TASCENSO ODT Fingolimod Lauryl Sulfate .5 mg Tablet, Orally Disintegrating — NDC 70709-065-30 (Billing 70709-0065-30)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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.

12.2Pharmacodynamics Heart Rate and Rhythm Fingolimod causes a transient reduction in heart rate and AV conduction at treatment initiation [see Warnings and Precautions (5.1) ] . Heart rate progressively increases after the first day, returning to baseline values within 1 month of the start of chronic treatment. 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 capsules at steady-state, when a negative chronotropic effect of fingolimod was still present, fingolimod treatment resulted in a prolongation of QTc, with the upper boundary of the 90% confidence interval (CI) of 14.0 msec. 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 the QT interval, but patients at risk for QT prolongation were not included in clinical studies. Immune System Effects on Immune Cell Numbers in the Blood In a study in which 12 adult subjects received fingolimod 0.5 mg capsules daily, the lymphocyte count decreased to approximately 60% of baseline within 4 to 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/mcL or approximately 30% of baseline.

In a placebo-controlled study in 1272 MS patients (of whom 425 received fingolimod 0.5 mg capsules daily and 418 received placebo), 18% (N = 78) of patients on fingolimod 0.5 mg reached a nadir of < 200 cells/mcL on at least 1 occasion. No patient on placebo reached a nadir of < 200 cells/mcL. Low lymphocyte counts are maintained with chronic daily dosing of fingolimod 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 Fingolimod reduces the immune response to vaccination, as evaluated in 2 studies. In the first study, 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 adult volunteers. Compared to placebo, antigen-specific IgM titers were decreased by 91% and 25% in response to KLH and PPV-23, respectively, in subjects on fingolimod 0.5 mg capsules.

Similarly, IgG titers were decreased by 45% and 50%, in response to KLH and PPV-23, respectively, in subjects on fingolimod 0.5 mg daily compared to placebo. The responder rate for fingolimod 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 toxo… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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.

12.3Pharmacokinetics Absorption The T max of fingolimod is 12 to 16 hours. The apparent absolute oral bioavailability is 93%. Food intake does not alter C max or (AUC) of fingolimod or fingolimod-phosphate.

Therefore, TASCENSO ODT may be taken without regard to meals. Steady-state blood concentrations of fingolimod 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 [ 14 C] 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 ±

2.3L/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 max and AUC are increased by 32% and 43%, respectively, and fingolimod-phosphate C max and AUC are increased by 25% and 14%, respectively, with no change in apparent elimination half-life. Based on these findings, the TASCENSO ODT 0.5 mg dose is appropriate for use in adult patients with renal impairment. TASCENSO ODT 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… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Heart Rate and Rhythm Fingolimod causes a transient reduction in heart rate and AV conduction at treatment initiation [see Warnings and Precautions (5.1) ] . Heart rate progressively increases after the first day, returning to baseline values within 1 month of the start of chronic treatment. 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 capsules at steady-state, when a negative chronotropic effect of fingolimod was still present, fingolimod treatment resulted in a prolongation of QTc, with the upper boundary of the 90% confidence interval (CI) of 14.0 msec. 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 the QT interval, but patients at risk for QT prolongation were not included in clinical studies. Immune System Effects on Immune Cell Numbers in the Blood In a study in which 12 adult subjects received fingolimod 0.5 mg capsules daily, the lymphocyte count decreased to approximately 60% of baseline within 4 to 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/mcL or approximately 30% of baseline.

In a placebo-controlled study in 1272 MS patients (of whom 425 received fingolimod 0.5 mg capsules daily and 418 received placebo), 18% (N = 78) of patients on fingolimod 0.5 mg reached a nadir of < 200 cells/mcL on at least 1 occasion. No patient on placebo reached a nadir of < 200 cells/mcL. Low lymphocyte counts are maintained with chronic daily dosing of fingolimod 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 Fingolimod reduces the immune response to vaccination, as evaluated in 2 studies. In the first study, 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 adult volunteers. Compared to placebo, antigen-specific IgM titers were decreased by 91% and 25% in response to KLH and PPV-23, respectively, in subjects on fingolimod 0.5 mg capsules.

Similarly, IgG titers were decreased by 45% and 50%, in response to KLH and PPV-23, respectively, in subjects on fingolimod 0.5 mg daily compared to placebo. The responder rate for fingolimod 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 fingolimod 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 (5.2) ] . In the second study, the immunogenicity of Northern hemisphere seasonal influenza and tetanus toxoid vaccination was assessed in a 12-week steady-state, randomized, placebo-controlled study of fingolimod 0.5 mg capsules in adult multiple sclerosis patients (n = 136). The responder rate 3 weeks after vaccination, defined as seroconversion or a ≥ 4-fold increase in a… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES The efficacy of TASCENSO ODT is based on the relative bioavailability of TASCENSO ODT orally disintegrating tablets compared to fingolimod capsules in healthy adults [see Clinical Pharmacology (12.3) ]. The clinical studies described below were conducted using fingolimod capsules.

14.1Adults The efficacy of fingolimod was demonstrated in 2 studies that evaluated once-daily doses of fingolimod capsules 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 fingolimod 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 fingolimod than in patients who received placebo. The secondary endpoint was the time to 3-month confirmed disability progression as measured by at least a 1-point 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 fingolimod treatment compared to placebo.

The 1.25 mg dose resulted in no additional benefit over the fingolimod 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 Fingolimod Capsules 0.5 mg Placebo p-value N = 425 N = 418 Clinical Endpoints Annualized relapse rate (primary endpoint) 0.18 0.40 < 0.001 Percentage of patients without relapse 70% 46% < 0.001 Hazard ratio § of disability progression (95% CI) 0.70 (0.52, 0.96)

0.02MRI Endpoint 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 Abbreviation: CI, confidence interval. 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 fingolimod 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 fingolimod capsules 0.5 mg (N = 431), 1.25 mg (N = 426), or interferon beta-1a, 30 mcg via the intramuscular route (IM) once-weekly (N = 435) for up to 12 months. Median time on study drug was 365 days on fingolimod 0.5 mg, 354 days on 1.25 mg, and 361 days on interferon beta-… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Oral carcinogenicity studies of fingolimod were conducted in mice and rats. In mice, fingolimod was administered at oral doses of 0, 0.025, 0.25, and 2.5 mg/kg/day for up to 2 years. The incidence of malignant lymphoma was increased in males and females at the mid and high dose.

The lowest dose tested (0.025 mg/kg/day) is less than the RHD of 0.5 mg/day on a body surface area (mg/m 2 ) basis. In rats, fingolimod was administered at oral doses of 0, 0.05, 0.15, 0.5, and 2.5 mg/kg/day. No increase in tumors was observed.

The highest dose tested (2.5 mg/kg/day) is approximately 50 times the RHD on a mg/m 2 basis. Fingolimod was negative in a battery of in vitro (Ames, mouse lymphoma thymidine kinase, chromosomal aberration in mammalian cells) and in vivo (micronucleus in mouse and rat) assays. When fingolimod was administered orally (0, 1, 3, and 10 mg/kg/day) to male and female rats prior to and during mating, and continuing to Day 7 of gestation in females, no effect on fertility was observed up to the highest dose tested (10 mg/kg), which is approximately 200 times the RHD on a mg/m 2 basis.

13.2Animal Toxicology and/or Pharmacology Lung toxicity was observed in 2 different strains of rats and in dogs and monkeys. The primary findings included increase in lung weight, associated with smooth muscle hypertrophy, hyperdistention 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 rats and monkeys, lung toxicity was observed at all oral doses tested in chronic studies. The lowest doses tested in rats (0.05 mg/kg/day in the 2-year carcinogenicity study) and monkeys (0.5 mg/kg/day in the 39-week toxicity study) are similar to and approximately 20 times the RHD on a mg/m 2 basis, respectively. In the 52-week oral study in monkeys, 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 rats, ketamine was shown to potentiate the bronchoconstrictive effects of fingolimod. The relevance of these findings to humans is unknown.