etrasimod

Etrasimod is a medication used in the treatment of adults with moderately-to-severely active ulcerative colitis, a chronic inflammatory disease that affects the gastrointestinal (GI) tract. Etrasimod is an oral drug that belongs to a class of medications known as sphingosine 1-phosphate receptor modulators. Etrasimod is the second drug in this class for treating ulcerative colitis approved by the FDA in October 2023.

The exact mechanism of etrasimod in ulcerative colitis is unclear, but it is believed to control inflammation in the GI tract by reducing the migration of lymphocytes to the intestines. Lymphocytes are immune cells that develop in the thymus gland and bone marrow and are found in large numbers in the intestines promoting inflammation in ulcerative colitis. Etrasimod blocks the ability of lymphocytes to egress from the lymphoid organs and migrate to the bowel.

Sphingosine 1-phosphate (S1P), a fatty signaling molecule produced and secreted by red blood cells, endothelial cells and platelets, plays an important role in many cellular processes. S1P signaling through S1P receptors enables migration of lymphocytes to the intestines. Etrasimod binds to three types of S1P receptors, 1, 4 and 5 and prevents lymphocytes from leaving the lymphoid organs, entering the bloodstream and then into the intestines.

• Do not use etrasimod to treat patients who have experienced any of the following conditions within the previous 6 months:
  • Heart attack (myocardial infarction)
  • Worsening chest pain (unstable angina pectoris)
  • Stroke
  • Brief impairment of blood flow to brain (transient ischemic attack/TIA)
  • Class III or IV heart failure
  • Decompensated heart failure requiring hospitalization
• Do not use etrasimod to treat patients with a history of heart rhythm disorders (unless they have a functional pacemaker) including:
  • Mobitz type II second-degree or third-degree atrioventricular block
  • Sino-atrial block
  • Sick sinus syndrome
• Etrasimod reduces lymphocyte count in blood and hence can increase the risk for infections, including life-threatening, and rarely, fatal infections.
  • Obtain the patient’s lymphocyte count before initiating etrasimod.
  • Delay etrasimod treatment if the patient has an active infection until the infection is cleared.
  • Monitor patient for development of infection during treatment and for 5 weeks after discontinuation of etrasimod.
  • If the patient develops signs and symptoms of any serious infection, withhold etrasimod, evaluate the patient and treat the infection promptly.
• Serious infections that can develop in a patient treated with etrasimod include:
  • Herpes viral infections including herpes simplex encephalitis, varicella zoster meningitis, and localized herpes viral infections. Before starting etrasimod:
    • Test for varicella zoster virus (VZV) antibodies in patients without documented history of chickenpox or VZV immunization.
    • Administer a full course of VZV vaccination in patients negative for antibodies and delay therapy for 4 weeks to let vaccination take effect.
  • Cryptococcal meningitis (CM) and disseminated cryptococcal infections.
  • Progressive multifocal leukoencephalopathy (PML) caused by JC virus, an opportunistic viral infection that affects the brain, and associated complications that can result in severe disability or death. Discontinue etrasimod if PML is diagnosed, treat appropriately and continue monitoring for complications.
• There is no information on the safety and efficacy of vaccinations during treatment with etrasimod. Vaccinations may be less effective.
• Do not use live attenuated vaccines during treatment with etrasimod. Live attenuated vaccines should be administered 4 weeks before or at least 5 weeks after treatment.
• Avoid other anticancer, immune-modulating, or non-corticosteroid immunosuppressive therapies concurrently with etrasimod or within a few weeks of etrasimod treatment. It can have additive immunosuppressive effects.
• Etrasimod can cause transient slowing down of heart rate (bradycardia) in some patients, with or without symptoms, which typically resolves on its own. Etrasimod can also cause transient electrical disturbances such as atrioventricular (AV) conduction delays. Consult with a cardiologist before prescribing etrasimod to patients with:
  • Significant QT prolongation
  • Rhythm disorders that require Class Ia or Class III anti-arrhythmic drugs or QT prolonging drugs
  • History of Mobitz type I second-degree AV block, unless the patient has a functioning pacemaker
  • Uncontrolled hypertension, unstable ischemic heart disease, Class I or II heart failure, history of cardiac arrest or cerebrovascular disease
  • Resting heart rate below 50 bpm
  • Symptomatic bradycardia, severe untreated sleep apnea of recurrent heart-related fainting episodes (cardiogenic syncope)
• Etrasimod can cause liver injury. Obtain liver function tests before initiating etrasimod. Advise patients to report liver-related symptoms, evaluate, and if significant liver injury is confirmed, discontinue etrasimod.
• Etrasimod therapy can increase the risk of macular edema. Monitor the patient’s macular and vision status periodically and discontinue if the patient develops macular edema.
• Etrasimod can increase blood pressure. Monitor the patient’s blood pressure during etrasimod treatment and manage appropriately.
• Etrasimod can cause fetal harm if used during pregnancy. Advise women of pregnancy potential to use effective contraception for the recommended period during and after treatment.
• Malignancies, including skin malignancies, have been associated with S1P receptor modulator treatment.
  • Perform regular skin examinations before and during treatment with etrasimod, particularly in patients with high risk for cancer.
  • Investigate any suspicious skin lesions.
  • Advise patients to use sunscreen and other measures to reduce exposure to sunlight and ultraviolet, and to report unusual skin lesions.
• Although rare, etrasimod has been known to lead to posterior reversible encephalopathy syndrome (PRES), a condition that can cause neurologic and psychiatric symptoms. Advise patient to report such symptoms and if PRES is confirmed, discontinue etrasimod.
• Etrasimod can have respiratory effects. Monitor the patient’s lung function during treatment with etrasimod, particularly in ulcerative colitis patients with pulmonary conditions such as asthma or chronic obstructive pulmonary disease (COPD).
• When switching from drugs with prolonged immune effects to etrasimod, consider the half-life and mode of action of these drugs to prevent unintended additive immune suppression.
• Lymphocytes typically return to normal ranges in 4 to 5 weeks after treatment with etrasimod. Use of other immunosuppressive drugs can have additive effects. Monitor patients on concurrent immunosuppressants for infection for at least up to 5 weeks after final dose of etrasimod.

Common side effects of etrasimod include:

• Headache
• Migraine
• Elevated liver function tests including:
  • Increase in transaminases ALT and AST
  • Increase in alkaline phosphatase (ALK)
  • Increase in gamma-glutamyl transferase (GGT)
  • High bilirubin level in blood (hyperbilirubinemia)
  • Impaired bile flow (cholestasis)
• Dizziness
• Joint pain (arthralgia)
• Nausea
• High blood pressure (hypertension)
• High cholesterol levels in blood (hypercholesterolemia)
• Transient slow heart rate (bradycardia)
• Transient atrioventricular conduction delays
• Urinary tract infection
• Bladder inflammation (cystitis)
• Genitourinary infection
• Herpes viral infections including:
  • Herpes zoster
  • Oral herpes
  • Herpes simplex
• Increased risk for serious infections such as:
  • Progressive multifocal leukoencephalopathy
  • Cryptococcal meningitis
• Decrease in visual acuity
• Swelling of macula, the central portion of the retina (macular edema)
• Malignancies
• Posterior reversible encephalopathy syndrome, a neurological disorder

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Tablet

• 2 mg

Adult:

Ulcerative Colitis

• Indicated for adults with moderately-to-severely active ulcerative colitis (UC)
• 2 mg orally once daily

Dosage Modifications

Renal impairment

• Minimally excreted in urine; no dosage adjustment necessary

Hepatic impairment

• Mild or moderate (Child-Pugh A and B): No dosage adjustment necessary
• Severe (Child-Pugh C): Not recommended

Dosing Considerations

Assessments, medications, and vaccinations before initiating

• Complete blood count (CBC): Obtain recent (i.e., within last 6 months or after discontinuation of prior UC therapy), including lymphocyte count
• Cardiac evaluation: Obtain electrocardiogram (ECG) to determine whether preexisting conduction abnormalities are present; consult cardiologist in patients with certain preexisting conditions
• Liver function tests: Obtain recent (i.e., within last 6 months) transaminase and bilirubin levels
• Ophthalmic assessment: Obtain baseline evaluation of the fundus, including the macula, near the start of treatment
• Current or prior medications
  • Determine if patients are taking drugs that could slow heart rate or atrioventricular (AV) conduction
  • If patients are taking antineoplastic, immune modulating, or non-corticosteroid immunosuppressive therapies, or history of prior use, consider possible unintended additive immunosuppressive effects before initiating
• 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
  • VZV vaccination of antibody-negative patients is recommended before starting treatment
  • If live attenuated vaccine immunizations are required, administer at least 4 weeks before initiating
  • Update immunizations in agreement with current immunization guidelines before initiating
• Skin examination
  • Obtain skin examination before or shortly after initiating
  • If suspicious skin lesion observed, promptly evaluate

Pediatric:

• Safety and efficacy not established

Overdose

There is no information available on etrasimod overdose.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Etrasimod has no listed severe interactions with other drugs.
• Etrasimod has serious interactions with at least 332 different drugs.
• Etrasimod has moderate interactions with at least 73 different drugs.
• Etrasimod has no listed mild interactions with other drugs.

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• There is insufficient data available on the use of etrasimod in pregnant women to identify a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal studies indicate etrasimod can cause fetal harm if administered during pregnancy.
• Published data suggest that inflammatory bowel disease is associated with increased disease activity during pregnancy and can lead to adverse pregnancy outcomes including preterm delivery, low birth weight infants, and small for gestational age at birth.
• Advise women of reproductive potential to practice effective contraception during treatment with etrasimod and for one week following the last dose.
• There is no information on the presence of etrasimod in breastmilk or its effects on milk production or the breastfed infant. 
• Decision to breastfeed should be based on the nursing mother’s clinical need for etrasimod, health and developmental benefits of breastfeeding, and the risks to the breastfed infant from exposure to the drug or the mother’s underlying condition.
• There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to etrasimod (Velsipity) during pregnancy. Pregnant women exposed to Velisipity and healthcare providers are encouraged to contact the pregnancy registry by calling 1-800-616-3791.

• Take etrasimod exactly as prescribed.
• Report to your physician immediately if you experience:
  • Any signs and symptoms of an infection
  • Symptoms of progressive multifocal leukoencephalopathy (PML), a viral brain infection that can cause neurological and psychiatric symptoms, which include progressive weakness on one side of the body, clumsiness of limbs, vision disturbance, altered mental status and confusion
  • Liver-related symptoms such as unexplained nausea, vomiting, abdominal pain, loss of appetite, fatigue, or jaundice and/or dark urine
  • Vision changes
  • New onset or worsening of shortness of breath
  • Symptoms of posterior reversible encephalopathy syndrome including headache, seizure, visual disturbances or altered mental status
• Reduce your exposure to direct sunlight and ultraviolet light, wear protective clothing and use a sunscreen with a high protection factor. Report to your physician immediately if you notice any unusual skin lesion.
• Do not take live vaccinations during, within 4 weeks prior to and 5 weeks after treatment with etrasimod.
• Store etrasimod carefully out of reach of children.
• In the event of suspected or actual overdose, seek medical care or contact Poison Control.