO ODT because of the risk of infection. It is recommended that pediatric patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating TASCENSO ODT therapy. 7.4 Antineoplastic, Immunosuppressive, or Immune-Modulating Therapies Antineoplastic, immune-modulating, or immunosuppressive therapies, (including corticosteroids) are expected to increase the risk of immunosuppression, and the risk of additive immune system effects must be considered if these therapies are coadministered with TASCENSO ODT. When switching from drugs with prolonged immune effects, such as natalizumab, teriflunomide or mitoxantrone, the duration and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects when initiating TASCENSO ODT [see Warnings and Precautions (5.2) ]. 7.5 Drugs That Slow Heart Rate or Atrioventricular Conduction (e.g., beta blockers or diltiazem) Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or AV conduction (e.g., beta blockers, digoxin, or heart rate-slowing calcium channel blockers such as diltiazem or verapamil) is limited. Because initiation of TASCENSO ODT treatment may result in an additional decrease in heart rate, concomitant use of these drugs during TASCENSO ODT initiation may be associated with severe bradycardia or heart block. Seek advice from the physician prescribing these drugs regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating TASCENSO ODT. Patients who cannot switch should have overnight continuous ECG monitoring after the first dose [see Dosage and Administration (2.4) , Warnings and Precautions (5.1) ]. 7.6 Laboratory Test Interaction Because fingolimod reduces blood lymphocyte counts via redistribution in secondary lymphoid organs, peripheral blood lymphocyte counts cannot be utilized to evaluate the lymphocyte subset status of a patient treated with fingolimod. A recent CBC should be available before initiating treatment with TASCENSO ODT.

8.1 Pregnancy Risk Summary Based on findings from animal studies, TASCENSO ODT may cause fetal harm when administered to a pregnant woman. Data from prospective reports to the fingolimod pregnancy registry are currently not sufficient to allow for an adequate assessment of the drug-associated risk for birth defects and miscarriage in humans. In oral studies conducted in rats and rabbits, fingolimod demonstrated developmental toxicity, including an increase in malformations (rats) and embryolethality, when given to pregnant animals. In rats, the highest no-effect dose was less than the recommended human dose of 0.5 mg/day on a body surface area (mg/m 2 ) basis. The most common fetal visceral malformations in rats were persistent truncus arteriosus and ventricular septal defect. The receptor affected by fingolimod (sphingosine 1-phosphate receptor) is known to be involved in vascular formation during embryogenesis (see Data ). Advise pregnant women of the potential risk to a fetus. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations In females planning to become pregnant, TASCENSO ODT should be stopped 2 months before planned conception. The possibility of severe increase in disability should be considered in women who discontinue or are considering discontinuation of TASCENSO ODT because of pregnancy or planned pregnancy. In many of the cases in which increase in disability was reported after stopping fingolimod, the active moiety in TASCENSO ODT, patients had stopped fingolimod because of pregnancy or planned pregnancy [see Warnings and Precautions (5.9 ] . Data Animal Data When fingolimod was orally administered to pregnant rats during the period of organogenesis (0, 0.03, 0.1, and 0.3 mg/kg/day or 0, 1, 3, and 10 mg/kg/day), increased incidences of fetal malformations and embryofetal deaths were observed at all but the lowest dose tested (0.03 mg/kg/day), which is less than the recommended human dose (RHD) on a mg/m 2 basis. Oral administration to pregnant rabbits during organogenesis (0, 0.5, 1.5, and 5 mg/kg/day) resulted in increased incidences of embryofetal mortality and fetal growth retardation at the mid and high doses. The no-effect dose for these effects in rabbits (0.5 mg/kg/day) is approximately 20 times the RHD on a mg/m 2 basis. When fingolimod was orally administered to female rats during pregnancy and lactation (0, 0.05, 0.15, and 0.5 mg/kg/day), pup survival was decreased at all doses and a neurobehavioral (learning) deficit was seen in offspring at the high dose. The low-effect dose of 0.05 mg/kg/day is similar to the RHD on a mg/m 2 basis.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in labeling: Bradyarrhythmia and Atrioventricular Blocks [see Warnings and Precautions (5.1) ] Infections [see Warnings and Precautions (5.2) ] Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.3) ] Macular Edema [see Warnings and Precautions (5.4) ] Liver Injury [see Warnings and Precautions (5.5) ] Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.6) ] Respiratory Effects [see Warnings and Precautions (5.7) ] Fetal Risk [see Warnings and Precautions (5.8) ] Severe Increase in Disability After Stopping TASCENSO ODT [see Warnings and Precautions (5.9) ] Tumefactive Multiple Sclerosis [see Warnings and Precautions (5.10) ] Increased Blood Pressure [see Warnings and Precautions (5.11) ] Malignancies [see Warnings and Precautions (5.12) ] Immune System Effects Following TASCENSO ODT Discontinuation [see Warnings and Precautions (5.13) ] Hypersensitivity Reactions [see Warnings and Precautions (5.14) ] Most common adverse reactions (incidence ≥ 10% and greater than placebo): Headache, liver transaminase elevation, diarrhea, cough, influenza, sinusitis, back pain, abdominal pain, and pain in extremity. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Cycle Pharmaceuticals Ltd at 1-888-533-1625 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. Adults In clinical trials (Studies 1, 2, and 3), a total of 1212 patients with relapsing forms of multiple sclerosis received fingolimod 0.5 mg capsules. This included 783 patients who received fingolimod 0.5 mg in the 2-year placebo-controlled trials (Studies 1 and 3) and 429 patients who received fingolimod 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 fingolimod 0.5 mg capsules. In all clinical studies, including uncontrolled extension studies, the exposure to fingolimod 0.5 mg capsules was approximately 4119 person-years. In placebo-controlled trials, the most frequent adverse reactions (incidence ≥ 10% and greater than placebo) for fingolimod 0.5 mg capsules 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 fingolimod 0.5 mg capsules, 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 in clinical studies in adults that occurred in ≥ 1% of fingolimod-treated patients and ≥ 1% higher rate than for placebo. Table 1: Adverse Reactions Reported in Adult Studies 1 and 3 (Occurring in ≥ 1% of Patients and Reported for Fingolimod 0.5 mg Capsules at ≥ 1% Higher Rate than for Placebo) Fingolimod 0.5 mg Capsules N = 783 Placebo N = 773 Adverse Drug Reactions % % 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…