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Mechanism of Action
Fingolimod is metabolized by sphingosine kinase to the active metabolite, fingolimod-phosphate. Fingolimod-phosphate is a sphingosine 1-phosphate receptor modulator, and binds with high affinity to sphingosine 1-phosphate receptors 1, 3, 4, and 5. Fingolimod-phosphate blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which fingolimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.
Heart rate and rhythm
Fingolimod causes a transient reduction in heart rate and AV conduction at treatment initiation [see WARNINGS AND PRECAUTIONS].
Autonomic responses of the heart, including diurnal variation of heart rate and response to exercise, are not affected by fingolimod treatment.
Fingolimod treatment is not associated with a decrease in cardiac output.
Potential to prolong the QT interval
In a thorough QT interval study of doses of 1.25 or 2.5 mg fingolimod at steady-state, when a negative chronotropic effect of fingolimod was still present, fingolimod treatment resulted in a prolongation of QTc, with the upper bound of the 90% confidence interval (CI) of 14.0 ms. There is no consistent signal of increased incidence of QTc outliers, either absolute or change from baseline, associated with fingolimod treatment. In MS studies, there was no clinically relevant prolongation of QT interval, but patients at risk for QT prolongation were not included in clinical studies.
Effects on immune cell numbers in the blood
In a study in which 12 subjects received GILENYA 0.5 mg daily, the lymphocyte count decreased to approximately 60% of baseline within 4-6 hours after the first dose. With continued daily dosing, the lymphocyte count continued to decrease over a 2-week period, reaching a nadir count of approximately 500 cells/μL or approximately 30% of baseline. In a placebo-controlled study in 1272 MS patients (of whom 425 received fingolimod 0.5 mg daily and 418 received placebo), 18% (N=78) of patients on fingolimod 0.5 mg reached a nadir of < 200 cells/μL on at least one occasion. No patient on placebo reached a nadir of < 200 cells/μL. Low lymphocyte counts are maintained with chronic daily dosing of GILENYA 0.5 mg daily.
Chronic fingolimod dosing leads to a mild decrease in the neutrophil count to approximately 80% of baseline. Monocytes are unaffected by fingolimod.
Peripheral lymphocyte count increases are evident within days of stopping fingolimod treatment and typically normal counts are reached within 1 to 2 months.
Effect on antibody response
The immunogenicity of keyhole limpet Hemocyanin (KLH) and pneumococcal polysaccharide vaccine (PPV-23) immunization were assessed by IgM and IgG titers in a steady-state, randomized, placebo-controlled study in healthy volunteers. Compared to placebo, antigen-specific IgM titers were decreased by 91% and 25% in response to KLH and PPV, respectively, in subjects on GILENYA 0.5 mg. Similarly, IgG titers were decreased by 45% and 50%, in response to KLH and PPV, respectively, in subjects on GILENYA 0.5 mg daily compared to placebo. The responder rate for GILENYA 0.5 mg as measured by the number of subjects with a > 4-fold increase in KLH IgG was comparable to placebo and 25% lower for PPV-23 IgG, while the number of subjects with a > 4 fold increase in KLH and PPV-23 IgM was 75% and 40% lower, respectively, compared to placebo. The capacity to mount a skin delayed-type hypersensitivity reaction to Candida and tetanus toxoid was decreased by approximately 30% in subjects on GILENYA 0.5 mg daily, compared to placebo. Immunologic responses were further decreased with fingolimod 1.25 mg (a dose higher than recommended in MS) [see WARNINGS AND PRECAUTIONS].
Single fingolimod doses ≥ 5 mg (10-fold the recommended dose) are associated with a dose-dependent increase in airway resistance. In a 14-day study of 0.5, 1.25, or 5 mg/day, fingolimod was not associated with impaired oxygenation or oxygen desaturation with exercise or an increase in airway responsiveness to methacholine. Subjects on fingolimod treatment had a normal bronchodilator response to inhaled beta-agonists.
In a 14-day placebo-controlled study of patients with moderate asthma, no effect was seen for GILENYA 0.5mg (recommended dose in MS). A 10% reduction in mean FEV1 at 6 hour after dosing was observed in patients receiving fingolimod 1.25 mg (a dose higher than recommended for use in MS) on Day 10 of treatment. Fingolimod 1.25 mg was associated with a 5-fold increase in the use of rescue short acting beta-agonists.
The Tmax of fingolimod is 12-16 hours. The apparent absolute oral bioavailability is 93%.
Food intake does not alter Cmax or exposure (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.
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.
The biotransformation of fingolimod in humans occurs by three main pathways: by reversible stereoselective phosphorylation to the pharmacologically active (S)-enantiomer of fingolimod-phosphate, by oxidative biotransformation mainly via the cytochrome P450 4F2 isoenzyme and subsequent fatty acid-like degradation to inactive metabolites, and by formation of pharmacologically inactive non-polar ceramide analogs of fingolimod.
Fingolimod is primarily metabolized via human CYP4F2 with a minor contribution of CYP2D6, 2E1, 3A4, and 4F12. Inhibitors or inducers of these isozymes might alter the exposure of fingolimod or fingolimod-phosphate. The
involvement of multiple CYP isoenzymes in the oxidation of fingolimod suggests that the metabolism of fingolimod will not be subject to substantial inhibition in the presence of an inhibitor of a single specific CYP isozyme.
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%)].
Fingolimod blood clearance is 6.3±2.3 L/h, and the average apparent terminal half-life (t½) is 6-9 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.
In patients with severe renal impairment, fingolimod Cmax and AUC are increased by 32% and 43%, respectively, and fingolimod-phosphate Cmax and 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 patients with renal impairment. The systemic exposure of two 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.
In subjects with mild, moderate, or severe hepatic impairment, no change in fingolimod Cmax was observed, but fingolimod AUC was increased respectively by 12%, 44%, and 103%. In patients with severe hepatic impairment, fingolimod-phosphate Cmax was decreased by 22% and AUC was not substantially changed. The pharmacokinetics of fingolimod-phosphate were 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 should be closely monitored, as the risk of adverse reactions is greater [See WARNINGS AND PRECAUTIONS].
No dose adjustment is needed in patients with mild or moderate hepatic impairment.
The effects of race on fingolimod and fingolimod-phosphate pharmacokinetics cannot be adequately assessed due to a low number of non-white patients in the clinical program.
Gender has no clinically significant influence on fingolimod and fingolimod-phosphate pharmacokinetics.
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.
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].
Potential of fingolimod and fingolimod-phosphate to inhibit the metabolism of co-medications
In vitro inhibition studies in pooled human liver microsomes and specific metabolic probe substrates demonstrate that fingolimod has little or no capacity to inhibit the activity of the following CYP450 enzymes: CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or CYP4A9/11, and similarly fingolimod-phosphate has little or no capacity to inhibit the activity of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 at concentrations up to three 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 cytochrome P450 isoenzymes described above. The potential of fingolimod to inhibit CYP2C8 and fingolimodphosphate to inhibit CYP2B6 is unknown.
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 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 CYP450 enzymes and MDR1 with respect to the vehicle control; therefore, no clinically relevant induction of the tested CYP450 enzymes or MDR1 by fingolimod are expected at therapeutic concentrations. The potential of fingolimod-phosphate to induce CYP450 isoenzymes is unknown.
Fingolimod as well as fingolimod-phosphate are not expected to inhibit the uptake of co-medications and/or biologics transported by OATP1B1, OATP1B3, or NTCP. Similarly, they are not expected to inhibit the efflux of co-medications and/or biologics transported by the breast cancer resistant protein (MXR), the bile salt export pump (BSEP), the multidrug resistance-associated protein 2 (MRP2), and MDR1-mediated transport at therapeutic concentrations.
The pharmacokinetics of single-dose fingolimod were 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 the clearance of drugs mainly cleared by CYP3A4 and show that the potent inhibition of transporters MDR1, MRP2, and OATP-C 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 two 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) and carbamazepine (potent enzyme inducer) on fingolimod or fingolimod-phosphate pre-dose concentrations. In addition, the following commonly co-prescribed substances had no clinically relevant effect ( < 20%) on fingolimod or fingolimod-phosphate pre-dose concentrations: baclofen, gabapentin, oxybutynin, amantadine, modafinil, amitriptyline, pregabalin, and corticosteroids.
Animal Toxicology and/or Pharmacology
Lung toxicity was observed in two different strains of rat and in dog and monkey. The primary findings included increase in lung weight, associated with smooth muscle hypertrophy, hyperdistension of the alveoli, and/or increased collagen. Insufficient or lack of pulmonary collapse at necropsy, generally correlated with microscopic changes, was observed in all species. In rat and monkey, lung toxicity was observed at all oral doses tested in chronic studies. The lowest doses tested in rat (0.05 mg/kg/day in the 2-year carcinogenicity study) and monkey (0.5 mg/kg/day in the 39-week toxicity study) are similar to and approximately 20 times the RHD on a mg/m² basis, respectively.
In the 52-week oral study in monkey, respiratory distress associated with ketamine administration was observed at doses of 3 and 10 mg/kg/day; the most affected animal became hypoxic and required oxygenation. As ketamine is not generally associated with respiratory depression, this effect was attributed to fingolimod. In a subsequent study in rat, ketamine was shown to potentiate the bronchoconstrictive effects of fingolimod. The relevance of these findings to humans is unknown.
The efficacy of GILENYA was demonstrated in 2 studies that evaluated once-daily doses of GILENYA 0.5 mg and 1.25 mg in patients with relapsing remitting MS (RRMS). Both studies included patients who had experienced at least 2 clinical relapses during the 2 years prior to randomization or at least 1 clinical relapse during the 1 year prior to randomization, and had an Expanded Disability Status Scale (EDSS) score from 0 to 5.5. Study 1 was a 2-year randomized, double-blind, placebo-controlled study in patients with RRMS who had not received any interferon-beta or glatiramer acetate for at least the previous 3 months and had not received any natalizumab for at least the previous 6 months. Neurological evaluations were performed at screening, every 3 months and at time of suspected relapse. MRI evaluations were performed at screening, month 6, month 12, and month 24. The primary endpoint was the annualized relapse rate.
Median age was 37 years, median disease duration was 6.7 years and median EDSS score at baseline was 2.0. Patients were randomized to receive GILENYA 0.5 mg (n=425), 1.25 mg (n=429), or placebo (n=418) for up to 24 months. Median time on study drug was 717 days on 0.5 mg, 715 days on 1.25 mg and 719 days on placebo.
The annualized relapse rate was significantly lower in patients treated with GILENYA than in patients who received placebo. The secondary endpoint was the time to 3-month confirmed disability progression as measured by at least a 1point increase from baseline in EDSS (0.5 point increase for patients with baseline EDSS of 5.5) sustained for 3 months. Time to onset of 3-month confirmed disability progression was significantly delayed with GILENYA treatment compared to placebo. The 1.25 mg dose resulted in no additional benefit over the GILENYA 0.5 mg dose. The results for this study are shown in Table 2 and Figure 1.
Table 2 : Clinical and MRI Results of Study 1
|GILENYA 0.5 mg
|Annualized relapse rate (primary endpoint)||0.18||0.4||< 0.001|
|Percentage of patients without relapse Hazard ratio‡ of disability progression (95% CI)||70% 0.70 (0.52, 0.96)||46%||< 0.001 0.02|
|Mean (median) number of new or newly enlarging T2 lesions over 24 months||2.5(0)||9.8 (5.0)||< 0.001|
|Mean (median) number of T1 Gd-enhancing lesions at Month 24||0.2 (0)||1.1 (0)||< 0.001|
|All analyses of clinical endpoints
were intent-to–treat. MRI analysis used evaluable dataset.
‡ Hazard ratio is an estimate of the relative risk of having the event of disability progression on GILENYA as compared to placebo.
Figure 1 : Time to 3-month
Confirmed Disability Progression – Study 1 (ITT population)
Study 2 was a 1-year randomized, double-blind, double-dummy, active-controlled study in patients with RRMS who had not received any natalizumab in the previous 6 months. Prior therapy with interferon-beta or glatiramer acetate up to the time of randomization was permitted.
Neurological evaluations were performed at screening, every 3 months, and at the time of suspected relapses. MRI evaluations were performed at screening and at month 12. The primary endpoint was the annualized relapse rate.
Median age was 36 years, median disease duration was 5.9 years, and median EDSS score at baseline was 2.0. Patients were randomized to receive GILENYA 0.5 mg (n=431), 1.25 mg (n=426), or interferon beta-1a, 30 micrograms via the intramuscular route (IM) once weekly (n=435) for up to 12 months. Median time on study drug was 365 days on GILENYA 0.5 mg, 354 days on 1.25 mg, and 361 days on interferon beta-1a IM.
The annualized relapse rate was significantly lower in patients treated with GILENYA 0.5 mg than in patients who received interferon beta-1a IM. The key secondary endpoints were number of new and newly enlarging T2 lesions and time to onset of 3-month confirmed disability progression as measured by at least a 1-point increase from baseline in EDSS (0.5 point increase for those with baseline EDSS of 5.5) sustained for 3 months. The number of new and newly enlarging T2 lesions was significantly lower in patients treated with GILENYA than in patients who received interferon beta-1a IM. There was no significant difference in the time to 3-month confirmed disability progression between GILENYA and interferon beta-1a-treated patients at 1 year. The 1.25 mg dose resulted in no additional benefit over the GILENYA 0.5 mg dose. The results for this study are shown in Table 3.
Table 3 : Clinical and MRI Results of Study 2
|GILENYA 0.5 mg
|Interferon beta-1a IM 30 μg
|Annualized relapse rate (primary endpoint)||0.16||0.33||< 0.001|
|Percentage of patients without relapse||83%||70%||< 0.001|
|Hazard ratio‡ of disability progression (95% CI)||0.71 (0.42, 1.21)||0.21|
|Mean (median) number of new or newly enlarging T2 lesions over 12 months||1.6 (0)||2.6 (1.0)||0.002|
|Mean (median) number of T1 Gd enhancing lesions at Month 12||0.2 (0)||0.5 (0)||< 0.001|
|All analyses of clinical endpoints
were intent-to–treat. MRI analysis used evaluable dataset.
‡ Hazard ratio is an estimate of the relative risk of having the event of disability progression on GILENYA as compared to control.
Pooled results of study 1 and study 2 showed a consistent and statistically significant reduction of annualized relapse rate compared to comparator in subgroups defined by gender, age, prior MS therapy, and disease activity.
Last reviewed on RxList: 5/18/2012
This monograph has been modified to include the generic and brand name in many instances.
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