Gilenya

GILENYA 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.

GILENYA is available as:

• 0.25 mg hard capsules with an ivory opaque body and cap, with black radial imprint “FTY 0.25 mg” on the cap and a black radial band on the capsule body.
• 0.5 mg hard capsules with a white opaque body and bright yellow cap imprinted with “FTY 0.5 mg” on the cap and 2 radial bands imprinted on the capsule body with yellow ink.

Available observational pregnancy registry data suggest that use of GILENYA is associated with an increased prevalence of major birth defects in comparison to the general population. However, limitations in the number of exposed pregnant women and in the study design preclude definitive conclusions (

Based on findings from animal studies, GILENYA may cause fetal harm when administered to a pregnant woman.

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% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

In females planning to become pregnant, GILENYA 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 GILENYA because of pregnancy or planned pregnancy. In many of the cases in which increase in disability was reported after stopping GILENYA, patients had stopped GILENYA because of pregnancy or planned pregnancy

In a prospective observational GILENYA pregnancy registry (GPR) (2011 - 2024), the rate of major birth defects among 147 live births, stillbirths, or terminations of pregnancy due to fetal anomalies from women who were administered fingolimod during the first trimester was 8.2% (95% CI: 4.3-13.8) using the European Registration of Congenital Anomalies and Twin classification and 10.9% (95% CI: 6.4-17.1) using the Metropolitan Atlanta Congenital Defects Program classification. The most frequent major birth defects were congenital heart defects, renal/urinary malformations, and limb/musculoskeletal malformations. Study limitations include no adjustment for confounders, no re-adjudication in case of spontaneous resolution, lack of an internal comparator cohort, and small sample size.

In fingolimod prospective pharmacovigilance data, the most frequent major birth defect types were similar to those reported in the GPR.

The pattern of malformations reported for GILENYA is similar to that observed in the general population. There is no evidence of clustering of specific birth defects with GILENYA.

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/m² basis. 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/m² basis.

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/m² basis.

• Infections:
  GILENYA 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     Infections

  Risk of Infections

  GILENYA causes a dose-dependent reduction in peripheral lymphocyte count to 20%–30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues. GILENYA 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 GILENYA.

  Before initiating treatment with GILENYA, a recent CBC (i.e., within 6 months or after discontinuation of prior therapy) should be available. Consider suspending treatment with GILENYA 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 GILENYA 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 GILENYA was similar to placebo. However, bronchitis, herpes zoster, influenza, sinusitis, and pneumonia were more common in GILENYA-treated patients. Serious infections occurred at a rate of 2.3% in the GILENYA 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 GILENYA. 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 GILENYA 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 GILENYA in the postmarketing setting. Include disseminated herpetic infections in the differential diagnosis of patients who are receiving GILENYA 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 GILENYA in the postmarketing setting. Cryptococcal infections have generally occurred after approximately 2 years of GILENYA 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 GILENYA did not receive concomitant treatment with antineoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies used for treatment of MS. Concomitant use of GILENYA 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 GILENYA 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 GILENYA. VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with GILENYA, following which initiation of treatment with GILENYA 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 GILENYA in the postmarketing setting. Vaccination against HPV should be considered prior to treatment initiation with GILENYA, 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 GILENYA 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 GILENYA 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 GILENYA-treated patients; the majority of cases have occurred in patients treated with GILENYA for at least 18 months.

  At the first sign or symptom suggestive of PML, withhold GILENYA 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 GILENYA. 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 GILENYA should be discontinued.

  Immune reconstitution inflammatory syndrome (IRIS) has been reported in patients treated with S1P receptor modulators, including GILENYA, 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 GILENYA. 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 GILENYA if macular edema develops. Diabetes mellitus and uveitis increase the risk. (
  5.4     Macular Edema

  S1P receptor modulators, including GILENYA, 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 GILENYA. 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 GILENYA 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 GILENYA 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 GILENYA in the postmarketing setting, usually within the first 6 months of treatment.

  Continuation of GILENYA 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 GILENYA 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 GILENYA 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). GILENYA 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 GILENYA 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 GILENYA 0.5 mg and 3% of patients on placebo. Elevations 5-fold the ULN or greater occurred in 4.5% of patients on GILENYA and 1% of patients on placebo. The majority of elevations occurred within 6 to 9 months. In clinical trials, GILENYA was discontinued if the elevation exceeded 5 times the ULN. Serum transaminase levels returned to normal within approximately 2 months after discontinuation of GILENYA. Recurrence of liver transaminase elevations occurred with rechallenge in some patients.

  Prior to starting treatment with GILENYA (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 GILENYA 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 GILENYA 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 GILENYA 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)]

  .
  ,
  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 (5.5), 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, GILENYA may be taken without regard to meals.

  Steady-state blood concentrations 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 GILENYA 0.5 mg dose is appropriate for use in adult patients with renal impairment. GILENYA 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_{0-96 hours}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 (5.5)]

  .

  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 GILENYA 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 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 GILENYA 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 GILENYA. (
  5.6     Posterior Reversible Encephalopathy Syndrome

  There have been rare cases of posterior reversible encephalopathy syndrome (PRES) reported in adult patients receiving GILENYA. 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, GILENYA 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 GILENYA 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 GILENYA 0.5 mg 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 GILENYA 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 GILENYA 0.5 mg and 7% of patients receiving placebo. Several patients discontinued GILENYA because of unexplained dyspnea during the extension (uncontrolled) studies. GILENYA 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 GILENYA 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 GILENYA. (
  5.8     Fetal Risk

  GILENYA 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 GILENYA 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 GILENYA from the body, advise females of reproductive potential to use effective contraception to avoid pregnancy during and for 2 months after stopping GILENYA treatment

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

  .
  ,
  8.1     Pregnancy

  Risk Summary

  Available observational pregnancy registry data suggest that use of GILENYA is associated with an increased prevalence of major birth defects in comparison to the general population. However, limitations in the number of exposed pregnant women and in the study design preclude definitive conclusions (

  see Data

  ). Data from prospective reports to the pregnancy registry are currently not sufficient to allow for an adequate assessment of the drug-associated risk for miscarriage.

  Based on findings from animal studies, GILENYA may cause fetal harm when administered to a pregnant woman.

  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% to 4% and 15% to 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, GILENYA 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 GILENYA because of pregnancy or planned pregnancy. In many of the cases in which increase in disability was reported after stopping GILENYA, patients had stopped GILENYA because of pregnancy or planned pregnancy

  [see Warnings and Precautions (5.9)]

  .

  Data

  Human Data

  In a prospective observational GILENYA pregnancy registry (GPR) (2011 - 2024), the rate of major birth defects among 147 live births, stillbirths, or terminations of pregnancy due to fetal anomalies from women who were administered fingolimod during the first trimester was 8.2% (95% CI: 4.3-13.8) using the European Registration of Congenital Anomalies and Twin classification and 10.9% (95% CI: 6.4-17.1) using the Metropolitan Atlanta Congenital Defects Program classification. The most frequent major birth defects were congenital heart defects, renal/urinary malformations, and limb/musculoskeletal malformations. Study limitations include no adjustment for confounders, no re-adjudication in case of spontaneous resolution, lack of an internal comparator cohort, and small sample size.

  In fingolimod prospective pharmacovigilance data, the most frequent major birth defect types were similar to those reported in the GPR.

  The pattern of malformations reported for GILENYA is similar to that observed in the general population. There is no evidence of clustering of specific birth defects with GILENYA.

  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 GILENYA

  [see Use in Specific Populations (8.1)]

  .

  Contraception

  Before initiation of GILENYA treatment, 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 GILENYA

  [see Warnings and Precautions (5.8) 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 GILENYA:
  Monitor for development of severe increase in disability following discontinuation and begin appropriate treatment as needed. (
  5.9     Severe Increase in Disability After Stopping GILENYA

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

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

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

  [see Warnings and Precautions (5.3)]

  .
  )
• 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 GILENYA therapy and after GILENYA discontinuation in the postmarketing setting. Most reported cases of tumefactive MS in patients receiving GILENYA have occurred within the first 9 months after GILENYA 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 GILENYA discontinuation. Tumefactive MS should be considered when a severe MS relapse occurs during GILENYA treatment, especially during initiation, or after discontinuation of GILENYA, prompting imaging evaluation and initiation of appropriate treatment.
  )
  
• Increased Blood Pressure (BP):
  Monitor BP in adult and pediatric patients during treatment. (
  5.11     Increased Blood Pressure

  Increases in blood pressure have been observed in patients treated with GILENYA.

  In adult MS controlled clinical trials, patients treated with GILENYA 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 GILENYA 0.5 mg and in 4% of patients on placebo.

  Monitor blood pressure (BP) in adult and pediatric patients during treatment with GILENYA.
  )
• 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 GILENYA 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 GILENYA 0.5 mg and 1% in patients on placebo

  [see Adverse Reactions (6.1)]

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

  [see Warnings and Precautions (5.2)]

  , and Merkel cell carcinoma have been reported with GILENYA 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 GILENYA.

  Lymphoma

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