Fingolimod - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS • Infections: Fingolimod 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. • Progressive Multifocal Leukoencephalopathy (PML): Withhold fingolimod at the first sign or symptom suggestive of PML. • 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.

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 if macular edema develops.

Diabetes mellitus and uveitis increase the risk. • 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. • Respiratory Effects: Evaluate when clinically indicated. • 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. ( 5.8 , 8.1 , 8.3 ) • Severe Increase in Disability After Stopping Fingolimod : Monitor for development of severe increase in disability following discontinuation and begin appropriate treatment as needed. • Tumefactive MS : Consider when severe MS relapse occurs during treatment or after discontinuation.

Obtain imaging and begin treatment as needed. • Increased Blood Pressure (BP): Monitor BP in adult and pediatric patients during treatment. • Malignancies: Skin examination prior to or shortly after the start of treatment and periodically thereafter is recommended.

Suspicious skin lesions should be evaluated.

5.1 Bradyarrhythmia and Atrioventricular Blocks Because of a risk for bradyarrhythmia and AV blocks, patients should be monitored during fingolimod treatment initiation [ see Dosage and Administration ].

Reduction in Heart Rate After the first dose of fingolimod, 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-induced bradycardia, or experience serious rhythm disturbances after the first dose of fingolimod.

Prior to treatment with fingolimod, these patients should have a cardiac evaluation by a physician appropriately trained to conduct such evaluation, and if treated with fingolimod, should be monitored overnight with continuous ECG in a medical facility after the first dose.

Since initiation of fingolimod treatment results in decreased heart rate and may prolong the QT interval, patients with a prolonged QTc interval (>450 msec adult and pediatric males, >470 msec adult females, or >460 msec pediatric 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.

Following the second dose, a further decrease in heart rate may occur when compared to the heart rate prior to the second dose, but this change is of a smaller magnitude than that observed following the first dose.