Tascenso Odt

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.

• Assessments are required prior to initiating TASCENSO ODT (
  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 ]

  .

  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 ]

  .

  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.
  )
• 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 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 monitoring (unless the previous treatment was discontinued more than 14 days prior)

  [see Dosage and Administration ].

  TASCENSO ODT can be taken with or without food.

  Inform the patient about the following administration instructions for TASCENSO ODT:

  • Store the orally disintegrating tablet (ODT) in the sealed blister until ready to administer.
  • Do not push the ODT through the lidding foil.
  • Use dry hands when opening the blister pack.
  • Peel back the lidding foil from one blister, then push the underside of the foil packet to release the ODT and gently remove the ODT.
  • Take the ODT immediately after opening the blister pack.
  • Place the ODT on the tongue and allow it to dissolve before swallowing.
  • The ODT may be taken with or without water.
  ,
  2.3 Recommended Dosage

  In adults and pediatric patients 10 years of age and older weighing more than 40 kg, the recommended dosage of TASCENSO ODT is

  0.5 mg orally once-daily.

  In pediatric patients 10 years of age and older weighing less than or equal to 40 kg, the recommended dosage of TASCENSO ODT is

  0.25 mg orally once daily.

  Fingolimod doses higher than 0.5 mg are associated with a greater incidence of adverse reactions without additional benefit.
  )
• 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 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 monitoring (unless the previous treatment was discontinued more than 14 days prior)

  [see Dosage and Administration ].

  TASCENSO ODT can be taken with or without food.

  Inform the patient about the following administration instructions for TASCENSO ODT:

  • Store the orally disintegrating tablet (ODT) in the sealed blister until ready to administer.
  • Do not push the ODT through the lidding foil.
  • Use dry hands when opening the blister pack.
  • Peel back the lidding foil from one blister, then push the underside of the foil packet to release the ODT and gently remove the ODT.
  • Take the ODT immediately after opening the blister pack.
  • Place the ODT on the tongue and allow it to dissolve before swallowing.
  • The ODT may be taken with or without water.
  ,
  2.3 Recommended Dosage

  In adults and pediatric patients 10 years of age and older weighing more than 40 kg, the recommended dosage of TASCENSO ODT is

  0.5 mg orally once-daily.

  In pediatric patients 10 years of age and older weighing less than or equal to 40 kg, the recommended dosage of TASCENSO ODT is

  0.25 mg orally once daily.

  Fingolimod doses higher than 0.5 mg are associated with a greater incidence of adverse reactions without additional benefit.
  ).
• Administer TASCENSO ODT with or without water. Place tablet directly on the tongue and allow it to dissolve before swallowing. (
  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 monitoring (unless the previous treatment was discontinued more than 14 days prior)

  [see Dosage and Administration ].

  TASCENSO ODT can be taken with or without food.

  Inform the patient about the following administration instructions for TASCENSO ODT:

  • Store the orally disintegrating tablet (ODT) in the sealed blister until ready to administer.
  • Do not push the ODT through the lidding foil.
  • Use dry hands when opening the blister pack.
  • Peel back the lidding foil from one blister, then push the underside of the foil packet to release the ODT and gently remove the ODT.
  • Take the ODT immediately after opening the blister pack.
  • Place the ODT on the tongue and allow it to dissolve before swallowing.
  • The ODT may be taken with or without water.
  )
• 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 First-Dose Monitoring

    Initiation of TASCENSO ODT 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 TASCENSO ODT 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 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 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 TASCENSO ODT
    • 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)]
      .
    )
  • 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 First-Dose Monitoring

    Initiation of TASCENSO ODT 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 TASCENSO ODT 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 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 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 TASCENSO ODT
    • 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)]
      .
    )
  • Monitor symptomatic bradycardia with ECG until resolved. Continue overnight if intervention is required; repeat first-dose monitoring for second dose. (
    2.4 First-Dose Monitoring

    Initiation of TASCENSO ODT 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 TASCENSO ODT 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 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 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 TASCENSO ODT
    • 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)]
      .
    )
  • 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 First-Dose Monitoring

    Initiation of TASCENSO ODT 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 TASCENSO ODT 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 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 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 TASCENSO ODT
    • 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)]
      .
    ,
    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)].
    )

TASCENSO ODT is available as:

• 0.25 mg orally disintegrating tablets are white to off white, round tablets debossed with .

• 0.5 mg orally disintegrating tablets are white to off white, round tablets debossed with .

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/m²) 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

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.

• Bradyarrhythmia and Atrioventricular Blocks
  : Because of a risk for bradyarrhythmia and AV blocks, monitor during initiation of treatment (
  2.4 First-Dose Monitoring

  Initiation of TASCENSO ODT 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 TASCENSO ODT 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 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 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 TASCENSO ODT
  • 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)]
    .
  ,
  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 disturbances after the first dose of TASCENSO ODT. Prior to treatment with TASCENSO ODT, these patients should have a cardiac evaluation by a physician appropriately trained to conduct such evaluation, and if treated with TASCENSO ODT, should be monitored overnight with continuous ECG in a medical facility after the first dose.

  Since initiation of TASCENSO ODT 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 fingolimod 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. With continued fingolimod dosing, the heart rate returns to baseline within 1 month of chronic treatment. Clinical data indicate effects of TASCENSO ODT on heart rate are maximal after the first dose although milder effects on heart rate may persist for, on average, 2 to 4 weeks after initiation of therapy at which time heart rate generally returns to baseline. Physicians should continue to be alert to patient reports of cardiac symptoms.

  Atrioventricular Blocks

  Initiation of TASCENSO ODT treatment has resulted in transient AV conduction delays. In controlled clinical trials in adult patients, first-degree AV block after the first dose occurred in 4.7% of patients receiving fingolimod capsules and 1.6% of patients on placebo. In a study of 697 patients with available 24-hour Holter monitoring data after their first dose (N = 351 receiving fingolimod capsules and N = 346 on placebo), second-degree AV blocks (Mobitz Types I [Wenckebach] or 2:1 AV blocks) occurred in 4% (N = 14) of patients receiving fingolimod capsules and 2% (N = 7) of patients on placebo. Of the 14 patients receiving fingolimod capsules, 7 patients had 2:1 AV block (5 patients within the first 6 hours postdose and 2 patients after 6 hours postdose). All second-degree AV blocks on placebo were Mobitz Type I and occurred after the first 12 hours postdose. The conduction abnormalities were usually transient and asymptomatic, and resolved within the first 24 hours on treatment, but they occasionally required treatment with atropine or isoproterenol.

  Postmarketing Experience

  In the postmarketing setting, third-degree AV block and AV block with junctional escape have been observed during the first-dose 6-hour observation period with fingolimod. Isolated delayed onset events, including transient asystole and unexplained death, have occurred within 24 hours of the first dose. These events were confounded by concomitant medications and/or preexisting disease, and the relationship to fingolimod is uncertain. Cases of syncope were also reported after the first dose of fingolimod.
  )
• 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 Infections

  Risk of Infections

  TASCENSO ODT causes a dose-dependent reduction in peripheral lymphocyte count to 20%-30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues. TASCENSO ODT may therefore increase the risk of infections, some serious in nature

  [see Clinical Pharmacology (12.2)].

  Life-threatening and fatal infections have occurred in association with fingolimod, the active moiety in TASCENSO ODT.

  Before initiating treatment with TASCENSO ODT, results from a recent CBC (i.e., within 6 months or after discontinuation of prior therapy) should be reviewed. Initiation of treatment with TASCENSO ODT should be delayed in patients with severe active infection until resolution. Because residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, may persist for up to 2 months after discontinuation of TASCENSO ODT, vigilance for infection should be continued throughout this period

  [see Warnings and Precautions (5.13)].

  In MS placebo-controlled trials in adult patients treated with fingolimod capsules, the overall rate of infections (72%) with fingolimod capsules was similar to placebo. However, bronchitis, herpes zoster, influenza, sinusitis, and pneumonia were more common in fingolimod-treated patients. Serious infections occurred at a rate of 2.3% in the fingolimod group versus 1.6% in the placebo group.

  In the postmarketing setting, serious infections with opportunistic pathogens including viruses (e.g., John Cunningham virus (JCV), herpes simplex viruses 1 and 2, varicella zoster virus), fungi (e.g., cryptococci), and bacteria (e.g., atypical mycobacteria) have been reported with fingolimod. Patients with symptoms and signs consistent with any of these infections should undergo prompt diagnostic evaluation and appropriate treatment.

  Herpes Viral Infections

  In placebo-controlled trials in adult patients treated with fingolimod capsules, the rate of herpetic infections was 9% in patients receiving fingolimod 0.5 mg and 7% on placebo.

  Two patients died of herpetic infections during controlled trials. One death was due to disseminated primary herpes zoster and the other was to herpes simplex encephalitis. In both cases, the patients were taking a 1.25 mg dose of fingolimod (higher than the recommended 0.5 mg dose) and had received high-dose corticosteroid therapy to treat suspected MS relapses.

  Serious, life-threatening events of disseminated varicella zoster and herpes simplex infections, including cases of encephalitis and multiorgan failure, have occurred with fingolimod in the postmarketing setting. Include disseminated herpetic infections in the differential diagnosis of patients who are receiving TASCENSO ODT and present with an atypical MS relapse or multiorgan failure.

  Cases of Kaposi's sarcoma have been reported in patients treated with fingolimod in the postmarketing setting. Kaposi's sarcoma is an angioproliferative disorder that is associated with infection with human herpes virus 8 (HHV-8). Patients with symptoms or signs consistent with Kaposi's sarcoma should be referred for prompt diagnostic evaluation and management.

  Cryptococcal Infections

  Cryptococcal infections, including cases of fatal cryptococcal meningitis and disseminated cryptococcal infections, have been reported with fingolimod in the postmarketing setting. Cryptococcal infections have generally occurred after approximately 2 years of fingolimod treatment but may occur earlier. The relationship between the risk of cryptococcal infection and the duration of treatment is unknown. Patients with symptoms and signs consistent with a cryptococcal infection should undergo prompt diagnostic evaluation and treatment.

  Prior and Concomitant Treatment with Antineoplastic, Immunosuppressive, or Immune-Modulating Therapies

  In clinical studies, patients who received fingolimod capsules did not receive concomitant treatment with antineoplastic, non- corticosteroid immunosuppressive, or immune-modulating therapies used for treatment of MS. Concomitant use of TASCENSO ODT with any of these therapies, and also with corticosteroids, would be expected to increase the risk of immunosuppression

  [see Drug Interactions (7.4)]

  .

  When switching to fingolimod from immune-modulating or immunosuppressive medications, consider the duration of their effects and their mode of action to avoid unintended additive immunosuppressive effects.

  Varicella Zoster Virus Antibody Testing/Vaccination

  Patients without a healthcare professional confirmed history of chickenpox or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating TASCENSO ODT. VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with TASCENSO ODT, following which initiation of treatment with TASCENSO ODT should be postponed for 1 month to allow the full effect of vaccination to occur

  [see Drug Interactions (7.3), Use in Specific Populations (8.4)].

  Human Papilloma Virus Infection

  Human papilloma virus (HPV) infections, including papilloma, dysplasia, warts, and HPV-related cancer, have been reported in patients treated with fingolimod in the postmarketing setting. Vaccination against HPV should be considered prior to treatment initiation with TASCENSO ODT, taking into account vaccination recommendations. Cancer screening, including Papanicolaou (Pap) test, is recommended as per standard of care for patients using an immunosuppressive therapy.
  )
• Progressive Multifocal Leukoencephalopathy (PML)
  : Withhold TASCENSO ODT at the first sign or symptom suggestive of PML. (
  5.3 Progressive Multifocal Leukoencephalopathy

  Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients with MS who received fingolimod, the active moiety in TASCENSO ODT, in the postmarketing setting. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. PML has occurred in patients who had not been treated previously with natalizumab, which has a known association with PML, were not taking any other immunosuppressive or immunomodulatory medications concomitantly and did not have any ongoing systemic medical conditions resulting in compromised immune system function. Longer treatment duration increases the risk of PML in fingolimod-treated patients; the majority of cases have occurred in patients treated with fingolimod for at least 18 months.

  At the first sign or symptom suggestive of PML, withhold TASCENSO ODT and perform an appropriate diagnostic evaluation. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.

  Magnetic resonance imaging (MRI) findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with MS medications associated with PML, including fingolimod. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. Lower PML-related mortality and morbidity have been reported following discontinuation of another MS medication associated with PML in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early detection and discontinuation of MS treatment or due to differences in disease in these patients.

  If PML is confirmed, treatment with TASCENSO ODT should be discontinued.

  Immune reconstitution inflammatory syndrome (IRIS) has been reported in patients treated with S1P receptor modulators, including fingolimod, who developed PML and subsequently discontinued treatment. IRIS presents as a clinical decline in the patient’s condition that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes on MRI. The time to onset of IRIS in patients with PML was generally within a few months after S1P receptor modulator discontinuation. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken.
  )
• 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 Macular Edema

  S1P receptor modulators, including TASCENSO ODT, have been associated with an increased risk of macular edema. Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with TASCENSO ODT. Perform an examination of the fundus, including the macula, 3 to 4 months after starting treatment, periodically while on therapy, and any time there is a change in vision.

  A dose-dependent increase in the risk of macular edema occurred in the fingolimod capsules clinical development program.

  In 2-year double-blind, placebo-controlled studies in adult patients with multiple sclerosis, macular edema with or without visual symptoms occurred in 1.5% of patients (11/799) treated with fingolimod 1.25 mg capsules, 0.5% of patients (4/783) treated with fingolimod 0.5 mg capsules, and 0.4% of patients (3/773) treated with placebo. Macular edema occurred predominantly during the first 3 to 4 months of therapy. These clinical trials excluded patients with diabetes mellitus, a known risk factor for macular edema (see below

  Macular Edema in Patients with History of Uveitis or Diabetes Mellitus).

  Symptoms of macular edema included blurred vision and decreased visual acuity. Routine ophthalmological examination detected macular edema in some patients with no visual symptoms. Macular edema generally partially or completely resolved with or without treatment after drug discontinuation. Some patients had residual visual acuity loss even after resolution of macular edema. Macular edema has also been reported in patients taking fingolimod in the postmarketing setting, usually within the first 6 months of treatment.

  Continuation of TASCENSO ODT in patients who develop macular edema has not been evaluated. Macular edema over an extended period of time (i.e., 6 months) can lead to permanent visual loss. Consider discontinuing TASCENSO ODT if macular edema develops; this decision should include an assessment of the potential benefits and risks for the individual patient. The risk of recurrence after rechallenge has not been evaluated.

  Macular Edema in Patients with History of Uveitis or Diabetes Mellitus

  Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema during TASCENSO ODT therapy. In the combined clinical trial experience in adult patients with all doses of fingolimod capsules, the rate of macular edema was higher in MS patients with a history of uveitis compared to those without a history of uveitis (approximately 20% versus 0.6%, respectively). Fingolimod, the active moiety in TASCENSO ODT, has not been tested in MS patients with diabetes mellitus.
  )
• 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 Liver Injury

  Clinically significant liver injury has occurred in patients treated with fingolimod in the postmarketing setting. Signs of liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, have occurred as early as ten days after the first dose and have also been reported after prolonged use. Cases of acute liver failure requiring liver transplant have been reported.

  In 2-year placebo-controlled clinical trials in adult patients, elevation of liver enzymes (ALT, AST and GGT) to 3-fold the upper limit of normal (ULN) or greater occurred in 14% of patients treated with fingolimod 0.5 mg capsules and 3% of patients on placebo. Elevations 5-fold the ULN or greater occurred in 4.5% of patients on fingolimod capsules and 1% of patients on placebo. The majority of elevations occurred within 6 to 9 months. In clinical trials, fingolimod capsules were discontinued if the elevation exceeded 5 times the ULN. Serum transaminase levels returned to normal within approximately 2 months after discontinuation of fingolimod capsules. Recurrence of liver transaminase elevations occurred with rechallenge in some patients.

  Prior to starting treatment with TASCENSO ODT (within 6 months), obtain serum transaminases (ALT and AST) and total bilirubin levels. Obtain transaminase levels and total bilirubin levels periodically until two months after TASCENSO ODT discontinuation.

  Patients should be monitored for signs and symptoms of any hepatic injury. Measure liver transaminase and bilirubin levels promptly in patients who report symptoms that may indicate liver injury, including new or worsening fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. In this clinical context, if the patient is found to have an alanine aminotransferase (ALT) greater than three times the reference range with serum total bilirubin greater than two times the reference range, treatment with TASCENSO ODT treatment should be interrupted. Treatment should not be resumed if a plausible alternative etiology for the signs and symptoms cannot be established, because these patients are at risk for severe drug-induced liver injury.

  Because fingolimod exposure is doubled in patients with severe hepatic impairment, these patients should be closely monitored during treatment with TASCENSO ODT, as the risk of adverse reactions is greater

  [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
  ,
  8.6 Hepatic Impairment

  Because fingolimod, but not fingolimod-phosphate, exposure is doubled in patients with severe hepatic impairment, patients with severe hepatic impairment should be closely monitored, as the risk of adverse reactions may be greater

  [see Warnings and Precautions (5.6)

  ,

  Clinical Pharmacology (12.3)].

  No dose adjustment is needed in patients with mild or moderate hepatic impairment.
  ,
  12.3 Pharmacokinetics

  Absorption

  The T_maxof fingolimod is 12 to 16 hours. The apparent absolute oral bioavailability is 93%.

  Food intake does not alter C_maxor (AUC) of fingolimod or fingolimod-phosphate. Therefore, TASCENSO ODT may be taken without regard to meals.

  Steady-state blood concentrations of fingolimod are reached within 1 to 2 months following once-daily administration and steady-state levels are approximately 10-fold greater than with the initial dose.

  Distribution

  Fingolimod highly (86%) distributes in red blood cells. Fingolimod-phosphate has a smaller uptake in blood cells of < 17%. Fingolimod and fingolimod-phosphate are > 99.7% protein bound. Fingolimod and fingolimod-phosphate protein binding is not altered by renal or hepatic impairment.

  Fingolimod is extensively distributed to body tissues with a volume of distribution of about 1200 ± 260 L.

  Metabolism

  The biotransformation of fingolimod in humans occurs by 3 main pathways: by reversible stereoselective phosphorylation to the pharmacologically active (

  S

  )-enantiomer of fingolimod-phosphate, by oxidative biotransformation catalyzed mainly by the cytochrome P450 4F2 (CYP4F2) and possibly other CYP4F isoenzymes with subsequent fatty acid-like degradation to inactive metabolites, and by formation of pharmacologically inactive non-polar ceramide analogs of fingolimod.

  Inhibitors or inducers of CYP4F2 and possibly other CYP4F isozymes might alter the exposure of fingolimod or fingolimod-phosphate.

  In vitro

  studies in hepatocytes indicated that CYP3A4 may contribute to fingolimod metabolism in the case of strong induction of CYP3A4.

  Following single oral administration of [¹⁴C] fingolimod, the major fingolimod-related components in blood, as judged from their contribution to the AUC up to 816 hours post-dose of total radiolabeled components, are fingolimod itself (23.3%), fingolimod-phosphate (10.3%), and inactive metabolites [M3 carboxylic acid metabolite (8.3%), M29 ceramide metabolite (8.9%), and M30 ceramide metabolite (7.3%)].

  Elimination

  Fingolimod blood clearance is 6.3 ± 2.3 L/h, and the average apparent terminal half-life (t_1/2) is 6 to 9 days. Blood levels of fingolimod-phosphate decline in parallel with those of fingolimod in the terminal phase, yielding similar half-lives for both.

  After oral administration, about 81% of the dose is slowly excreted in the urine as inactive metabolites. Fingolimod and fingolimod-phosphate are not excreted intact in urine but are the major components in the feces with amounts of each representing less than 2.5% of the dose.

  Specific Populations

  Pediatric Patients

  The median fingolimod-phosphate (fingolimod-P) concentration in pediatric MS patients aged 10 to less than 18 years was 1.10 ng/mL, as compared to 1.35 ng/mL in adult MS patients.

  Geriatric Patients

  
  
  The mechanism for elimination and results from population pharmacokinetics suggest that dose adjustment would not be necessary in elderly patients. However, clinical experience in patients aged above 65 years is limited.

  Gender

  Gender has no clinically significant influence on fingolimod and fingolimod-phosphate pharmacokinetics.

  Race

  The effects of race on fingolimod and fingolimod-phosphate pharmacokinetics cannot be adequately assessed due to a low number of patients who self-identified as Black or African American, Asian, or other races in the clinical program.

  Renal Impairment

  In adult patients with severe renal impairment, fingolimod C_maxand AUC are increased by 32% and 43%, respectively, and fingolimod-phosphate C_maxand AUC are increased by 25% and 14%, respectively, with no change in apparent elimination half-life. Based on these findings, the TASCENSO ODT 0.5 mg dose is appropriate for use in adult patients with renal impairment. TASCENSO ODT 0.25 mg and 0.5 mg are appropriate for use in pediatric patients with renal impairment. The systemic exposure of 2 metabolites (M2 and M3) is increased by 3-and 13-fold, respectively. The toxicity of these metabolites has not been fully characterized.

  A study in patients with mild or moderate renal impairment has not been conducted.

  Hepatic Impairment

  In subjects with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, and C), no change in fingolimod C_maxwas observed, but fingolimod AUC_0-∞was increased respectively by 12%, 44%, and 103%. In patients with severe hepatic impairment (Child-Pugh class C), fingolimod-phosphate C_maxwas decreased by 22% and AUC_0-96hours was decreased by 29%. The pharmacokinetics of fingolimod-phosphate was not evaluated in patients with mild or moderate hepatic impairment. The apparent elimination half-life of fingolimod is unchanged in subjects with mild hepatic impairment but is prolonged by about 50% in patients with moderate or severe hepatic impairment.

  Patients with severe hepatic impairment (Child-Pugh class C) should be closely monitored, as the risk of adverse reactions is greater

  [see Warnings and Precautions (5.6)].

  No dose adjustment is needed in patients with mild or moderate hepatic impairment (Child-Pugh class A and B).

  Drug Interactions

  Ketoconazole

  The coadministration of ketoconazole (a potent inhibitor of CYP3A and CYP4F) 200 mg twice-daily at steady-state and a single dose of fingolimod 5 mg led to a 70% increase in AUC of fingolimod and fingolimod-phosphate. Patients who use TASCENSO ODT and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is greater

  [see Drug Interactions (7.2)].

  Carbamazepine

  The coadministration of carbamazepine (a potent CYP450 enzyme inducer) 600 mg twice-daily at steady-state and a single dose of fingolimod 2 mg decreased blood concentrations (AUC) of fingolimod and fingolimod-phosphate by approximately 40%. The clinical impact of this decrease is unknown.

  Other strong CYP450 enzyme inducers, e.g., rifampicin, phenytoin, phenobarbital, and St. John's wort, may also reduce AUC of fingolimod and fingolimod-phosphate. The clinical impact of this potential decrease is unknown.

  Potential of Fingolimod and Fingolimod-phosphate to Inhibit the Metabolism of Comedications

  In vitro

  inhibition studies using pooled human liver microsomes and specific metabolic probe substrates demonstrate that fingolimod has little or no capacity to inhibit the activity of the following CYP enzymes: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or CYP4A9/11 (fingolimod only), and similarly fingolimod-phosphate has little or no capacity to inhibit the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 at concentrations up to 3 orders of magnitude of therapeutic concentrations. Therefore, fingolimod and fingolimod-phosphate are unlikely to reduce the clearance of drugs that are mainly cleared through metabolism by the major CYP isoenzymes described above.

  Potential of Fingolimod and Fingolimod-phosphate to Induce its Own and/or the Metabolism of Comedications

  Fingolimod was examined for its potential to induce human CYP3A4, CYP1A2, CYP4F2, and MDR1 (P-glycoprotein) mRNA and CYP3A, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP4F2 activity in primary human hepatocytes. Fingolimod did not induce mRNA or activity of the different CYP enzymes and MDR1 with respect to the vehicle control; therefore, no clinically relevant induction of the tested CYP enzymes or MDR1 by fingolimod are expected at therapeutic concentrations. Fingolimod-phosphate was also examined for its potential to induce mRNA and/or activity of human CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A, CYP4F2, CYP4F3B, and CYP4F12. Fingolimod-phosphate is not expected to have clinically significant induction effects on these enzymes at therapeutic doses of fingolimod.

  In vitro

  experiments did not provide an indication of CYP induction by fingolimod-phosphate.

  Transporters

  Based on

  in vitro

  data, fingolimod as well as fingolimod-phosphate are not expected to inhibit the uptake of comedications and/or biologics transported by the organic anion transporting polypeptides OATP1B1, OATP1B3, or the sodium taurocholate co-transporting polypeptide (NTCP). Similarly, they are not expected to inhibit the efflux of comedications and/or biologics transported by the breast cancer resistance protein (BCRP), the bile salt export pump (BSEP), the multidrug resistance-associated protein 2 (MRP2), or P-glycoprotein (P-gp) at therapeutic concentrations.

  Oral Contraceptives

  The coadministration of fingolimod 0.5 mg capsules daily with oral contraceptives (ethinylestradiol and levonorgestrel) did not elicit any clinically significant change in oral contraceptives exposure. Fingolimod and fingolimod-phosphate exposure were consistent with those from previous studies. No interaction studies have been performed with oral contraceptives containing other progestagens; however, an effect of fingolimod on their exposure is not expected.

  Cyclosporine

  The pharmacokinetics of single-dose fingolimod was not altered during coadministration with cyclosporine at steady-state, nor was cyclosporine steady-state pharmacokinetics altered by fingolimod. These data indicate that TASCENSO ODT is unlikely to reduce or increase the clearance of drugs cleared mainly by CYP3A4. Potent inhibition of transporters MDR1 (P-gp), MRP2, and OATP-1B1 does not influence fingolimod disposition.

  Isoproterenol, Atropine, Atenolol, and Diltiazem

  Single-dose fingolimod and fingolimod-phosphate exposure was not altered by coadministered isoproterenol or atropine. Likewise, the single-dose pharmacokinetics of fingolimod and fingolimod-phosphate and the steady-state pharmacokinetics of both atenolol and diltiazem were unchanged during the coadministration of the latter 2 drugs individually with fingolimod.

  Population Pharmacokinetics Analysis

  A population pharmacokinetics evaluation performed in MS patients did not provide evidence for a significant effect of fluoxetine and paroxetine (strong CYP2D6 inhibitors) on fingolimod or fingolimod-phosphate predose concentrations. In addition, the following commonly coprescribed substances had no clinically relevant effect (< 20%) on fingolimod or fingolimod-phosphate predose concentrations: baclofen, gabapentin, oxybutynin, amantadine, modafinil, amitriptyline, pregabalin, and corticosteroids.
  )
• Posterior Reversible Encephalopathy Syndrome (PRES)
  : If suspected, discontinue TASCENSO ODT. (
  5.6 Posterior Reversible Encephalopathy Syndrome

  There have been rare cases of posterior reversible encephalopathy syndrome (PRES) reported in adult patients receiving fingolimod. Symptoms reported included sudden onset of severe headache, altered mental status, visual disturbances, and seizure. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, TASCENSO ODT should be discontinued.
  )
• Respiratory Effects
  : Evaluate when clinically indicated. (
  5.7 Respiratory Effects

  Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) and diffusion lung capacity for carbon monoxide (DLCO) were observed in patients treated with fingolimod, the active moiety in TASCENSO ODT, as early as 1 month after treatment initiation. In 2-year placebo-controlled trials in adult patients, the reduction from baseline in the percent of predicted values for FEV1 at the time of last assessment on drug was 2.8% for fingolimod 0.5 mg capsules and 1.0% for placebo. For DLCO, the reduction from baseline in percent of predicted values at the time of last assessment on drug was 3.3% for fingolimod 0.5 mg capsules and 0.5% for placebo. The changes in FEV1 appear to be reversible after treatment discontinuation. There is insufficient information to determine the reversibility of the decrease of DLCO after drug discontinuation. In MS placebo-controlled trials in adult patients, dyspnea was reported in 9% of patients receiving fingolimod 0.5 mg capsules and 7% of patients receiving placebo. Several patients discontinued fingolimod capsules because of unexplained dyspnea during the extension (uncontrolled) studies. Fingolimod, the active moiety in TASCENSO ODT, has not been tested in MS patients with compromised respiratory function.

  Spirometric evaluation of respiratory function and evaluation of DLCO should be performed during therapy with TASCENSO ODT if 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 TASCENSO ODT. (
  5.8 Fetal Risk

  Based on findings from animal studies, TASCENSO ODT may cause fetal harm when administered to a pregnant woman. In animal reproduction studies conducted in rats and rabbits, developmental toxicity was observed with administration of fingolimod at doses less than the recommended human dose. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Because it takes approximately 2 months to eliminate fingolimod from the body, advise females of reproductive potential to use effective contraception to avoid pregnancy during and for 2 months after stopping TASCENSO ODT treatment

  [see Use in Specific Populations (8.1, 8.3)]

  .
  ,
  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/m²) 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/m²basis. 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/m²basis.

  
  
  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/m²basis.
  ,
  8.3 Females and Males of Reproductive Potential

  Pregnancy Testing

  The pregnancy status of females of reproductive potential should be verified prior to starting treatment with TASCENSO ODT

  [see Use in Specific Populations (8.1)].

  Contraception

  Before initiation of TASCENSO ODT, females of reproductive potential should be counseled on the potential for a serious risk to the fetus and the need for effective contraception during treatment with TASCENSO ODT

  [see Warnings and Precautions (5.9)and Use in Specific Populations (8.1)]

  . Since it takes approximately 2 months to eliminate the compound from the body after stopping treatment, the potential risk to the fetus may persist and women should use effective contraception during this period

  [see Warnings and Precautions (5.8, 5.13)]

  .
  )
• 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 Severe Increase in Disability After Stopping TASCENSO ODT

  Severe increase in disability accompanied by multiple new lesions on MRI has been reported after discontinuation of fingolimod in the postmarketing setting. Patients in most of these reported cases did not return to the functional status they had before stopping fingolimod. The increase in disability generally occurred within 12 weeks after stopping fingolimod but was reported up to 24 weeks after fingolimod discontinuation.

  Monitor patients for development of severe increase in disability following discontinuation of TASCENSO ODT and begin appropriate treatment as needed.

  After stopping TASCENSO ODT in the setting of PML, monitor for development of immune reconstitution inflammatory syndrome (PML-IRIS)

  [see Warnings and Precautions ].
  )
• Tumefactive MS
  : Consider when severe MS relapse occurs during treatment or after discontinuation. Obtain imaging and begin treatment as needed. (
  5.10 Tumefactive Multiple Sclerosis

  MS relapses with tumefactive demyelinating lesions on imaging have been observed during fingolimod therapy and after fingolimod discontinuation in the postmarketing setting. Most reported cases of tumefactive MS in patients receiving fingolimod have occurred within the first 9 months after fingolimod initiation, but tumefactive MS may occur at any point during treatment. Cases of tumefactive MS have also been reported within the first 4 months after fingolimod discontinuation.

  Tumefactive MS should be considered when a severe MS relapse occurs during TASCENSO ODT treatment, especially during initiation, or after discontinuation of TASCENSO ODT, prompting imaging evaluation and initiation of appropriate treatment.
  )
• Increased Blood Pressure (BP)
  : Monitor BP during treatment. (
  5.11 Increased Blood Pressure

  In adult MS controlled clinical trials, patients treated with fingolimod 0.5 mg capsules had an average increase over placebo of approximately 3 mmHg in systolic pressure, and approximately 2 mmHg in diastolic pressure, first detected after approximately 1 month of fingolimod treatment initiation and persisting with continued treatment. Hypertension was reported as an adverse reaction in 8% of patients on fingolimod 0.5 mg capsules and in 4% of patients on placebo. Blood pressure should be monitored during treatment with TASCENSO ODT.
  )
• 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 Malignancies

  Cutaneous Malignancies

  The risk of cutaneous malignancies (including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma) is increased in patients treated with S1P receptor modulators. Use of fingolimod, the active moiety in TASCENSO ODT, has been associated with an increased risk of BCC and melanoma.

  In two-year placebo-controlled trials in adult patients, the incidence of BCC was 2% in patients on fingolimod 0.5 mg capsules and 1% in patients on placebo

  [see Adverse Reactions ]

  . Melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi’s sarcoma

  [see Warnings and Precautions ]

  , and Merkel cell carcinoma have been reported with fingolimod in the postmarketing setting.

  Skin examinations are recommended prior to or shortly after the start of treatment and periodically thereafter for all patients, particularly those with risk factors for skin cancer. Providers and patients are advised to monitor for suspicious skin lesions. If a suspicious skin lesion is observed, it should be promptly evaluated. As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Concomitant phototherapy with UV-B radiation or PUVA photochemotherapy is not recommended in patients taking TASCENSO ODT.

  Lymphoma

  Cases of lymphoma, including both T-cell and B-cell types and CNS lymphoma, have occurred in patients receiving fingolimod, the active moiety in TASCENSO ODT. The reporting rate of non-Hodgkin lymphoma with fingolimod is greater than that expected in the general population adjusted by age, gender, and region. Cutaneous T-cell lymphoma (including mycosis fungoides) has also been reported with fingolimod in the postmarketing setting.
  )