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28 X 0.5 mg
General target population: The recommended dose of Fingolimod is one 0.5 mg capsule taken orally once daily, which can be taken with or without food. If a dose is missed, treatment should be continued with the next dose as planned.
First Dose: Initiation of Fingolimod treatment results in a decrease in heart . After the first dose of Fingolimod, the heart rate decrease starts within an hour and the Day 1 nadir generally occurs within approximately 6 hours, although the nadir can be observed up to 24 hours after the first dose in some patients. The first dose of Fingolimod should be administered in a setting in which resources to appropriately manage symptomatic bradycardia are available. In order to assess patient response to the first dose of Fingolimod, observe all patients for 6 hours for signs and symptoms of bradycardia with hourly pulse and blood pressure measurement. Obtain in all patients an electrocardiogram prior to dosing, and at the end of the observation period. Additional observation should be instituted until the finding has resolved in the following situations: If the heart rate 6 hours post-dose is <45 bpm Or if the heart rate 6 hours post-dose is at the lowest value post-dose (suggesting that the maximum pharmacodynamic effect on the heart may not have occurred). Patients with some pre-existing conditions (e.g., ischemic heart disease, history of myocardial infarction, congestive heart failure, history of cardiac arrest, cerebrovascular disease, history of symptomatic bradycardia, history of recurrent syncope, uncontrolled hypertension, severe untreated sleep apnea, AV block, sino-atrial heart block) may poorly tolerate the Fingolimod -induced bradycardia, or experience serious rhythm disturbances after the first dose of Fingolimod.
For recommendations related to switching patients from other disease modifying therapies to Fingolimod See prescribing information for full details.
Re-initiation of Therapy Following Discontinuation: If Fingolimod therapy is discontinued for more than 14 days, after the first month of treatment, the effects on heart rate and AV conduction may recur on reintroduction of Fingolimod treatment and the same precautions (first dose monitoring) as for initial dosing should apply. Within the first 2 weeks of treatment, first dose procedures are recommended after interruption of one day or more, during week 3 and 4 of treatment first dose procedures are recommended after treatment interruption of more than 7 days.
Dosing in special populations
Renal impairment: No Fingolimod dose adjustments are needed in patients with renal impairment.
Hepatic impairment: No Fingolimod dose adjustments are needed in patients with mild or moderate hepatic impairment. Fingolimod should be used with caution in patients with severe hepatic impairment (Child-Pugh class C).
Pediatrics patients: Fingolimod is not indicated for use in pediatric patients.
Geriatrics patients: Fingolimod should be used with caution in patients aged 65 years and over.
Ethnicity: No Fingolimod dose adjustments are needed based on ethnic origin.
Gender: No Fingolimod dose adjustments are needed based on gender.
Diabetic patients: Fingolimod should be used with caution in patients with diabetes mellitus due to a potential increased risk of macular edema.
For full details see prescribing information.
Indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability.
Patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization or Class III/IV heart failure). History or presence of Mobitz Type II second-degree or third-degree atrioventricular (AV) block or sick sinus syndrome, unless patient has a functioning pacemaker. Baseline QTc interval ≥500 ms. Treatment with Class Ia or Class III anti-arrhythmic drugs. Known hypersensitivity to fingolimod, or to any of the excipients
Infections: A core pharmacodynamic effect of Fingolimod is a dose-dependent reduction of peripheral lymphocyte count to 20-30% of baseline values. This is due to the reversible sequestration of lymphocytes in lymphoid tissues. The immune system effects Fingolimod may increase the risk of infections ). Before initiating treatment with Fingolimod, a recent complete blood count (CBC) (i.e. within 6 months or after discontinuation of prior therapy) should be available. Initiation of treatment with Fingolimod should be delayed in patients with severe active infection until resolution. Effective diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy. Because elimination of Fingolimod after discontinuation of Fingolimod may take up to two months, vigilance for infection should be continued throughout this period.
Vaccination: Vaccination may be less effective during and for up to two months after stopping treatment with Fingolimod . The use of live attenuated vaccines should be avoided.
Macular edema: Macular edema with or without visual symptoms has been reported in 0.5% of patients treated with Fingolimod 0.5 mg, occurring predominantly in the first 3-4 months of therapy. An ophthalmic evaluation is therefore recommended 3-4 months after treatment initiation. If patients report visual disturbances at any time while on Fingolimod therapy, an evaluation of the fundus, including the macula, should be carried out. Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema . Fingolimod has not been studied in multiple sclerosis patients with concomitant diabetes mellitus. It is recommended that multiple sclerosis patients with diabetes mellitus or a history of uveitis undergo an ophthalmic evaluation prior to initiating Fingolimod therapy and have follow-up evaluations while receiving Fingolimod therapy.
Bradyarrhythmia and Atrio-ventricular Blocks: Because of a risk for bradyarrhythmia and atrio-ventricular (AV) blocks, patients should be monitored during Fingolimod treatment initiation.
Reduction in heart rate: After the first dose of Fingolimod, the heart rate decrease starts within an hour. On Day 1, the maximal decline in heart rate generally occurs within 6 hours and recovers, although not to baseline levels, by 8-10 hours post dose. Because of physiological diurnal variation, there is a second period of heart rate decrease within 24 hours after the first dose. 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 one month of chronic treatment.
Atrioventricular blocks: Initiation of Gilenya treatment has been associated with atrio-ventricular conduction delays, usually as first-degree atrio-ventricular blocks (prolonged PR interval on electrocardiogram). Second-degree atrio-ventricular blocks, usually Mobitz type I (Wenckebach) have been observed in less than 0.5% of patients receiving Gilenya 0.5 mg in clinical trials. The conduction abnormalities typically were transient, asymptomatic, usually did not require treatment and resolved within the first 24-hours on treatment.
Post-marketing experience: In the post-marketing setting, third degree AV block and AV block with junctional escape have been observed during the first-dose six-hour observation period with Gilenya. 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 pre-existing disease, and the relationship to Gilenya is uncertain. Cases of syncope were also reported after the first dose of Gilenya. Gilenya has not been studied in patients with arrhythmias requiring treatment with Class Ia (e.g. quinidine, procainamide) or Class III anti-arrhythmic drugs (e.g., amiodarone, sotalol). Class Ia and Class III anti-arrhythmic drugs have been associated with cases of Torsades de Pointes in patients with bradycardia. Since initiation of Gilenya treatment results in decreased heart rate, Gilenya should not be used concomitantly with these drugs.
Liver function: During clinical trials, 3-fold or greater elevation in liver transaminases occurred in 8.5% of patients treated with Gilenya 0.5 mg and drug was discontinued if the elevation exceeded 5-fold increase. Recurrence of liver transaminase elevations occurred upon re-challenge in some patients, supporting a relationship to the drug. Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine, should have liver enzymes checked and Gilenya should be discontinued if significant liver injury is confirmed. Although there are no data to establish that patients with preexisting liver disease are at increased risk to develop elevated liver function tests (LFTs) when taking Gilenya, caution in the use of Gilenya should be exercised in patients with a history of significant liver disease.
Prior treatment with immunosuppressants: When switching patients from beta interferon or glatiramer acetate to Gilenya, a washout is not necessary, assuming any immune effects (i.e. cytopenia) of such therapies have resolved. Due to the long half-life of natalizumab, concomitant exposure, and thus concomitant immune effects, could occur if Gilenya is started within the first 2 to 3 months following discontinuation of natalizumab. Therefore careful case-by-case assessment regarding the timing of the initiation of Gilenya treatment is recommended when switching patients from natalizumab to Gilenya. When switching from other immunosuppressive medications, the duration and mode of action of such substances must be considered when initiating Gilenya to avoid additive immune suppressive effects.
Basal cell carcinoma: Basal cell carcinoma (BCC) has been reported in patients receiving Gilenya. Vigilance for BCC is warranted.
Stopping therapy: If a decision is made to stop treatment with Gilenya, the physician needs to be aware that fingolimod remains in the blood and has pharmacodynamic effects, such as decreased lymphocyte counts, for up to two months following the last dose. Lymphocyte counts typically return to normal range within 1-2 months of stopping therapy. Starting other therapies during this interval will result in a concomitant exposure to fingolimod. Use of immunosuppressants soon after the discontinuation of Gilenya may lead to an additive effect on the immune system and therefore caution should be applied. For full details see prescribing information.
Influenza, Sinusitis, Bronchitis, Herpes zoster, Tinea versicolor, Basal cell carcinoma, Bradycardia, Headache, Dizziness, Migraine, Diarrhea, Asthenia, Back pain, Eczema, Pruritus, Hepatic enzyme increased (increased ALT, GGT, AST), Blood triglycerides increased, Cough, Dyspnoea, Vision blurred, Hypertension, Lymphopenia, Leucopenia.
Infections: In multiple sclerosis clinical trials, the overall rate of infections (72%) and serious infections (2%) at the 0.5 mg dose was similar to placebo. However, lower respiratory tract infections, bronchitis and pneumonia, were more common in Gilenya treated patients. Two serious cases of disseminated herpes infection which were fatal have occurred on the 1.25 mg dose; a case of herpes encephalitis in a patient in whom initiation of acyclovir therapy was delayed by one week and a case of a primary disseminated varicella zoster infection in a patient not previously exposed to varicella receiving concomitant high-dose steroid therapy for a multiple sclerosis relapse.
Macular Edema: In clinical trials, macular edema occurred in 0.4% of patients treated with the recommended Gilenya dose of 0.5 mg and in 1.1% of patients treated with the higher 1.25 mg dose. The majority of cases in multiple sclerosis clinical trials occurred within the first 3-4 months of therapy. Some patients presented with blurred vision or decreased visual acuity, but others were asymptomatic and diagnosed on routine ophthalmologic examination. The macular edema generally improved or resolved spontaneously after drug discontinuation. The risk of recurrence after re-challenge has not been evaluated. Macular edema incidence is increased in multiple sclerosis patients with a history of uveitis (approximately 20% with a history of uveitis vs 0.6% without a history of uveitis). Gilenya has not been tested in multiple sclerosis patients with diabetes mellitus. In renal transplant clinical studies where patients with diabetes mellitus were included, therapy with Gilenya 2.5 mg and 5 mg resulted in a 2-fold increase in the incidence of macular edema. Multiple sclerosis patients with diabetes mellitus are therefore expected to be at a higher risk for macular edema.
Bradyarrhythmia: Initiation of Gilenya treatment results in a transient decrease in heart rate and may also be associated with atrio-ventricular conduction delays. In multiple sclerosis clinical trials the mean maximal decrease in heart rate after the first dose intake was seen 4 – 5 hours post-dose, with declines in mean heart rate, as measured by pulse, of 8 beats per minute for Gilenya 0.5 mg. The second dose may result in a slight further decrease. Heart rates below 40 beats per minute were rarely observed in patients on Gilenya 0.5 mg. Heart rate returned to baseline within 1 month of chronic dosing. In the multiple sclerosis clinical program first-degree atrio-ventricular block (prolonged PR interval on electrocardiogram) was detected following drug initiation in 4.7% of patients on Gilenya 0.5 mg, in 2.8% of patients on intramuscular interferon beta-1a IM and in 1.5% of patients on placebo. Second degree atrio-ventricular block were detected in less than 0.5 % patients on Gilenya 0.5 mg. The conduction abnormalities observed both in clinical trials and post-marketing were typically transient, asymptomatic and resolved within 24 hours on treatment. Although most patients did not require medical intervention, in clinical trials, in rare cases, they required treatment with atropine or isoproterenol.
Blood pressure: In multiple sclerosis clinical trials Gilenya 0.5 mg was associated with a mild increase of approximately 1 mmHg on average in mean arterial pressure manifesting after approximately 1 month of treatment initiation. This increase persisted with continued treatment. Hypertension was reported in 6.1% of patients on Gilenya 0.5 mg and in 3.8 % of patients on placebo.
Liver transaminases: In multiple sclerosis clinical trials, 8.5% and 1.9% of patients treated with Gilenya 0.5mg experienced asymptomatic elevation in serum levels of hepatic transaminases ≥3x ULN and ≥5x ULN, respectively, compared with corresponding figures in the placebo group of 1.7% and 1.0% respectively. The majority of elevations occurred within 6-9 months. Serum transaminase levels returned to normal within approximately 2 months after discontinuation of Gilenya. In the few patients who experienced liver transaminase elevations ≥5x ULN and who continued on Gilenya therapy, the elevations returned to normal within approximately 5 months.
Respiratory System: Minor dose-dependent reductions in forced expiratory volume in 1 second (FEV1) and in the diffusing capacity of the lung for carbon monoxide (DLCO) values were observed with fingolimod treatment starting at month 1 and remaining stable thereafter. At month 24, the reduction from baseline values in percent of predicted FEV1 was 3.1% for fingolimod 0.5 mg and 2.0% for placebo, a difference that resolved after treatment discontinuation. For DLCO the reductions at month 24 were 3.8% for fingolimod 0.5 mg and 2.7% for placebo.
Vascular events: In phase III clinical trials rare cases of peripheral arterial occlusive disease occurred in patients treated with Gilenya at higher doses (1.25 or 5.0 mg). Rare cases of posterior reversible encephalopathy syndrome have been reported at 0.5 mg dose in clinical trials and in the post-marketing setting. Rare cases of ischemic and hemorrhagic strokes have also been reported at 0.5 mg dose in clinical trials and in the post-marketing setting although a causal relationship has not been established.
Lymphomas: Cases of lymphoma (cutaneous T-cell lymphoproliferative disorders or diffuse B-cell lymphoma) were reported in premarketing clinical trials in MS patients receiving Gilenya at, or above, the recommended dose of 0.5 mg. Based on the small number of reported cases and short duration of exposure, the relationship to Gilenya remains uncertain.
For full details see prescribing information.
Pharmacodynamic interactions: Anti-neoplastic, immune modulating or immunosuppressive therapies (including corticosteroids) should be co-administered with caution due to the risk of additive immune system effects. Specific decisions as to the dosage and duration of concomitant treatment with corticosteroids should be based on clinical judgment. Co-administration of a short course of corticosteroids (up to 5 days as per study protocols) did not increase the overall rate of infection in patients treated with Fingolimod in the Phase III clinical trials, compared to placebo. Caution should also be applied when switching patients from long-acting therapies with immune effects such as natalizumab, teriflunomide or mitoxantrone. When Fingolimod is used with atenolol, there is an additional 15% reduction in heart rate upon Fingolimod initiation, an effect not seen with diltiazem. Treatment with Fingolimod should not be initiated in patients receiving beta blockers, heart rate lowering calcium channel blockers (such as verapamil, diltiazem or ivabradine), or other substances which may decrease heart rate (e.g. digoxin) because of the potential additive effects on heart rate. If treatment with Fingolimodis considered, advice from a cardiologist should be sought regarding the switch to non heart-rate lowering medicinal products or appropriate monitoring for treatment initiation (should last overnight.
QT prolonging drugs:Fingolimod 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 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.
Vaccination: During and for up to two months after treatment with Fingolimod vaccination may be less effective. The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided.
Pharmacokinetic interactions: Fingolimod is primarily cleared via cytochrome P450 4F2 (CYP4F2) and possibly other CYP4F isoenzymes. In vitro studies in hepatocytes indicated that CYP3A4 may contribute to Fingolimod metabolism in the case of strong induction of CYP3A4.
Potential of Fingolimod and Fingolimod-phosphate to inhibit the metabolism of co-medications.: In vitro inhibition studies using pooled human liver microsomes and specific metabolic probe substrates demonstrated that Fingolimod and Fingolimod-phosphate have little or no capacity to inhibit the activity of CYP enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or CYP4A9/11 (Fingolimod only)). Therefore, Fingolimod and Fingolimod-phosphate are unlikely to reduce the clearance of drugs that are mainly cleared through metabolism by the major CYP isoenzymes.
Potential of Fingolimod and Fingolimod-phosphate to induce its own and/or the metabolism of co-medications: Fingolimod was examined for its potential to induce human CYP3A4, CYP1A2, CYP4F2, and ABCB1 (P-gp) 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 ABCB1 with respect to the vehicle control. Therefore, no clinically relevant induction of the tested CYP enzymes or ABCB1 (P-gp) by Fingolimod is expected at therapeutic concentrations. In vitro experiments did not provide an indication of CYP induction by Fingolimod-phosphate.
Potential of Fingolimod and Fingolimod-phosphate to inhibit the active transport of co-medications: Based on in vitro data, Fingolimod as well as Fingolimod-phosphate are not expected to inhibit the uptake of co-medications and/or biologics transported by the organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1, OATP1B3) or the sodium taurocholate co-transporting polypeptide (NTCP). Similarly, they are not expected to inhibit the efflux of co-medications 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 co-administration of Fingolimod 0.5 mg daily with oral contraceptives (ethinylestradiol and levonorgestrel) did not elicit any change in oral contraceptive 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 were not altered during co-administration with cyclosporine at steady-state, nor were cyclosporine steady-state pharmacokinetics altered by single-dose, or multi-dose (28 days) Fingolimod administration. These data indicate that Fingolimod is unlikely to reduce or increase the clearance of drugs mainly cleared by CYP3A4 and that inhibition of CYP3A4 is unlikely to reduce the clearance of Fingolimod. Potent inhibition of transporters P-gp, MRP2 and OATP1B1 does not influence Fingolimod disposition.
Ketoconazole: The co-administration of ketoconazole 200 mg twice daily at steady-state and a single dose of Fingolimod 5 mg led to a modest increase in the AUC of Fingolimod and Fingolimod-phosphate (1.7-fold increase) by inhibition of CYP4F2.
Isoproterenol, atropine, atenolol and diltiazem: Single-dose Fingolimod and Fingolimod-phosphate exposure was not altered by co-administered 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 co-administration of the latter two drugs with Fingolimod.
Carbamazepine: The co-administration of carbamazepine 600 mg twice daily at steady-state and a single dose of Fingolimod 2 mg had a weak effect on the AUC of Fingolimod and Fingolimod-phosphate, decreasing both by approximately 40%. The clinical relevance of this decrease is unknown.
Pregnancy and Lactation
Pregnancy: The use of Gilenya in women who are or may become pregnant should only be considered if the potential benefit justifies the potential risk to fetus (see below subsection Women of childbearing potential). Animal studies have shown reproductive toxicity including fetal loss and organ defects, notably persistent truncus arteriosus and ventricular septal defect. Furthermore, the receptor affected by fingolimod (sphingosine-1-phosphate receptor) is known to be involved in vascular formation during embryogenesis. At the present time it is not known whether cardiovascular malformations will be found in humans. There are very limited data from the use of fingolimod in pregnant women. In clinical trials, 20 pregnancies were reported in patients exposed to fingolimod at the time of diagnosis of pregnancy, but data are too limited to draw conclusions on safety of Gilenya in pregnancy.
Breast-feeding: Fingolimod is excreted in milk of treated animals during lactation. Because of the potential for serious adverse drug reactions in nursing infants from fingolimod, women receiving Gilenya should not breast feed.
Single doses up to 80-fold the recommended dose (0.5 mg) were well tolerated in healthy volunteers. At 40 mg, 5 of 6 subjects reported mild chest tightness or discomfort which was clinically consistent with small airway reactivity. Fingolimod can induce bradycardia. The decline in heart rate usually starts within one hour of the first dose, and is maximal within 6 hours. There have been reports of slow atrioventricular conduction with isolated reports of transient, spontaneously resolving complete AV block. In case of Fingolimod overdose, observe patients overnight with continuous ECG monitoring in a medical facility, and obtain regular measurements of blood pressure. Neither dialysis nor plasma exchange would result in meaningful removal of fingolimod from the body.
Storage: Do not store above 25°C; protect from moisture.