Etrasimod

VELSIPITY is indicated for the treatment of moderately to severely active ulcerative colitis (UC) in adults. VELSIPITY is a sphingosine 1-phosphate receptor modulator indicated for the treatment of moderately to severely active ulcerative colitis in adults. ( 1 )

Tablets: 2 mg of etrasimod as a round, green, film-coated tablet, debossed with “ETR” on one side and “2” on the other side. Tablets: 2 mg of etrasimod ( 3 )

VELSIPITY is contraindicated in patients who:

• In the last 6 months, have experienced a myocardial infarction, unstable angina pectoris, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III or IV heart failure [see Warnings and Precautions (5.2) ] .
• Have a history or presence of Mobitz type II second-degree or third-degree AV block, sick sinus syndrome, or sino-atrial block, unless the patient has a functioning pacemaker [see Warnings and Precautions (5.2) ] .
• In the last 6 months, experienced myocardial infarction, unstable angina pectoris, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III or IV heart failure. ( 4 , 5.2 )
• History or presence of Mobitz type II second-degree or third-degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial block, unless the patient has a functioning pacemaker. ( 4 , 5.2 )

• Infections : May increase the risk of infections. Obtain a complete blood count (CBC) before initiation of treatment. Monitor for infection during treatment and for 5 weeks after discontinuation. Consider interruption of treatment if a serious infection develops. Avoid use of live attenuated vaccines during and for up to 5 weeks after treatment. ( 5.1 )
• Bradyarrhythmia and Atrioventricular Conduction Delays : May result in a transient decrease in heart rate and AV conduction delays. Obtain an electrocardiogram (ECG) to assess for preexisting cardiac conduction abnormalities before starting treatment. Consider cardiology consultation for conduction abnormalities or concomitant use with other drugs that decrease heart rate. ( 2.1 , 5.2 , 7 )
• Liver Injury : Elevations of aminotransferases may occur. Obtain transaminase and bilirubin levels before initiating VELSIPITY. Discontinue if significant liver injury is confirmed. ( 2.1 , 5.3 )
• Macular Edema : May increase the 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. Consider discontinuing VELSIPITY if macular edema develops. ( 2.1 , 5.4 )
• Increased Blood Pressure : Monitor blood pressure during treatment. ( 5.5 )
• Fetal Risk : May cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for one week after stopping VELSIPITY. ( 5.6 , 8.3 )
• Cutaneous Malignancies : Obtain a skin examination prior to or shortly after the start of treatment and periodically during treatment, especially if risk factors. Promptly evaluate suspicious skin lesions. ( 2.1 , 5.7 )
• Posterior Reversible Encephalopathy Syndrome (PRES) : If symptoms develop, obtain a physical and neurological exam, and consider MRI. ( 5.8 )
• Respiratory Effects : May cause a decline in pulmonary function. Assess pulmonary function (e.g., spirometry) if clinically indicated. ( 5.9 )
• Unintended Additive Immune System Effects from Prior Treatment with Immunosuppressive or Immune-Modulating Drugs : Consider the half-life and mode of action of prior therapies. ( 5.10 )
• Immune System Effects After Stopping VELSIPITY : If using concomitant immunosuppressants, monitor patients for infectious complications for up to 5 weeks after the last dose of VELSIPITY. ( 5.11 )

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 10 9 /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, and duration of use). Based on data from patients with MS, longer treatment duration increases the risk of PML in patients treated with S1P receptor modulators, and the majority of PML cases have occurred in patients treated with S1P receptor modulators for at least 18 months. VELSIPITY is not indicated for the treatment of MS. 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. […]

The following serious adverse reactions are described elsewhere in the labeling:

• Infections [see Warnings and Precautions (5.1) ]
• Bradyarrhythmia and Atrioventricular Conduction Delays [see Warnings and Precautions (5.2) ]
• Liver Injury [see Warnings and Precautions (5.3) ]
• Macular Edema [see Warnings and Precautions (5.4) ]
• Increased Blood Pressure [see Warnings and Precautions (5.5) ]
• Fetal Risk [see Warnings and Precautions (5.6) ]
• Cutaneous Malignancies [see Warnings and Precautions (5.7) ]
• Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.8) ]
• Respiratory Effects [see Warnings and Precautions (5.9) ]
• Unintended Additive Immune System Effects from Prior Treatment with Immunosuppressive or Immune-Modulating Drugs [see Warnings and Precautions (5.10) ]
• Immune System Effects After Stopping VELSIPITY [see Warnings and Precautions (5.11) ] Most common adverse reactions (incidence ≥5%) are: headache, elevated liver tests, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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 1: Adverse Reactions Reported in at least 2% of subjects and at a higher rate than placebo. in Subjects with Ulcerative Colitis in a Placebo-Controlled 52-Week Study (UC-1) Adverse Reaction VELSIPITY 2 mg Once Daily N = 289 % Placebo N = 144 % Headache Headache includes related terms headache, migraine, and tension headache. 9 5 Elevated liver tests Elevated liver tests includes related terms ALT increased, AST increased, blood alkaline phosphatase increased, cholestasis, GGT increased, hepatic enzyme increased, hyperbilirubinemia, liver function test increased, and transaminases increased. 6 5 Dizziness Dizziness includes related terms dizziness, dizziness exertional, and dizziness postural. 5 2 Arthralgia 4 2 Hypertension Hypertension includes related terms hypertension, and blood pressure increased. 3 1 Urinary tract infection Urinary tract infection includes related terms urinary tract infection and cystitis. 3 2 Nausea 3 1 Hypercholesterolemia Hypercholesterolemia includes related terms hypercholesterolemia and blood cholesterol increased. 3 0 Herpes viral infection Herpes viral infection includes related terms herpes zoster, oral herpes, and herpes simplex. 2 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. Table 2: Adverse Reactions Reported in at least 2% of subjects and at a higher rate than placebo. in Subjects with Ulcerative Colitis in Placebo-Controlled 12-Week Studies (UC-2 and UC-3) Adverse Reaction VELSIPITY 2 mg Once Daily N = 288 % Study-size adjusted % for each group are based on the Mantel-Haenszel weights. Placebo N = 170 % Headache Headache includes related terms headache, migraine, and sinus headache. 6 4 Elevated liver tests Elevated liver tests includes related terms ALT increased, AST increased, blood alkaline phosphatase increased, blood bilirubin increased, cholestasis, GGT increased, hepatic enzyme increased, hepatic function abnormal, liver function test abnormal, and transaminases increased. 5 <1 Nausea 4 2 Bradycardia Bradycardia includes related terms bradycardia, sinus bradycardia, and heart rate decreased. 3 0 Urinary tract infection Urinary tract infection includes related terms urinary tract infection, cystitis, and genitourinary tract infection. 3 0 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) ] .

Etrasimod is primarily metabolized by CYP2C8, CYP2C9, and CYP3A4. Table 3 includes drugs with clinically important drug interactions when administered concomitantly with VELSIPITY and instructions for preventing or managing them. Consult the labeling of concomitantly used drugs to obtain further information. The effect of concomitant use of VELSIPITY with a combination of separate drugs that are moderate to strong inhibitors or inducers of either CYP2C8, CYP2C9, or CYP3A4 is unknown. However, based on the information below, a similar clinically significant change in exposure cannot be ruled out when two or more metabolic pathways are affected. Table 3: Drugs That Affect VELSIPITY CYP-Mediated Metabolic Pathways Anti-Arrhythmic Drugs and QT Prolonging Drugs Clinical Impact A transient decrease in heart rate and AV conduction delays may occur when initiating VELSIPITY [see Warnings and Precautions (5.2) ] . Because of the potential additive effect on heart rate, VELSIPITY may increase the risk of QT prolongation and Torsades de Pointes with concomitant use of Class Ia and Class III anti-arrhythmic drugs and QT prolonging drugs. Prevention or Management Seek the advice of a cardiologist before initiating VELSIPITY treatment with Class Ia (e.g., quinidine, procainamide), Class III anti-arrhythmic drugs (e.g., amiodarone, sotalol), or other drugs that prolong the QT interval. Beta-Blockers or Calcium Channel Blockers Clinical Impact A transient decrease in heart rate and AV conduction delays may occur when initiating VELSIPITY [see Warnings and Precautions (5.2) ] . Concomitant use of VELSIPITY in patients receiving stable beta blocker treatment did not result in additive effects on heart rate reduction [see Clinical Pharmacology (12.2) ] . However, the risk of additive heart rate reduction following initiation of beta blocker therapy with stable VELSIPITY treatment or concomitant use with other drugs that may decrease heart rate is unknown. Prevention or Management VELSIPITY can be initiated in patients receiving stable doses of beta blocker treatment. Seek the advice of a cardiologist before initiating a beta blocker in a patient receiving stable VELSIPITY treatment or concomitant use with other drugs that may decrease heart rate (e.g., calcium channel blockers). Anti-Neoplastic, Immune-Modulating, or Non-Corticosteroid Immunosuppressive Therapies Clinical Impact Risk of additive immune system effects with VELSIPITY VELSIPITY has not been studied in combination with anti-neoplastic, immune-modulating, or non-corticosteroid immunosuppressive therapies. Prevention or Management Avoid concomitant administration during and in the weeks following administration of VELSIPITY. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects [see Warnings and Precautions (5.10) ] . Moderate to Strong Inhibitors of CYP2C9 and CYP3A4 Clinical Impact Increased exposure of etrasimod was observed with concomitant use with a drug that is a moderate inhibitor of CYP2C9 and a moderate inhibitor of CYP3A4 (i.e., fluconazole) [see Clinical Pharmacology (12.3) ] . Prevention or Management Concomitant use with a drug that is a moderate to strong inhibitor of CYP2C9 and a moderate to strong inhibitor of CYP3A4 is not recommended. CYP2C9 Poor Metabolizers Using Moderate to Strong Inhibitors of CYP2C8 or CYP3A4 Clinical Impact 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 [see Clinical Pharmacology (12.3 , 12.5) ] . Prevention or Management Concomitant use not recommended. Rifampin Clinical Impact Concomitant use with a drug that is a combined CYP3A4 (strong), CYP2C8 (moderate) and CYP2C9 (moderate) inducer (i.e., rifampin) decreases exposure to etrasimod [see Clinical Pharmacology (12.3) ] . Prevention or Management Concomitant use not recommended. See full prescribing information for a list of clinically important drug interactions. ( 7 )

Severe Hepatic Impairment : Use is not recommended. ( 8.6 )

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to VELSIPITY during pregnancy. Pregnant females exposed to VELSIPITY and healthcare providers are encouraged to contact the pregnancy registry by calling 1-800-616-3791. Risk Summary Based on findings from animal studies, VELSIPITY may cause fetal harm when administered to a pregnant woman. Available data from reports of pregnancies from the clinical development program with VELSIPITY are insufficient to identify a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with increased disease activity in women with inflammatory bowel disease during pregnancy (see Clinical Considerations ). In animal reproduction studies, administration of etrasimod during organogenesis produced adverse effects on development, including embryolethality and fetal malformations, in both rats and rabbits at maternal exposures 5 and 6 times, respectively, the exposure at the maximum recommended human dose (MRHD). Administration of VELSIPITY to pregnant rats during organogenesis through lactation resulted in decreased pup growth and viability at maternal exposures 5 times the exposure at the MRHD, as well as impaired reproductive performance in first generation offspring, including decreased implantations and increased pre-implantation loss at maternal exposures 24 times the exposure at the MRHD (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that the risk of adverse pregnancy outcomes in women with inflammatory bowel disease is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. Data Animal Data In an embryo-fetal development study in pregnant rats, etrasimod was orally administered at 1, 2, or 4 mg/kg/day (5, 11, and 21 times the exposure at the MRHD of 2 mg, based on AUC comparison) during the period of organogenesis, from gestation day 6 to 17. No maternal toxicity was observed up to 21 times the exposure at the MRHD. Increased post-implantation loss with a corresponding decrease in the number of viable fetuses was observed at 4 mg/kg/day (21 times the exposure at the MRHD). Etrasimod-related fetal external and/or visceral malformations were noted at all dose levels (≥5 times the exposure at the MRHD). In an embryo-fetal development study in pregnant rabbits, etrasimod was orally administered at 2, 10, or 20 mg/kg/day (0.8, 6, and 11 times the exposure at the MRHD of 2 mg, based on AUC comparison) during the period of organogenesis, from gestation day 7 to 20. Increased post-implantation loss with a corresponding decrease in the number of viable fetuses was observed at 10 and 20 mg/kg/day (6 and 11 times the exposure at the MRHD). Etrasimod-related fetal malformations including aortic arch defects and fused sternebrae were noted at 10 and/or 20 mg/kg/day (6 and 11 times the exposure at the MRHD). There were no adverse effects on embryofetal development at 2 mg/kg/day (less than the exposure at the MRHD). In a pre- and post-natal development study in rats, etrasimod was orally administered at 0.4, 2, or 4 mg/kg/day (2, 10, and 24 times the exposure at the MRHD of 2 mg, based on AUC comparison) throughout pregnancy and lactation, from gestation day 6 through lactation day 20. Mortality during delivery and impaired maternal performance including increased post-implantation loss, increased number of females with stillborn pups, increased number of stillborn pups per litter, decreased viability index, and/or decreased lactation index was observed at 2 and 4 mg/kg/day (10 and 24 times the exposure at the MRHD). Etrasimod was detected in the plasma of F1 offspring, indicating exposure from the milk of the lactating dam. Decreased pup body weights were observed during the preweaning period at all dose levels (maternal exposures ≥2 times the exposure at the MRHD), and decreased pup viability was observed at 2 and 4 mg/kg/day (maternal exposures 10 and 24 times the exposure at the MRHD). Reduced fertility and reproductive performance including reduction in implantations and increased preimplantation loss in F1 offspring occurred at the highest dose tested (maternal exposures 24 times the exposure at the MRHD).

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) ]. Contraception Females Before initiation of VELSIPITY treatment, females of reproductive potential should be counseled on the potential for a serious risk to the fetus and the need for effective contraception during treatment with VELSIPITY and for one week following the last dose [see Warnings and Precautions (5.6) and 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) ] .

Etrasimod is a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptors 1, 4, and 5 (S1P 1,4,5 ). Etrasimod has minimal activity on S1P 3 (25-fold lower than C max at the recommended dose) and no activity on S1P 2 . 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.