Fingolimod

2 DOSAGE AND ADMINISTRATION · Assessments are required prior to initiating fingolimod capsules. ( 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 ) · First-Dose Monitoring (including reinitiation after discontinuation greater than 14 days and dose increases): o 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 ) o 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 ) o Monitor symptomatic bradycardia with ECG until resolved. Continue overnight if intervention is required; repeat first-dose monitoring for second dose. ( 2.4 ) o 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 Fingolimod Cardiac Evaluation Obtain a cardiac evaluation in patients with certain preexisting conditions [ see 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 fingolimod (i.e., within 6 months), obtain 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 the treatment with fingolimod [see Warnings and Precautions ( 5.4 )] . Skin Examination Obtain a baseline skin examination prior to or shortly after initiation of fingolimod. 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 before initiating treatment with fingolimod [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.4 )] . Vaccinations Test patients for antibodies to varicella zoster virus (VZV) before initiating fingolimod; VZV vaccination of antibody- negative patients is recommended prior to commencing treatment with fingolimod [see Warnings and Precautions ( 5.2 )] . It is recommended that pediatric patients if possible, complete all immunizations in accordance with current immunization guidelines prior to initiating fingolimod therapy. 2.2 Important Administration Instructions Patients who initiate fingolimod 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 [see Dosage and Administration (2.4, 2.5)]. Fingolimod capsules can be taken with or without food. 2.3 Recommended Dosage In adults and pediatric patients 10 years of age and older weighing more than 40 kg, the recommended dosage of fingolimod capsules 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. 2.4 First-Dose Monitoring Initiation of fingolimod capsules treatment results in a decrease in heart rate, for which monitoring is recommended [see Warnings and Precautions ( 5.1 ), Clinical Pharmacology ( 12.2 )]. Prior to dosing and at the end of the observation period, obtain an electrocardiogram (ECG) in all patients. First 6-Hour Monitoring Administer the first dose of fingolimod in a setting in which resources to appropriately manage symptomatic bradycardia are available. Monitor all patients for 6 hours after the first dose for signs and symptoms of bradycardia with hourly pulse and blood pressure measurement. Additional Monitoring After 6-Hour Monitoring Continue monitoring until the abnormality resolves if any of the following is present (even in the absence of symptoms) after 6 hours: the heart rate 6 hours postdose is less than 45 beats per minute (bpm) in adults, less than 55 bpm in pediatric patients 12 years of age and older, or less than 60 bpm in pediatric patients 10 or 11 years of age; 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. If postdose symptomatic bradycardia occurs, initiate appropriate management, begin continuous ECG monitoring, and continue monitoring until the symptoms have resolved if no pharmacological treatment is required. If pharmacological treatment is required, continue monitoring overnight and repeat 6-hour monitoring after the second dose. Overnight Monitoring Continuous overnight ECG monitoring in a medical facility should be instituted: in patients that require pharmacologic intervention for symptomatic bradycardia. In these patients, the first-dose monitoring strategy should be repeated after the second dose of fingolimod; in patients with some preexisting heart and cerebrovascular conditions [see Warnings and Precautions ( 5.1 )]; in patients with a prolonged QTc interval before dosing or during 6-hour observation, or at additional risk for QT prolongation, or on concurrent therapy with QT prolonging drugs with a known risk of torsades de pointes [see Warnings and Precautions ( 5.1 ), Drug Interactions ( 7.1 )]; in patients receiving concurrent therapy with drugs that slow heart rate or AV conduction [ see Drug Interactions ( 7.5 )]. 2.5 Monitoring After Reinitiation of Therapy Following Discontinuation When restarting fingolimod capsules after discontinuation for more than 14 days after the first month of treatment, perform first-dose monitoring, because effects on heart rate and AV conduction may recur on reintroduction of fingolimod capsules treatment [see Dosage and Administration ( 2.4 )] . The same precautions (first-dose monitoring) as for initial dosing are applicable. 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.

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1 INDICATIONS AND USAGE Fingolimod capsules are 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.