Fingolimod

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

7.1 QT Prolonging Drugs GILENYA 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 GILENYA 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 GILENYA and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is increased.

7.3 Vaccines GILENYA reduces the immune response to vaccination. Vaccination may be less effective during and for up to 2 months after discontinuation of treatment with GILENYA [see Clinical Pharmacology (12.2)] . Avoid the use of live attenuated vaccines during and for 2 months after treatment with GILENYA 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 GILENYA 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 GILENYA. 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 GILENYA [see Warnings and Precautions (5.2)] .

7.5 Drugs That Slow Heart Rate or Atrioventricular Conduction (e.g., beta blockers or diltiazem) Experience with GILENYA 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 GILENYA treatment may result in an additional decrease in heart rate, concomitant use of these drugs during GILENYA 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 GILENYA. 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 GILENYA 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 GILENYA. A recent CBC should be available before initiating treatment with GILENYA.

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/m 2 ) 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…