Etrasimod Arginine (Monograph)

Brand name: Velsipity
Drug class: Immunomodulatory Agents

Medically reviewed by Drugs.com on Nov 10, 2024. Written by ASHP.

Introduction

Sphingosine 1-phosphate (S1P) receptor modulator.

Uses for Etrasimod Arginine

Ulcerative Colitis

Treatment of moderately to severely active ulcerative colitis in adults.

Etrasimod Arginine Dosage and Administration

General

Pretreatment Screening

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

• Obtain a baseline ECG to determine if preexisting cardiac conduction abnormalities are present; in patients with certain preexisting conditions, seek advice from a cardiologist.

• Obtain recent (i.e., within last 6 months) transaminase and bilirubin levels.

• Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with etrasimod.

• Obtain a skin examination prior to, or shortly after initiation of etrasimod. Promptly evaluate any suspicious skin lesions.

• Review any current or prior medications, and determine if the patient is receiving any medications that could slow the heart rate or decrease atrioventricular conduction. In patients using antineoplastic, immunomodulating, or non-corticosteroid immunosuppressive medications, consider the possibility of unintended additive immunosuppression before treatment initiation with etrasimod.

• Before initiating etrasimod, test for antibodies to varicella zoster virus (VZV) in patients without a confirmed history of varicella (chickenpox) or without documentation of a full course of vaccination against VZV.

• Update immunizations in accordance with current immunization guidelines prior to initiating etrasimod. If live-attenuated vaccine immunizations are required, administer at least 4 weeks prior to initiation of etrasimod.

Patient Monitoring

• Monitor for infections during etrasimod therapy and for 5 weeks after discontinuing the drug.

• In patients receiving concomitant immunosuppressants, monitor for infectious complications during etrasimod therapy and for 5 weeks following the last dose.

• Monitor blood pressure during therapy with etrasimod.

• Periodically conduct an evaluation of the fundus, including the macula, while on etrasimod therapy and any time there is a change in vision.

• If clinically indicated, perform spirometric evaluation of respiratory function during etrasimod therapy.

• Perform periodic skin examinations shortly after starting etrasimod therapy and periodically thereafter in all patients, particularly those with risk factors for skin cancer. Monitor for suspicious skin lesions.

• Monitor for development of immune reconstitution inflammatory syndrome in patients who discontinue etrasimod therapy in the setting of progressive multifocal leukoencephalopathy.

Other General Considerations

• As usual for patients with increased risk for skin cancer, limit exposure to sunlight and ultraviolet light by wearing protective clothing and applying a sunscreen with a high protection factor.

• Avoid the use of live-attenuated vaccines during etrasimod therapy and for 5 weeks following the last dose.

Administration

Oral Administration

Available as tablets containing 2 mg of etrasimod.

Administer orally once daily. Swallow tablets whole with or without food.

If a dose of etrasimod is missed, skip missed dose and resume dosing at next scheduled time.

Dosage

Dosage of etrasimod arginine expressed in terms of etrasimod.

Adults

Ulcerative Colitis

Oral

2 mg once daily.

Special Populations

Hepatic Impairment

No dosage adjustment necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A or B).

Not recommended in patients with severe hepatic impairment (Child-Pugh class C).

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Etrasimod Arginine

Contraindications

• History of MI, unstable angina pectoris, stroke, TIA, decompensated heart failure (HF) requiring hospitalization, or Class III or IV HF 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 there is a functioning pacemaker.

Warnings/Precautions

Infections

Reduction in peripheral blood lymphocyte count with etrasimod therapy increases risk of infections, including life-threatening infections.

Before initiating etrasimod, obtain a recent (i.e., within 6 months or after discontinuation of prior ulcerative colitis therapy) CBC and lymphocyte count. Delay initiation of therapy in patients with active infection until resolution. Consider interrupting etrasimod therapy if serious infection develops.

Peripheral lymphocyte count lowering effects may persist up to 5 weeks after discontinuation of etrasimod. Inform patients and providers of continued infection risk through this period.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) reported in patients with multiple sclerosis (MS) receiving sphingosine 1-phosphate (S1P) receptor modulators; was associated with certain risk factors (e.g., immunocompromised patients, use of multiple immunosuppressants, longer duration of treatment). Etrasimod not indicated for treatment of MS.

Prescribers should be vigilant for clinical symptoms or unexplained neurologic findings suggestive of PML. Findings on MRI may be detectable before clinical signs or symptoms occur. Temporarily withhold etrasimod therapy if PML suspected, until PML excluded by an appropriate diagnostic evaluation. Discontinue etrasimod if PML confirmed.

Immune reconstitution inflammatory syndrome (IRIS) reported in patients with MS receiving S1P receptor modulators who developed PML and subsequently discontinued treatment. Onset of IRIS typically within a few months of discontinuing the S1P receptor modulator. Monitor patients for development of IRIS; initiate appropriate treatment of the associated inflammation.

Herpes Viral Infections

Herpes simplex encephalitis, varicella zoster meningitis, and localized herpes viral infections reported.

Test for varicella zoster virus (VZV) antibodies before initiation of etrasimod in patients without a healthcare professional-confirmed history of varicella (chickenpox), or without documentation of a full course of vaccination against VZV.

Cryptococcal Infection

Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections reported.

Observe patients for clinical signs or symptoms of CM. Prompt diagnostic evaluation and treatment recommended in patients who develop signs or symptoms of cryptococcal infection; withhold etrasimod until cryptococcal infection diagnosis excluded. In the event of a CM diagnosis, initiate appropriate treatment.

Prior and Concomitant Treatment with Antineoplastic, Immunomodulating, or Non-corticosteroid Immunosuppressive Therapies

Concomitant use with antineoplastic, immunomodulating, or non-corticosteroid immunosuppressive therapies not studied.

Avoid concomitant use with etrasimod and in the weeks following discontinuation due to risk of additive immunosuppression.

Vaccinations

Test for VZV antibodies before initiation of etrasimod in patients without a healthcare professional-confirmed history of varicella (chickenpox), or without documentation of a full course of vaccination against VZV. Full course of VZV vaccination recommended in antibody-negative patients prior to initiating treatment with etrasimod; postpone etrasimod initiation for 4 weeks following vaccination to allow for full effects of vaccination.

Clinical data not available on safety and efficacy of vaccinations during etrasimod therapy; vaccinations may be less effective if administered during etrasimod therapy.

If live-attenuated vaccinations required, administer ≥4 weeks prior to initiating etrasimod. Avoid use of live-attenuated vaccinations during therapy and for 5 weeks after discontinuing etrasimod.

Update immunizations in accordance with current immunization guidelines prior to initiation of etrasimod.

Bradyarrhythmia and Atrioventricular Conduction Delays

Initiation of etrasimod causes transient decreases in heart rate and AV conduction.

If considering treatment with etrasimod, seek cardiologist input for individuals with: significant QT prolongation (QTcF ≥450 msec in males, ≥470 msec in females); arrhythmias that require treatment with Class Ia or Class III anti-arrhythmic drugs or QT prolonging drugs; unstable ischemic heart disease, Class I or II HF, history of cardiac arrest, cerebrovascular disease, or uncontrolled hypertension; resting heart rate of <50 beats/minute; history of symptomatic bradycardia, recurrent cardiogenic syncope, or severe, untreated sleep apnea; or a history of Mobitz type I second-degree AV block (unless the patient has a functioning pacemaker).

Liver Injury

Transaminase elevations can occur.

If not recently available (i.e., within last 6 months), obtain transaminase and bilirubin levels before initiation of etrasimod. Also obtain transaminases and bilirubin levels in patients who develop symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine). If significant liver injury confirmed, discontinue etrasimod.

Macular Edema

Increased risk of macular edema.

Obtain baseline evaluation of the fundus, including the macula, soon after beginning treatment with etrasimod. Conduct periodic evaluation of the fundus, including the macula, during therapy and any time there is a change in vision. Consider discontinuation of etrasimod if macular edema occurs.

Blood Pressure Elevations

Potential for increased SBP and DBP.

Monitor blood pressure during etrasimod therapy and manage appropriately.

Fetal/Neonatal Morbidity and Mortality

Based on animal data, may cause fetal harm when administered during pregnancy. Embryofetal toxicity demonstrated in animals.

Apprise pregnant women and females of reproductive potential of the potential hazard to a fetus. Advise females of reproductive potential to use effective contraception during etrasimod therapy and for 1 week following the final dose.

Cutaneous Malignancies

Increased risk of skin malignancies (including basal cell carcinoma, squamous cell carcinoma, and melanoma) in patients receiving S1P receptor modulators.

Skin examinations recommended prior to or shortly after etrasimod initiation and periodically thereafter, particularly in patients with risk factors for skin cancer. Monitor for suspicious skin lesions; if observed, promptly evaluate.

Limit exposure to sunlight and UV light by wearing protective clothing and applying a sunscreen with a high protection factor. Phototherapy with UV-B radiation or psoralen plus ultraviolet A (PUVA)-photochemotherapy not recommended during treatment with etrasimod.

Posterior Reversible Encephalopathy Syndrome (PRES)

Cases of PRES reported.

Promptly schedule a complete physical and neurologic examination, and consider MRI if patient develops any neurological or psychiatric signs or symptoms (e.g., cognitive deficits, behavioral changes, cortical visual disturbances, or any other neurological cortical symptoms/signs), or any signs or symptoms that suggest an increase in intracranial pressure, or accelerated neurological deterioration.

Discontinue etrasimod if PRES suspected.

Respiratory Effects

Reductions in absolute FEV₁ reported in patients as early as 3 months after treatment initiation. Unknown if decreases in FEV₁ are reversible following drug discontinuation.

Perform spirometric evaluation of respiratory function during etrasimod therapy if clinically indicated.

Additive Immunosuppressive Effects

When switching to etrasimod from drugs with prolonged immunosuppressive effects, consider half-life and mechanism of action of the drugs in order to avoid unintended additive immunosuppressive effects.

Immunosuppression Following Therapy Discontinuation

Within 4—5 weeks of etrasimod discontinuation, lymphocyte counts return to normal values in 90% of patients. Use of concomitant immunosuppressants during this period may result in additive immunosuppressive effects.

Monitor patients receiving concomitant immunosuppressive therapy for development of infectious complications for at least 5 weeks after discontinuation of etrasimod.

Pharmacogenomic Considerations

Reduced CYP2C9 activity in patients with variant CYP2C9*2 and CYP2C9*3 alleles.

Reduced etrasimod clearance when used concomitantly with moderate to strong inhibitors of CYP2C8 or CYP3A4 in poor metabolizers of CYP2C9 (e.g., *2/*3, *3/*3); concomitant use not recommended.

Possible reduced clearance of etrasimod in intermediate metabolizers of CYP2C9 (e.g., *1/*2, *1/*3, *2/*2) when used concomitantly with moderate to strong inhibitors of CYP2C8 or CYP3A4, although this effect is unknown.

Specific Populations

Pregnancy

Pregnancy exposure registry available at 1-800-616-3791. May cause fetal harm based on animal data. Available data in humans insufficient to identify drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

Available data suggest increased risk of adverse pregnancy outcomes (e.g., preterm delivery, low birth weight, small for gestational age) in women with inflammatory bowel disease with increased disease activity.

Lactation

Not known if present in human milk. Effects on breast-fed infant or on milk production unknown. Animal data indicate etrasimod is excreted into milk.

Consider developmental and health benefits of breast-feeding along with mother's clinical need for etrasimod and any potential adverse effects on breast-fed infant from etrasimod or from underlying maternal condition.

Females and Males of Reproductive Potential

Animal data indicate may cause fetal harm.

Before initiating etrasimod, advise females of reproductive potential of potential serious fetal risk and the need for effective contraception during treatment with etrasimod and for 1 week after the final dose.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Clinical studies did not include a sufficient number of patients ≥65 years of age to assess differences in response compared to younger adults. Pharmacokinetics similar in patients ≥65 years of age compared to younger adults.

Hepatic Impairment

Mild and moderate hepatic impairment (Child-Pugh class A or B): similar etrasimod exposure compared to normal hepatic function.

Severe hepatic impairment (Child-Pugh class C): increased etrasimod exposure compared to normal hepatic function; no clinically important differences in unbound etrasimod AUC. Use not recommended in severe hepatic impairment (Child-Pugh class C).

Renal Impairment

Severe renal impairment (eGFR ≤29 mL/minute): no clinically important differences in pharmacokinetics observed.

Common Adverse Effects

Adverse effects reported in ≥5% of patients receiving etrasimod include headache, elevated liver tests, dizziness.

Drug Interactions

Primarily metabolized by CYP isoenzymes 2C8, 2C9, and 3A4.

In vitro, does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4, and does not induce CYP1A2, CYP2B6, or CYP3A4.

In vitro, does not inhibit UGT1A3, UGT1A4, UGT1A9, UGT2B7, or UGT2B17.

Not a substrate of, nor an inhibitor of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt exporter pump (BSEP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, multidrug and toxin extrusion (MATE) 1, or MATE2-K.

Drugs Affecting Hepatic Microsomal Enzymes

Effect of concomitant use of etrasimod with a combination of separate drugs that are moderate to strong inhibitors or inducers of either CYP2C8, CYP2C9, or CYP3A4 unknown. However, a clinically important change in exposure cannot be excluded when ≥2 metabolic pathways affected.

Moderate to Strong Inhibitors of CYP2C9 and CYP3A4

Combined moderate to strong inhibitors of CYP2C9 and CYP3A4: potential for increased etrasimod exposure.

Concomitant use not recommended.

Poor Metabolizers of CYP2C9 Using Moderate to Strong Inhibitors of CYP2C8 or CYP3A4

In poor metabolizers of CYP2C9, concomitant use of moderate or strong inhibitors of CYP2C8 or CYP3A4 with etrasimod expected to increase etrasimod exposure.

Concomitant use not recommended.

Specific Drugs

Etrasimod Arginine Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentration and AUC dose-proportional over oral dosage range of 0.7—2 mg.

Peak plasma concentrations attained approximately 4 hours (range: 2—8 hours) after oral administration.

Steady-state concentrations attained in approximately 7 days, with accumulation of approximately 2—3 fold compared to first dose.

Food

Absorption not affected by administration with a high-fat meal (800—1000 calories).

Special Populations

Age (>65 years), sex, body weight, race, ethnicity, or disease (healthy patients versus patients with ulcerative colitis) do not affect pharmacokinetics.

Distribution

Extent

Not known if distributed into human milk.

Plasma Protein Binding

97.9%.

Elimination

Metabolism

Undergoes oxidation and dehydrogenation; primarily mediated by CYP2C8, CYP2C9, and CYP3A4, and to a lesser extent, by CYP2C19 and CYP2J2.

Also undergoes conjugation; primarily mediated by UGTs, and to a lesser extent, by sulfotransferases.

Elimination Route

Eliminated in feces (82% [11% as unchanged drug]), and urine (5%).

Half-life

Approximately 30 hours.

Stability

Storage

Oral

Tablets, Film-Coated

Store at 20—25°C; excursions permitted to 15—30°C.

Actions

• Sphingosine 1-phosphate (S1P) receptor modulator.

• Binds with high affinity to S1P receptors 1, 4, and 5 (S1P_1,4,5). Minimal effects on S1P₃; does not affect S1P₂.

• Prevents egress of lymphocytes from lymphoid organs, reducing the number of circulating lymphocytes.

• Mechanism of therapeutic effect in ulcerative colitis unknown; may involve reduction of lymphocyte migration into the intestines.

Advice to Patients

• Advise patients 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 discontinuing the medication, and that they should contact their clinician 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 ≥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.

• Inform patients that initiation of etrasimod may cause transient decreases in heart rate.

• Inform patients that etrasimod may increase liver enzymes. Advise patients that they should contact their clinician 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. Advise patients 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 clinician if they experience any changes in their vision while taking etrasimod.

• Advise patients to limit exposure to sunlight and ultraviolet (UV) light, wear protective clothing, and use a sunscreen with a high protection factor during treatment with etrasimod. Inform patients that concomitant phototherapy with UV-B radiation or psoralen plus ultraviolet A (PUVA)-photochemotherapy is not recommended in patients taking etrasimod. If a suspicious skin lesion is observed, advise patients to report it to their clinician.

• Advise patients of the risk of posterior reversible encephalopathy syndrome, and to immediately report any symptoms involving sudden onset of severe headache, altered mental status, visual disturbances, or seizure to their clinician. Inform patients that delayed treatment could lead to permanent neurological consequences.

• Advise patients to contact their clinician if they experience new onset or worsening dyspnea.

• Advise patients that etrasimod continues to have immunosuppressive effects for up to 5 weeks after the last dose, and to monitor for signs and symptoms of infection during that time.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Advise patients of the risk of fetal harm with etrasimod. Advise females to immediately inform their clinician of a known or suspected pregnancy. Inform patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to etrasimod during pregnancy.

• Advise females of reproductive potential to use effective contraception during treatment with etrasimod and for 1 week after stopping the drug.

• Advise patients to inform their clinician if they plan to breast-feed.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

Etrasimod is obtained through designated specialty pharmacies. Contact manufacturer for specific availability information.

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