FINGOLIMOD: 70,944 Adverse Event Reports & Safety Profile

Fingolimod is a sphingosine 1-phosphate receptor modulator. Chemically, fingolimod is 2-amino-2-[2-(4-octylphenyl)ethyl]propan-1,3-diol hydrochloride. Its structure is shown below: Fingolimod hydrochloride is a white to practically white powder that is freely soluble in water and alcohol and soluble in propylene glycol. It has a molecular weight of 343.93 g/mol. GILENYA is provided as 0.25 mg and 0.5 mg hard gelatin capsules for oral use.

Each

0.25 mg capsule contains 0.28 mg of fingolimod hydrochloride, equivalent to 0.25 mg fingolimod.

Each

0.5 mg capsule contains 0.56 mg of fingolimod hydrochloride, equivalent to 0.5 mg of fingolimod. Each GILENYA 0.25 mg capsule contains the following inactive ingredients: gelatin, hydroxypropylbetadex, hydroxypropylcellulose, magnesium stearate, mannitol, titanium dioxide, and yellow iron oxide. Each GILENYA 0.5 mg capsule contains the following inactive ingredients: gelatin, magnesium stearate, mannitol, titanium dioxide, and yellow iron oxide. Fingolimod chemical structure

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. Fingolimod hydrochloride 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 )

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 )
• Recommended dosage for pediatric patients (10 years of age and above) weighing less than or equal to 40 kg: 0.25 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 Capsules Cardiac Evaluation Obtain a cardiac evaluation in patients with certain preexisting conditions <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> . Prior to starting treatment, determine whether patients are taking drugs that could slow heart rate or atrioventricular (AV) conduction <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 ), Drug Interactions ( 7.5 )]</span> .

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 capsules (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 capsules [see Warnings and Precautions ( 5.4 )] .

Skin Examination

Obtain a baseline skin examination prior to or shortly after initiation of fingolimod capsules. 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 capsules [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.4 )] .

Vaccinations

Test patients for antibodies to varicella zoster virus (VZV) before initiating fingolimod capsules; VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with fingolimod capsules [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 capsules therapy.

2.2 Important Administration Instructions Patients who initiate fingolimod capsules, 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 , 2.5 )]</span> . 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. In pediatric patients 10 years of age and older weighing less than or equal to 40 kg, the recommended dosage of fingolimod capsules 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.

2.4 First-Dose Monitoring Initiation of fingolimod capsules treatment results in a decrease in heart rate, for which monitoring is recommended <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 ), Clinical Pharmacology ( 12.2 )]</span> . 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 capsules 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 capsules;
• 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span> . 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.

Fingolimod capsules are contraindicated in patients who have:

• in the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (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 fingolimod capsules. Observed reactions include rash, urticaria and angioedema upon treatment initiation [see Warnings and Precautions ( 5.14 )].
• Recent myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), 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 )

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 Solco Healthcare US, LLC at 1-866-257-2597 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 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 capsules-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)

Fingolimod Capsules

0.5 mg Placebo Adverse drug reactions N = 783 % 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 disorders Cough 12 11 Dyspnea 9 7 Eye disorders Vision blurred 4 2 Vascular disorders Hypertension 8 4 Blood and lymphatic system disorders Lymphopenia 7 < 1 Leukopenia 2 < 1 Neoplasms benign, malignant, and unspecified (including cysts and polyps) Skin papilloma 3 2 Basal cell carcinoma 2 1 Abbreviations: ALT, alanine transaminase; AST, aspartate transferase; GGT, gamma-glutamyl transferase. Adverse reactions of seizure, dizziness, pneumonia, eczema, and pruritus were also reported in Studies 1 and 3, but did not meet the reporting rate criteria for inclusion in Table 1 (difference was less than 1%). Adverse reactions with fingolimod capsules 0.5 mg in Study 2, the 1-year active-controlled (versus interferon beta-1a) study were generally similar to those in Studies 1 and 3.

Vascular Events

Vascular events, including ischemic and hemorrhagic strokes, and peripheral arterial occlusive disease were reported in premarketing clinical trials in patients who received fingolimod capsules doses (1.25 mg to 5 mg) higher than recommended for use in MS. Similar events have been reported with fingolimod capsules in the postmarketing setting although a causal relationship has not been established.

Seizure

Cases of seizures, including status epilepticus, have been reported with the use of fingolimod capsules in clinical trials and in the postmarketing setting in adults [see Adverse Reactions ( 6.2 )]. In adult clinical trials, the rate of seizures was 0.9% in fingolimod capsules-treated patients and 0.3% in placebo-treated patients. It is unknown whether these events were related to the effects of multiple sclerosis alone, to fingolimod capsules, or to a combination of both.

Pediatric Patients

10 Years of Age and Older In the controlled pediatric trial (Study 4), the safety profile in pediatric patients receiving fingolimod capsules 0.25 mg or 0.5 mg daily was similar to that seen in adult patients. In the pediatric study, cases of seizures were reported in 5.6% of fingolimod capsules -treated patients and 0.9% of interferon beta-1a-treated patients [see Use in Specific Populations ( 8.4 )] .

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of fingolimod capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Hemolytic anemia and thrombocytopenia Hepatobiliary Disorders: Liver injury <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.5 )]</span> Infections: Infections, including cryptococcal infections <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span>, human papilloma virus (HPV) infection, including papilloma, dysplasia, warts and HPV-related cancer <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> , progressive multifocal leukoencephalopathy <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span> Musculoskeletal and connective tissue disorders: Arthralgia, myalgia Nervous System Disorders: Posterior reversible encephalopathy syndrome <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.6 )]</span>, seizures, including status epilepticus <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> Neoplasms, Benign, Malignant, and Unspecified (including cysts and polyps): melanoma, Merkel cell carcinoma, cutaneous T-cell lymphoma (including mycosis fungoides), Kaposi’s sarcoma, squamous cell carcinoma <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.12 )]</span> Skin and Subcutaneous Tissue Disorders: Hypersensitivity <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.14 )]</span>

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 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 Fingolimod Capsules treatment initiation <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span> . 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 Fingolimod Capsules, these patients should have a cardiac evaluation by a physician appropriately trained to conduct such evaluation, and if treated with Fingolimod Capsules, should be monitored overnight with continuous ECG in a medical facility after the first dose. Since initiation of Fingolimod Capsules 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. With continued dosing, the heart rate returns to baseline within 1 month of chronic treatment. Clinical data indicate effects of Fingolimod Capsules 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 Fingolimod Capsules 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 Capsules. 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 Capsules is uncertain. Cases of syncope were also reported after the first dose of Fingolimod Capsules.

5.2 Infections Risk of Infections Fingolimod Capsules causes a dose-dependent reduction in peripheral lymphocyte count to 20% to 30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues.

Fingolimod

Capsules 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 Capsules. Before initiating treatment with Fingolimod Capsules, a recent CBC (i.e., within 6 months or after discontinuation of prior therapy) should be available. Consider suspending treatment with Fingolimod Capsules if a patient develops a serious infection, and reassess the benefits and risks prior to reinitiation of therapy. Because the elimination of fingolimod after discontinuation may take up to 2 months, continue monitoring for infections throughout this period. Instruct patients receiving Fingolimod Capsules to report symptoms of infections to a physician. Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. In MS placebo-controlled trials in adult patients, 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 Capsules 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 Capsules. 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, the rate of herpetic infections was 9% in patients receiving Fingolimod Capsules 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 Capsules in the postmarketing setting. Include disseminated herpetic infections in the differential diagnosis of patients who are receiving Fingolimod Capsules and present with an atypical MS relapse or multiorgan failure. Cases of Kaposi’s sarcoma have been reported 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 Capsules in the postmarketing setting. Cryptococcal infections have generally occurred after approximately 2 years of Fingolimod Capsules 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 Fingolimod Capsules 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 Capsules 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 Fingolimod Capsules. VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with Fingolimod Capsules, following which initiation of treatment with Fingolimod Capsules 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 Capsules in the postmarketing setting. Vaccination against HPV should be considered prior to treatment initiation with Fingolimod Capsules, taking into account vaccination recommendations. Cancer screening, including Papanicolaou (Pap) test, is recommended as per standard of care for patients using an immunosuppressive therapy.

5.3 Progressive Multifocal Leukoencephalopathy Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients with MS who received Fingolimod Capsules 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 capsules-treated patients; the majority of cases have occurred in patients treated with fingolimod capsules for at least 18 months. At the first sign or symptom suggestive of PML, withhold Fingolimod Capsules 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 Capsules. 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 Fingolimod Capsules should be discontinued. Immune reconstitution inflammatory syndrome (IRIS) has been reported in patients treated with S1P receptor modulators, including Fingolimod Capsules, 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.

5.4 Macular Edema S1P receptor modulators, including fingolimod capsules, 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 fingolimod capsules. 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, 0.5% of patients (4/783) treated with Fingolimod Capsules 0.5 mg, 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 Capsules in the postmarketing setting, usually within the first 6 months of treatment. Continuation of Fingolimod Capsules 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 fingolimod capsules 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 Fingolimod Capsules therapy. In the combined clinical trial experience in adult patients with all doses of fingolimod, 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

Capsules has not been tested in MS patients with diabetes mellitus.

5.5 Liver Injury Clinically significant liver injury has occurred in patients treated with Fingolimod Capsules 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 Capsules 0.5 mg 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 was 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 Fingolimod Capsules (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 Fingolimod Capsules 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 Fingolimod Capsules 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

Capsules exposure is doubled in patients with severe hepatic impairment, these patients should be closely monitored, as the risk of adverse reactions is greater [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )].

5.6 Posterior Reversible Encephalopathy Syndrome There have been rare cases of posterior reversible encephalopathy syndrome (PRES) reported in adult patients receiving Fingolimod Capsules. 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, Fingolimod Capsules should be discontinued.

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 Capsules 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 Capsules 0.5 mg and 1% 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 Capsules 0.5 mg 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 Capsules 0.5 mg and 7% of patients receiving placebo. Several patients discontinued Fingolimod Capsules because of unexplained dyspnea during the extension (uncontrolled) studies.

Fingolimod

Capsules 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 Fingolimod Capsules if clinically indicated.

5.8 Fetal Risk Fingolimod Capsules 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. Available observational pregnancy registry data suggest that use of Fingolimod Capsule is associated with an increased prevalence of major birth defects in comparison to the general population. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Because it takes approximately 2 months to eliminate Fingolimod Capsules from the body, advise females of reproductive potential to use effective contraception to avoid pregnancy during and for 2 months after stopping Fingolimod Capsules treatment [ see Use in Specific Populations (8.1 , 8.3 )].

5.9 Severe Increase in Disability After Stopping Fingolimod Capsules Severe increase in disability accompanied by multiple new lesions on MRI has been reported after discontinuation of Fingolimod Capsules in the postmarketing setting. Patients in most of these reported cases did not return to the functional status they had before stopping Fingolimod Capsules. The increase in disability generally occurred within 12 weeks after stopping Fingolimod Capsules, but was reported up to 24 weeks after Fingolimod Capsules discontinuation. Monitor patients for development of severe increase in disability following discontinuation of Fingolimod Capsules and begin appropriate treatment as needed. After stopping Fingolimod Capsules in the setting of PML, monitor for development of immune reconstitution inflammatory syndrome (PML-IRIS) <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span>.

5.10 Tumefactive Multiple Sclerosis MS relapses with tumefactive demyelinating lesions on imaging have been observed during Fingolimod Capsules therapy and after Fingolimod Capsules discontinuation in the postmarketing setting. Most reported cases of tumefactive MS in patients receiving Fingolimod Capsules have occurred within the first 9 months after Fingolimod Capsules 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 Capsules discontinuation. Tumefactive MS should be considered when a severe MS relapse occurs during Fingolimod Capsules treatment, especially during initiation, or after discontinuation of Fingolimod Capsules, prompting imaging evaluation and initiation of appropriate treatment.

5.11 Increased Blood Pressure Increases in blood pressure have been observed in patients treated with Fingolimod Capsules. In adult MS controlled clinical trials, patients treated with Fingolimod Capsules 0.5 mg 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 treatment initiation, and persisting with continued treatment. Hypertension was reported as an adverse reaction in 8% of patients on Fingolimod Capsules 0.5 mg and in 4% of patients on placebo. Monitor blood pressure (BP) in adult and pediatric patients during treatment with Fingolimod Capsules.

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 capsules 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 Capsules 0.5 mg and 1% in patients on placebo <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi’s sarcoma <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 ) ]</span>, and Merkel cell carcinoma have been reported with Fingolimod Capsules 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 fingolimod capsules.

Lymphoma

Cases of lymphoma, including both T-cell and B-cell types and CNS lymphoma, have occurred in patients receiving Fingolimod Capsules. The reporting rate of non-Hodgkin lymphoma with Fingolimod Capsules 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 Capsules in the postmarketing setting.

5.13 Immune System Effects Following Fingolimod Capsules Discontinuation Fingolimod remains in the blood and has pharmacodynamic effects, including decreased lymphocyte counts, for up to 2 months following the last dose of Fingolimod Capsules. Lymphocyte counts generally return to the normal range within 1 to 2 months of stopping therapy <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.2 )]</span> . Because of the continuing pharmacodynamic effects of fingolimod, initiating other drugs during this period warrants the same considerations needed for concomitant administration (e.g., risk of additive immunosuppressant effects) <span class="opacity-50 text-xs">[see Drug Interactions ( 7.4 )]</span> .

5.14 Hypersensitivity Reactions Hypersensitivity reactions, including rash, urticaria, and angioedema have been reported with Fingolimod Capsules in the postmarketing setting.

Fingolimod

Capsules are contraindicated in patients with history of hypersensitivity to fingolimod or any of its excipients [see Contraindications ( 4 )] .

INTERACTIONS Systemic Ketoconazole: Monitor during concomitant use. ( 7.2 , 12.3 ) Vaccines: Avoid live attenuated vaccines during, and for 2 months after stopping fingolimod hydrochloride treatment. ( 5.2 , 7.3 )

7.1 QT Prolonging Drugs Fingolimod hydrochloride 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 hydrochloride 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 fingolimod hydrochloride and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is greater.

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

7.4 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 fingolimod hydrochloride. 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 hydrochloride [ 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 hydrochloride 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 hydrochloride treatment may result in an additional decrease in heart rate, concomitant use of these drugs during fingolimod hydrochloride 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 hydrochloride. 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 hydrochloride 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 hydrochloride. A recent CBC should be available before initiating treatment with fingolimod hydrochloride.