2.1 Assessments, Medications, and Vaccinations Prior to First Dose of VELSIPITY

Before initiation of treatment with VELSIPITY, assess the following:

Complete Blood Count

Obtain a recent (i.e., within the last 6 months or after discontinuation of prior UC therapy) complete blood count (CBC), including lymphocyte count [see Warnings and Precautions (5.1)].

Cardiac Evaluation

Obtain an electrocardiogram (ECG) to determine whether preexisting conduction abnormalities are present. In patients with certain preexisting conditions, advice from a cardiologist should be sought [see Warnings and Precautions (5.2)].

Liver Function Tests

Obtain recent (i.e., within the last 6 months) transaminase and bilirubin levels [see Warnings and Precautions (5.3)].

Ophthalmic Assessment

Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with VELSIPITY [see Warnings and Precautions (5.4)].

Current or Prior Medications

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Determine if patients are taking drugs that could slow heart rate or atrioventricular (AV) conduction [see Warnings and Precautions (5.2) and Drug Interactions (7)].

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If patients are taking anti-neoplastic, immune-modulating, or non-corticosteroid immunosuppressive therapies, or if there is a history of prior use of these drugs, consider possible unintended additive immunosuppressive effects before initiating treatment with VELSIPITY [see Warnings and Precautions (5.10) and Drug Interactions (7)].

Vaccinations

Patients without a healthcare professional-confirmed history of varicella (chickenpox) or without documentation of a full course of vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV before initiating VELSIPITY; VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with VELSIPITY.

If live attenuated vaccine immunizations are required, administer at least 4 weeks prior to initiation of VELSIPITY.

Update immunizations in agreement with current immunization guidelines prior to initiating VELSIPITY therapy [see Warnings and Precautions (5.1)].

Skin Examination

Obtain a skin examination prior to or shortly after initiation of VELSIPITY. If a suspicious skin lesion is observed, it should be promptly evaluated [see Warnings and Precautions (5.7)].

2.2 Recommended Dosage

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The recommended dosage of VELSIPITY is 2 mg orally once daily.

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Swallow the tablet whole, with or without food [see Clinical Pharmacology (12.3)].

5.1 Infections

Risk of Infections

VELSIPITY causes a mean reduction in peripheral blood lymphocyte count to approximately 45% of baseline values at Week 52 because of reversible sequestration of lymphocytes in lymphoid tissues [see Clinical Pharmacology (12.2)]. VELSIPITY may, therefore, increase the susceptibility to infections. Life-threatening and rare fatal infections have been reported in association with other sphingosine 1-phosphate (S1P) receptor modulators.

Before initiating treatment, obtain a recent (i.e., within 6 months or after discontinuation of prior UC therapy) CBC, including lymphocyte count.

Delay initiation of VELSIPITY in patients with an active infection until the infection is resolved.

In UC-1, the overall rate of infections in subjects treated with VELSIPITY was 24.9% compared to 22.2% in subjects who received placebo. In pooled data from UC-2 and UC-3, the overall rate of infections in subjects treated with VELSIPITY was 14.0% compared to 11.8% in subjects who received placebo. The most common infections were urinary tract infections and herpes viral infections in UC-1, and urinary tract infections in UC-2 and UC-3 [see Adverse Reactions (6.1)].

The proportion of subjects treated with VELSIPITY who experienced lymphocyte counts less than 0.2 x 109/L was 5.5% in UC-1 and 0.6% in UC-2 and UC-3. These events did not lead to treatment discontinuation. Peripheral blood absolute lymphocyte counts returned to the normal range in 90% of subjects within 4 to 5 weeks of stopping therapy [see Clinical Pharmacology (12.2)].

Consider interruption of treatment with VELSIPITY if a patient develops a serious infection.

Because residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, may persist up to 5 weeks after discontinuation of VELSIPITY, vigilance for infection should be continued throughout this period.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically occurs in patients who are immunocompromised, and that usually leads to death or severe disability. 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.

PML has been reported in multiple sclerosis (MS) patients treated with S1P receptor modulators and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants). Physicians should be vigilant for clinical symptoms or unexplained neurologic findings that may be suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. If PML is suspected, treatment with VELSIPITY should be suspended until PML has been excluded by an appropriate diagnostic evaluation.

If PML is confirmed, discontinue treatment with VELSIPITY.

Immune reconstitution inflammatory syndrome (IRIS) has been reported in MS patients treated with S1P receptor modulators 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.

Herpes Viral Infections

Herpes simplex encephalitis, varicella zoster meningitis, and localized herpes viral infections have been reported with S1P receptor modulators. In UC-1, herpes zoster was reported in 0.7% of subjects treated with VELSIPITY and in none of the subjects who received placebo. Patients without a healthcare professional-confirmed history of varicella (chickenpox), or without documentation of a full course of vaccination against varicella zoster virus (VZV), should be tested for antibodies to VZV before initiating VELSIPITY (see Vaccinations).

Cryptococcal Infection

Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with S1P receptor modulators. Physicians should be vigilant for clinical symptoms or signs of CM. Patients with symptoms or signs consistent with a cryptococcal infection should undergo prompt diagnostic evaluation and treatment. VELSIPITY treatment should be suspended until a cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.

Prior and Concomitant Treatment with Anti-neoplastic, Immune-modulating, or Non-corticosteroid Immunosuppressive Therapies

VELSIPITY has not been studied in combination with anti-neoplastic, immune-modulating, or non-corticosteroid immunosuppressive therapies. Avoid concomitant administration of these therapies with VELSIPITY and in the weeks following administration because of the risk of additive immunosuppressive effects [see Warnings and Precautions (5.10)].

Vaccinations

Patients without a healthcare professional-confirmed history of varicella (chickenpox) or without documentation of a full course of vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV before initiating VELSIPITY. A full course of VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with VELSIPITY, following which initiation of treatment with VELSIPITY should be postponed for 4 weeks to allow the full effect of vaccination to occur.

No clinical data are available on the safety and efficacy of vaccinations in patients taking VELSIPITY. Vaccinations may be less effective if administered during VELSIPITY treatment.

If live attenuated vaccine immunizations are required, administer at least 4 weeks prior to initiation of VELSIPITY. Avoid the use of live attenuated vaccines during and for 5 weeks after treatment with VELSIPITY.

Update immunizations in agreement with current immunization guidelines prior to initiating VELSIPITY therapy.

5.2 Bradyarrhythmia and Atrioventricular Conduction Delays

Initiation of VELSIPITY may result in a transient decrease in heart rate and AV conduction delays [see Clinical Pharmacology (12.2)].

Reduction in Heart Rate

Initiation of VELSIPITY may result in a transient decrease in heart rate. After the first dose of VELSIPITY 2 mg, subjects with UC experienced the greatest mean decrease from baseline in heart rate of 7.2 bpm at Hour 3 in UC-1 and Hour 2 in UC-2.

In UC-1, bradycardia was reported on the day of treatment initiation in 1% of subjects treated with VELSIPITY compared to none in subjects who received placebo. On Day 2, bradycardia was reported in 1 subject (0.3%) treated with VELSIPITY compared to none in subjects who received placebo. In UC-2 and UC-3, bradycardia was reported on the day of treatment initiation in 2.9% of subjects treated with VELSIPITY compared to none in subjects who received placebo. On Day 2, bradycardia was reported in 1 subject (0.3%) treated with VELSIPITY compared to none in subjects who received placebo. Subjects who experienced bradycardia were generally asymptomatic. Few subjects experienced symptoms, such as dizziness, and these symptoms resolved without intervention.

Atrioventricular Conduction Delays

Initiation of VELSIPITY may result in transient AV conduction delays.

On the day of treatment initiation of VELSIPITY 2 mg, first- or second-degree Mobitz type I AV blocks were observed in 0.7% of VELSIPITY-treated subjects compared to none in placebo in UC-1, and in 0.8% of VELSIPITY-treated subjects compared to none in placebo in UC-2 and UC-3. In UC-1, UC-2, and UC-3, Mobitz type II second- or third-degree AV blocks were not reported in VELSIPITY-treated subjects.

If treatment with VELSIPITY is considered, advice from a cardiologist should be sought for those individuals:

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With significant QT prolongation (QTcF ≥450 msec in males, ≥470 msec in females)

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With arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs or QT prolonging drugs [see Drug Interactions (7)]

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With unstable ischemic heart disease, Class I or II heart failure, history of cardiac arrest, cerebrovascular disease, or uncontrolled hypertension [see Contraindications (4)]

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With resting heart rate of less than 50 bpm

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With history of symptomatic bradycardia, recurrent cardiogenic syncope, or severe untreated sleep apnea

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With history of Mobitz type I second-degree AV block, unless the patient has a functioning pacemaker [see Contraindications (4)]

5.3 Liver Injury

Elevations of aminotransferases may occur in patients receiving VELSIPITY. In UC-1, elevations of alanine transaminase (ALT) greater than 3-fold the upper limit of normal (ULN) occurred in 4.5% of subjects who received VELSIPITY and 2.1% of subjects who received placebo. In UC-2 and UC-3, elevations of ALT greater than 3-fold the ULN occurred in 2.5% of subjects who received VELSIPITY and 0.5% of subjects who received placebo.

Obtain transaminase and bilirubin levels, if not recently available (i.e., within last 6 months), before initiation of VELSIPITY.

Obtain transaminases and bilirubin in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. Discontinue VELSIPITY if significant liver injury is confirmed.

5.4 Macular Edema

S1P receptor modulators, including VELSIPITY, 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 VELSIPITY. Periodically conduct an evaluation of the fundus, including the macula, while on therapy and any time there is a change in vision.

Macular edema over an extended period of time (i.e., 6 months) can lead to permanent visual loss. Consider discontinuing VELSIPITY if macular edema develops.

5.5 Increased Blood Pressure

In UC-1 and UC-2 and UC-3, subjects treated with VELSIPITY had an average increase of approximately 1 to 4 mm Hg in systolic blood pressure and approximately 1 to 2 mm Hg in diastolic blood pressure compared to <1.5 mm Hg and <1 mm Hg in subjects receiving placebo, respectively. The increase was first detected after 2 weeks of treatment and remained within the specified average range of BP increases throughout treatment. Hypertension was reported as an adverse reaction in UC-1 [see Adverse Reactions (6.1)].

Monitor blood pressure during treatment with VELSIPITY and manage appropriately.

5.6 Fetal Risk

Based on animal studies, VELSIPITY may cause fetal harm when administered to a pregnant woman. In animal reproduction studies conducted in rats and rabbits, embryofetal toxicity was observed with administration of etrasimod at clinically relevant doses. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception to avoid pregnancy during and for one week after stopping VELSIPITY [see Use in Specific Populations (8.1, 8.3)].

5.7 Malignancies

Cases of malignancies (including skin malignancies) have been reported in patients treated with S1P receptor modulators. 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 (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

5.8 Posterior Reversible Encephalopathy Syndrome

Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving S1P receptor modulators. If a patient develops any neurological or psychiatric symptoms/signs (e.g., cognitive deficits, behavioral changes, cortical visual disturbances, or any other neurological cortical symptoms/signs), any symptom/sign suggestive of an increase of intracranial pressure, or accelerated neurological deterioration, the physician should promptly schedule a complete physical and neurological examination and should consider an MRI. 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, discontinue treatment with VELSIPITY.

5.9 Respiratory Effects

Reductions in absolute forced expiratory volume over 1 second (FEV1) were observed in subjects treated with VELSIPITY as early as 3 months after treatment initiation. In UC-1, the decline in absolute FEV1 from baseline in subjects treated with VELSIPITY compared to placebo was 79 mL (95% CI: -152, -5) at 3 months. In UC-2, reductions in absolute FEV1 were not observed. There is insufficient information to determine the reversibility of the decrease in FEV1 after drug discontinuation. In UC-1 and UC-2, subjects with UC and asthma and/or chronic obstructive pulmonary disease were treated with VELSIPITY; however, interpretation of changes in pulmonary function test measures in this population are limited due to small sample sizes. Spirometric evaluation of respiratory function should be performed during therapy with VELSIPITY if clinically indicated.

5.10 Unintended Additive Immune System Effects from Prior Treatment with Immunosuppressive or Immune-Modulating Drugs

When switching to VELSIPITY from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects [see Drug Interactions (7)].

5.11 Immune System Effects After Stopping VELSIPITY

After stopping VELSIPITY, lymphocyte counts returned to the normal range in 90% of subjects within 4 to 5 weeks of stopping VELSIPITY [see Clinical Pharmacology (12.2)]. Use of immunosuppressants within this period may lead to an additive effect on the immune system, and therefore monitor patients receiving concomitant immunosuppressants for infectious complications up to 5 weeks after the last dose of VELSIPITY [see Drug Interactions (7)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of VELSIPITY 2 mg once daily in subjects with moderately to severely active ulcerative colitis was evaluated in two randomized, placebo-controlled studies of 52 weeks (UC-1) and 12 weeks (UC-2) duration [see Clinical Studies (14)]. Additional safety data were obtained from a randomized, double-blind, placebo-controlled dose-finding study of 12 weeks duration (UC-3).

In the 52-week study (UC-1), 433 subjects were enrolled of whom 289 received VELSIPITY 2 mg once daily. In the 12-week studies (UC-2 and UC-3), 458 subjects were enrolled of whom 288 received VELSIPITY 2 mg once daily.

Table 1 summarizes the adverse reactions reported in at least 2% of subjects and at a higher rate than placebo during UC-1.

Table 2 summarizes the adverse reactions reported in at least 2% of subjects and at a higher rate than placebo during UC-2 and UC-3.

Ophthalmologic Findings

In UC-1, for subjects with a baseline and follow-up examination, a decrease in visual acuity was reported in 2.6% (4/156) of subjects who received VELSIPITY and no subjects who received placebo [see Warnings and Precautions (5.4)].

8.1 Pregnancy

8.2 Lactation

Risk Summary

There are no data on the presence of etrasimod in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. When etrasimod was orally administered to female rats during pregnancy and lactation, etrasimod was detected in the plasma of the offspring, suggesting excretion of etrasimod in milk.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for VELSIPITY and any potential adverse effects on the breastfed infant from VELSIPITY or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Based on animal data, VELSIPITY may cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].

8.4 Pediatric Use

The safety and effectiveness of VELSIPITY in pediatric patients have not been established.

8.5 Geriatric Use

Of the 577 VELSIPITY-treated subjects in the three clinical trials (UC-1, UC-2, and UC-3), 30 subjects (5%) were 65 years of age and older, while 3 subjects (<1%) were 75 years of age and older. Clinical studies of VELSIPITY did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger adult subjects. The pharmacokinetics of etrasimod are similar in subjects 65 years of age and older compared to younger adult subjects [see Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

Etrasimod undergoes extensive hepatic metabolism. Exposure to etrasimod was similar in subjects with mild and moderate hepatic impairment (Child-Pugh A and B) compared to subjects with normal hepatic function; however, etrasimod exposure was increased in subjects with severe hepatic impairment (Child-Pugh C) compared to subjects with normal hepatic function [see Clinical Pharmacology (12.3)].

Use of VELSIPITY in patients with severe hepatic impairment is not recommended. No dosage adjustment is needed in patients with mild to moderate hepatic impairment.

8.7 CYP2C9 Poor Metabolizers

Increased exposure of etrasimod in patients who are CYP2C9 poor metabolizers is expected with concomitant use of moderate to strong inhibitors of CYP2C8 or CYP3A4. Concomitant use of VELSIPITY is not recommended in these patients [see Clinical Pharmacology (12.3, 12.5)].

12.1 Mechanism of Action

Etrasimod is a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptors 1, 4, and 5 (S1P1,4,5). Etrasimod has minimal activity on S1P3 (25-fold lower than Cmax at the recommended dose) and no activity on S1P2. Etrasimod partially and reversibly blocks the capacity of lymphocytes to egress from lymphoid organs, reducing the number of lymphocytes in peripheral blood. The mechanism by which etrasimod exerts therapeutic effects in UC is unknown but may involve the reduction of lymphocyte migration into the intestines.

12.2 Pharmacodynamics

Reduction in Blood Lymphocyte Counts

VELSIPITY causes a reduction in peripheral blood lymphocyte count [see Warnings and Precautions (5.1)]. In UC-1 and UC-2, mean lymphocyte counts decreased to approximately 50% of baseline at 2 weeks (approximate mean blood lymphocyte counts 0.9 x 109/L) and the lower lymphocyte counts were maintained during treatment with VELSIPITY.

Dose-response relationship analysis indicates there is a dose-dependent reduction in blood lymphocyte counts. After discontinuing VELSIPITY 2 mg once daily, the median time for peripheral blood lymphocytes to return to the normal range was 2.6 weeks, with approximately 90% of subjects in the normal range within 4.7 weeks.

Reduction in Heart Rate and AV Conduction Delays

VELSIPITY may result in a transient decrease in heart rate and AV conduction upon treatment initiation [see Warnings and Precautions (5.2)]. In UC-1 and UC-2, the mean (SD) decrease in heart rate was 7.2 (8.98) bpm at 2 to 3 hours after the first dose of VELSIPITY on Day 1.

Cardiac Electrophysiology

At 2 times the maximum recommended dose, etrasimod does not cause clinically significant QTc interval prolongation.

Pulmonary Function

Reductions in absolute FEV1 were observed in subjects treated with VELSIPITY [see Warnings and Precautions (5.9)].

Drug Interaction Studies

No clinically significant differences in heart rate reduction were observed when etrasimod was used concomitantly with stable beta blocker treatment. The effect of concomitant use of etrasimod with a calcium channel blocker on heart rate reduction is unknown [see Drug Interactions (7)].

12.3 Pharmacokinetics

Etrasimod mean (SD) steady-state maximum plasma concentration (Cmax) was 113 (27.5) ng/mL and area under the time concentration curve at the dosing interval (AUCtau) was 2162 (488) ng*h/mL at the recommended dosage. Etrasimod Cmax and AUC are approximately dose proportional from 0.7 mg to 2 mg (0.35 times up to the recommended dosage). Etrasimod steady state is reached within 7 days with an accumulation of approximately 2- to 3-fold compared to the first dose.

Absorption

The median (range) time to reach etrasimod Cmax (Tmax) is approximately 4 hours (range 2 to 8 hours) after oral administration.

Effect of Food

No clinically significant differences in the pharmacokinetics of etrasimod were observed following administration of VELSIPITY with a high-fat meal (800 to 1000 calories) [see Dosage and Administration (2.2)].

Distribution

The mean apparent volume of distribution of etrasimod is 66 (24) L. Etrasimod plasma protein binding is 97.9%.

Elimination

The mean plasma elimination half-life (t1/2) of etrasimod is approximately 30 hours with an apparent steady-state oral clearance of approximately 1 L/h after oral administration.

Metabolism

Etrasimod is metabolized by oxidation and dehydrogenation mediated primarily by CYP2C8, CYP2C9, and CYP3A4, with a minor contribution by CYP2C19 and CYP2J2. Etrasimod also undergoes conjugation primarily mediated by UGTs, with a minor contribution by sulfotransferases. Unchanged etrasimod is the main circulating component in plasma.

Excretion

Approximately 82% of total radioactive etrasimod dose was recovered in the feces and 5% in the urine within 336 hours. Approximately 11% of administered radioactive dose was excreted as unchanged etrasimod in feces and none was excreted unchanged in urine.

Specific Populations

No clinically significant differences in the pharmacokinetics of etrasimod were observed based on age (>65 years), sex, body weight, race, ethnicity, disease (healthy subjects vs. subjects with ulcerative colitis), and severe renal impairment (eGFR ≤29 mL/min).

Patients with Hepatic Impairment

Etrasimod AUC increased by 13% in subjects with mild (Child-Pugh A), 29% in moderate (Child-Pugh B), and 57% in severe (Child-Pugh C) hepatic impairment, respectively, compared with subjects with normal liver function. No clinically significant difference in the unbound etrasimod AUC was observed [see Use in Specific Populations (8.6)].

Drug Interaction Studies

Clinical Studies

Combined moderate CYP2C9 and CYP3A4 inhibitors: Concomitant use of etrasimod with steady-state fluconazole (moderate CYP2C9 and CYP3A4 inhibitor) increased etrasimod AUC by 84% [see Drug Interactions (7)].

Combined CYP3A4 (strong), CYP2C8 (moderate) and CYP2C9 (moderate) inducers: Concomitant use of etrasimod with rifampin (strong CYP3A4, moderate CYP2C8, and CYP2C9 inducer) decreased etrasimod AUC by 49% [see Drug Interactions (7)].

Oral Contraceptives: No clinically significant differences in the pharmacokinetics and pharmacodynamics of oral contraceptive containing 30 mcg ethinyl estradiol and 150 mcg levonorgestrel were observed when used concomitantly with etrasimod.

Other Drugs: Itraconazole (a P-gp and strong CYP3A inhibitor) increased etrasimod AUC by 32%. Gemfibrozil (an inhibitor of OATP1B1 and OAT3 and a strong inhibitor of CYP2C8) increased etrasimod AUC by 36%. These effects are unlikely to be clinically significant.

In Vitro Studies

Based on in vitro studies, etrasimod is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, nor an inducer of CYP1A2, CYP2B6, and CYP3A4 at clinically relevant concentrations.

Etrasimod is not an inhibitor of UGT1A3, UGT1A4, UGT1A9, UGT2B7, or UGT2B17 in vitro.

Etrasimod is not a substrate or an inhibitor of P-gp, BCRP, BSEP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, and MATE2-K transporters.

12.5 Pharmacogenomics

CYP2C9 activity is decreased in individuals with genetic variants such as CYP2C9*2 and CYP2C9*3 alleles. The impact of CYP2C9 genetic variants on the pharmacokinetics of etrasimod has not been directly evaluated. CYP2C9 poor metabolizers (e.g., *2/*3, *3/*3) may have decreased clearance of etrasimod when VELSIPITY is used concomitantly with moderate to strong inhibitors of CYP2C8 or CYP3A4 [see Drug Interactions (7) and Use in Specific Populations (8.7)].

CYP2C9 intermediate metabolizers (e.g., *1/*2, *1/*3, *2/*2) may have decreased clearance of etrasimod when VELSIPITY is used concomitantly with moderate to strong inhibitors of CYP2C8 or CYP3A4; however, the effect on VELSIPITY exposure in CYP2C9 intermediate metabolizers with concomitant CYP2C8 or CYP3A4 inhibitors is not known.

The prevalence of the CYP2C9 poor metabolizer phenotype is approximately 2 to 3% in White populations, 0.5 to 4% in Asian populations, and <1% in African-American populations. Other decreased or nonfunctional CYP2C9 alleles (e.g., *5, *6, *8, *11) are more prevalent in African-American populations.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Oral carcinogenicity studies with etrasimod were conducted in mice and rats. In mice administered etrasimod (2, 6, or 20 mg/kg/day) for up to 104 weeks, there was an increase in hemangiosarcoma and hemangioma in males and females at 6 and 20 mg/kg/day (exposures approximately 42 and 121 times, respectively, the exposure at the MRHD of 2 mg, based on AUC comparison). In rats, oral administration of etrasimod (2, 6, or 20 mg/kg/day) for up to 91 weeks did not result in an increase in tumors (male and female exposures 80 and 179 times, respectively, the exposure at the MRHD).

Mutagenesis

Etrasimod was negative in a battery of in vitro (Ames, chromosomal aberration in human peripheral blood lymphocytes) and in vivo (rat micronucleus) assays.

Impairment of Fertility

Etrasimod administered orally to male rats at 25, 100, or 200 mg/kg/day from pre-mating through mating had no adverse effects on male fertility at exposures up to 467 times the exposure at the MRHD of 2 mg, based on AUC comparison. Etrasimod administered orally to female rats at 1, 2, or 4 mg/kg/day from pre-mating to implantation had no adverse effects on female fertility at exposures up to 21 times the exposure at the MRHD.