Fingolimod .5 mg Capsule, 30-count — NDC 72205-227-30 (Billing 72205-0227-30)

5 WARNINGS AND PRECAUTIONS Infections : Fingolimod Capsules may increase the risk. Obtain a complete blood count (CBC) before initiating treatment. 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 Fingolimod Capsules 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 fingolimod capsules. 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 fingolimod capsules 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 Fingolimod Capsules. ( 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 Fingolimod Capsules. ( 5.8 , 8.1 , 8.3 ) Severe Increase in Disability After Stopping Fingolimod Capsules : 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 in adult and pediatric patients 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 )

5.1Bradyarrhythmia and Atrioventricular Blocks Because of a risk for bradyarrhythmia and AV blocks, patients should be monitored during Fingolimod Capsules treatment initiation [ see Dosage and Administration (2.4) ]. Reduction in Heart Rate After the first dose of Fingolimod Capsules, 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 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 Capsules 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 Fingolimod Capsules-induced bradycardia, or experience serious rhythm disturbances after the first dose of Fingolimod Capsules.

Prior to treatment with Fingolim…

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 Fingolimod Capsules [ 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 Fingolimod Capsules 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 Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 1,212 patients with relapsing forms of multiple sclerosis received Fingolimod Capsules 0.5 mg. This included 783 patients who received Fingolimod Capsules 0.5 mg in the 2-year placebo-controlled trials (Studies 1 and 3) and 429 patients who received Fingolimod Capsules 0.5 mg in the 1-year active-controlled trial (Study 2).

The overall exposure in the controlled trials was equivalent to 1,716 person-years. Approximately 1,000 patients received at least 2 years of treatment with Fingolimod Capsules 0.5 mg. In all clinical studies, including uncontrolled extension studies, the exposure to Fingolimod Capsules 0.5 mg was approximately 4,119 person-years.

In placebo-controlled trials, the most frequent adverse reactions (incidence ≥10% and greater than placebo) for Fingolimod Capsules 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 Fingolimod Capsules 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 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 Capsules 0.5 mg at ≥1% Higher Rate Than for Placebo) Adverse drug reactions Fingolimod Capsules 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 diso…

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 fingolimod treatment. ( 5.2 , 7.3 )

7.1QT Prolonging Drugs Fingolimod Capsules 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 Fingolimod Capsules 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) ].

7.2Ketoconazole The blood levels of fingolimod and fingolimod-phosphate are increased by 1.7-fold when used concomitantly with ketoconazole. Patients who use Fingolimod Capsules and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is increased.

7.3Vaccines Fingolimod Capsules reduces the immune response to vaccination. Vaccination may be less effective during and for up to 2 months after discontinuation of treatment with Fingolimod Capsules [ see Clinical Pharmacology (12.2) ] . Avoid the use of live attenuated vaccines during and for 2 months after treatment with Fingolimod Capsules 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 Fingolimod Capsules therapy.

7.4Antineoplastic, 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 Fingolimod Capsules. 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 Fingolimod Capsules [ see Warnings and Precautions (5.2) ].

7.5Drugs That Slow Heart Rate or Atrioventricular Conduction (e.g., beta blockers or diltiazem) Experience with Fingolimod Capsules 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 Fingolimod Capsules treatment may result in an additional decrease in heart rate, concomitant use of these drugs during Fingolimod Capsules 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 Fingolimod Capsules. 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) ].

7.6Laboratory Test Interaction Because Fingolimod Capsules 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 Capsules. A recent CBC should be available before initiating treatment with Fingolimod Capsules.