Etrasimod (Monograph)

Brand name: Velsipity
Drug class: Immunomodulatory Agents

Introduction

Etrasimod is a sphingosine 1-phosphate (S1P) receptor modulator.

Uses for Etrasimod

Etrasimod has the following uses:

Etrasimod is indicated for the treatment of moderately to severely active ulcerative colitis in adults.

Etrasimod Dosage and Administration

General

Etrasimod is available in the following dosage form(s) and strength(s):

Tablets: 2 mg of etrasimod

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Assessments and vaccinations are required prior to initiating etrasimod (see Full Prescribing Information for additional details).

• The recommended dosage of etrasimod is 2 mg orally once daily. Swallow tablets whole, with or without food.

Cautions for Etrasimod

Contraindications

• Patients who have experienced a myocardial infarction, unstable angina pectoris, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III or IV heart failure in the last 6 months.

• 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.

Warnings/Precautions

Infections

Etrasimod 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. Etrasimod 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 ulcerative colitis therapy) CBC, including lymphocyte count.

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

In the UC-1 study, the overall rate of infections in subjects treated with etrasimod was 24.9% compared to 22.2% in subjects who received placebo. In pooled data from the UC-2 and UC-3 studies, the overall rate of infections in subjects treated with etrasimod 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.

The proportion of subjects treated with etrasimod 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.

Consider interruption of treatment with etrasimod 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 etrasimod, 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 etrasimod should be suspended until PML has been excluded by an appropriate diagnostic evaluation. If PML is confirmed, discontinue treatment with etrasimod.

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 etrasimod 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 etrasimod.

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. Etrasimod 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 Antineoplastic, Immunomodulating, or Non-corticosteroid Immunosuppressive Therapies

Etrasimod has not been studied in combination with antineoplastic, immunomodulating, or non-corticosteroid immunosuppressive therapies. Avoid concomitant administration of these therapies with etrasimod and in the weeks following administration because of the risk of additive immunosuppressive effects.

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 etrasimod. A full course of VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with etrasimod, following which initiation of treatment with etrasimod 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 etrasimod. Vaccinations may be less effective if administered during etrasimod treatment.

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

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

Bradyarrhythmia and Atrioventricular Conduction Delays

Initiation of etrasimod may result in a transient decrease in heart rate. After the first dose of etrasimod 2 mg, subjects with ulcerative colitis experienced the greatest mean decrease from baseline in heart rate of 7.2 bpm at Hour 3 in the UC-1 study and Hour 2 in the UC-2 study. In UC-1, bradycardia was reported on the day of treatment initiation in 1% of subjects treated with etrasimod compared to none in subjects who received placebo. On Day 2, bradycardia was reported in 1 subject (0.3%) treated with etrasimod compared to none in subjects who received placebo. In the UC-2 and UC-3 studies, bradycardia was reported on the day of treatment initiation in 2.9% of subjects treated with etrasimod compared to none in subjects who received placebo. On Day 2, bradycardia was reported in 1 subject (0.3%) treated with etrasimod 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.

Initiation of etrasimod may result in transient AV conduction delays. On the day of treatment initiation of etrasimod 2 mg, first- or second-degree Mobitz type I AV blocks were observed in 0.7% of etrasimod-treated subjects compared to none in placebo in UC-1, and in 0.8% of etrasimod-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 etrasimod-treated subjects.

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

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

• With arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs or QT prolonging drugs

• With unstable ischemic heart disease, Class I or II heart failure, history of cardiac arrest, cerebrovascular disease, or uncontrolled hypertension

• With resting heart rate of less than 50 bpm

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

• With history of Mobitz type I second-degree AV block, unless the patient has a functioning pacemaker

Liver Injury

Elevations of aminotransferases may occur in patients receiving etrasimod. In UC-1, elevations of alanine transaminase (ALT) to 3-fold the upper limit of normal (ULN) occurred in 4.5% of subjects who received etrasimod and 2.1% of subjects who received placebo. In UC-2 and UC-3, elevations of ALT to 3-fold the ULN occurred in 2.5% of subjects who received etrasimod 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 etrasimod. 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 etrasimod if significant liver injury is confirmed.

Macular Edema

S1P receptor modulators, including etrasimod, 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 etrasimod. 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 etrasimod if macular edema develops.

Increased Blood Pressure

In UC-1 and UC-2 and UC-3, subjects treated with etrasimod 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.

Monitor blood pressure during treatment with etrasimod and manage appropriately.

Fetal Risk

Based on animal studies, etrasimod 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 etrasimod.

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.

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 etrasimod.

Respiratory Effects

Reductions in absolute forced expiratory volume over 1 second (FEV₁) were observed in subjects treated with etrasimod as early as 3 months after treatment initiation. In UC-1, the decline in absolute FEV₁ from baseline in subjects treated with etrasimod 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 ulcerative colitis and asthma and/or chronic obstructive pulmonary disease were treated with etrasimod; 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 etrasimod if clinically indicated.

Unintended Additive Immune System Effects from Prior Treatment with Immunosuppressive or Immunomodulating Drugs

When switching to etrasimod from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.

Immunosuppression Following Discontinuance of Therapy

After stopping etrasimod, lymphocyte counts returned to the normal range in 90% of subjects within 4 to 5 weeks of stopping etrasimod. 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 etrasimod.

Specific Populations

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to etrasimod during pregnancy. Pregnant females exposed to etrasimod and healthcare providers are encouraged to contact the pregnancy registry by calling 1-800-616-3791.

Based on findings from animal studies, etrasimod may cause fetal harm when administered to a pregnant woman. Available data from reports of pregnancies from the clinical development program with etrasimod 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.

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 etrasimod 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.

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.

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.

Lactation

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 etrasimod and any potential adverse effects on the breastfed infant from etrasimod or from the underlying maternal condition.

Females and Males of Reproductive Potential

Based on animal data, etrasimod may cause fetal harm when administered to pregnant women.

Before initiation of etrasimod 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 etrasimod and for one week following the last dose.

Pediatric Use

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

Geriatric Use

Of the 577 etrasimod-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 etrasimod did not include sufficient numbers of subjects 65 years of age 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.

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.

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

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 etrasimod is not recommended in these patients.

Common Adverse Effects

Most common adverse reactions (incidence ≥5%) are headache, elevated liver tests, and dizziness.

Related/similar drugs

Entyvio, Zeposia, dexamethasone, hydrocortisone, Humira, Stelara, Remicade

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

See full prescribing information for a list of clinically important drug interactions.

Actions

Mechanism of Action

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 S1P₃ (25-fold lower than C_max 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 ulcerative colitis is unknown but may involve the reduction of lymphocyte migration into the intestines.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Medication Guide).

• Inform patients that they may be more likely to get infections, some of which could be life-threatening, when taking etrasimod and for 5 weeks after stopping it, and that they should contact their healthcare provider if they develop symptoms of infection. Inform patients that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection.

• Advise patients that some vaccines containing live virus (live attenuated vaccines) should be avoided during treatment with etrasimod. Advise patients that if immunizations are planned, they should be administered at least 4 weeks prior to initiation of etrasimod. Inform patients that the use of live attenuated vaccines should be avoided during and for 5 weeks after treatment with etrasimod.

• Advise patients that initiation of etrasimod treatment may result in transient decrease in heart rate.

• Inform patients that etrasimod may increase liver enzymes. Advise patients that they should contact their healthcare provider if they have any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine.

• Advise patients that etrasimod may cause macular edema, and that they should obtain an eye exam near the start of treatment with etrasimod, have their eyes monitored periodically by an eye care professional while receiving therapy, and contact their healthcare provider if they experience any changes in their vision while taking etrasimod.

• Etrasimod may cause fetal harm. Advise females to immediately inform their healthcare provider of a known or suspected pregnancy.

• Advise females of reproductive potential to use effective contraception during treatment with etrasimod and for one week after stopping etrasimod.

• Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to etrasimod during pregnancy.

• Advise patients to limit exposure to sunlight and ultraviolet (UV) light, wear protective clothing, and use a sunscreen with a high protection factor. If a suspicious skin lesion is observed, patients should immediately report it to their healthcare provider.

• Advise patients to immediately report to their healthcare provider any symptoms involving sudden onset of severe headache, altered mental status, visual disturbances, or seizure. Inform patients that delayed treatment could lead to permanent neurological consequences.

• Advise patients that they should contact their healthcare provider if they experience new onset or worsening dyspnea.

• Advise patients that etrasimod continues to have effects, such as lowering effects on peripheral lymphocyte count, for up to 5 weeks after the last dose, and to monitor for signs and symptoms of infection during that time.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Reload page with references included

Medical Disclaimer