The information below is based on the summary of product characteristics approved by regulatory authorities. For full details from the SmPC ,please click here: https://www.medicines.org.uk/emc/product/15602/smpc

Additional related ECCO e-Learning resources can be found under IBD Curriculum Topic 6.1-6.11

Introduction and Mechanism of Action

Etrasimod is a sphingosine-1-phosphate (S1P) receptor modulator that binds to S1P receptors 1, 4 and 5 (S1P_1,4,5) and is a balanced G-protein and beta-arrestin agonist at S1P₁. Etrasimod has minimal activity on S1P₃ and no activity on S1P₂. It partially and reversibly blocks the capacity of lymphocytes to egress from lymphoid organs, reducing the number of lymphocytes in peripheral blood thereby lowering the migration of activated lymphocytes in the tissue.

The reduction of lymphocytes in the peripheral circulation has differential effects on leucocyte subpopulations, with greater decreases in cells involved in the adaptive immune response known to be involved in driving UC pathology. Etrasimod has minimal impact on cells involved in innate immune response, which contribute to immunosurveillance.

Therapeutic indications

Etrasimod is indicated for the treatment of adult patients and adolescents (of at least 16 years of age) with moderately to severely active ulcerative colitis (UC) who have had an inadequate response, lost response, or were intolerant to either conventional therapy, or a biological agent.

Dosing, administration

The recommended dose is 2 mg etrasimod taken orally once daily. The pill should be swallowed whole with water as splitting the pill has not been studied in clinical trials. It is recommended that etrasimod is administered with food for the first 3 days to attenuate potential transient heart rate lowering effects related to initiation of treatment. Then, etrasimod can be taken with or without food.

If a dose is missed, the prescribed dose should be taken at the next scheduled time without doubling the next dose

If treatment is interrupted for 7 or more consecutive days, it is recommended to resume treatment with food for the first 3 doses.

Special populations

Elderly: No dose adjustment is needed in patients over 65 years of age, although etrasimod should be used with caution in this group of individuals, given the limited data available and potential for an increased risk of adverse reactions.

Renal impairment: No dose adjustment is needed.

Hepatic impairment: No dose adjustment is needed for patients with mild or moderate hepatic impairment. On the other hand, etrasimod should not be used in patients with severe hepatic impairment.

Paediatric population: The safety and efficacy of etrasimod in children and adolescents less than 16 years of age have not yet been established. In addition, given the limited data in adolescents aged 16 and over, etrasimod should be used with caution especially when body weight is less than 40 kg due to the potential for increase in exposure.

Contraindications

• Hypersensitivity to the active substance or to any of the excipients.

• Immunodeficient state (see section 4.4 of the SmPC for full details).

• Patients who in the last 6 months experienced myocardial infarction, unstable angina pectoris, stroke, transient ischaemic attack (TIA), decompensated heart failure requiring hospitalisation, or New York Heart Association (NYHA) Class III/IV heart failure.

• Patients with history or presence of Mobitz type II second-degree or third-degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial block, unless patient has a functioning pacemaker.

• Severe active infections, active chronic infections such as hepatitis or tuberculosis.

• Active malignancies.

• Severe hepatic impairment.

• During pregnancy and in women of childbearing potential not using effective contraception: Clinical experience with another sphingosine-1-phosphate receptor modulator indicated a 2-fold higher risk of major congenital malformations when administered during pregnancy compared with the rate observed in the general population. Based on human experience etrasimod may cause congenital malformations when administered during the first trimester of pregnancy.

• During breastfeeding: It is unknown whether etrasimod is excreted in human milk. A study in lactating rats has indicated excretion of etrasimod in milk. A risk to newborns/infants cannot be excluded. Etrasimod should not be used during breast-feeding.

Adverse effects

The most common adverse reactions are lymphopenia (11%) and headache (7%).

Tabulated list of adverse reactions

The adverse reactions observed in patients treated with etrasimod are listed below by system organ class (SOC) and frequency category. Within each SOC and frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000).

Table 1: Adverse reactions

^a Urinary tract infection includes urinary tract infection and cystitis.

^b Lower respiratory tract infection includes bronchitis and pneumonia.

^c Lymphopenia includes lymphopenia, lymphocyte count decreased, and lymphocyte percentage decreased.

^d Hypercholesterolaemia includes hypercholesterolaemia and blood cholesterol increased.

^e Bradycardia includes bradycardia and sinus bradycardia. See “Description of selected adverse reactions” below.

^f Atrioventricular block includes first- or second-degree Mobitz type I. See “Description of selected adverse reactions” below.

Interactions with other Drugs

Interaction with other medicinal products, CYP2C9 polymorphism

Etrasimod should not be co-administered with a therapeutic agent or a combination of agents that are moderate to strong inhibitors of two or more of the following CYP enzymes (CYP2C8, CYP2C9, and CYP3A4) due to the risk of increased exposure to etrasimod.

The use of etrasimod is not recommended when co-administered with a therapeutic agent or a combination of agents that are moderate to strong inducers of two or more of the following CYP enzymes (CYP2C8, CYP2C9, and CYP3A4) due to the risk of decreased exposure to etrasimod.

The use of etrasimod is not recommended in patients who are known or suspected to be CYP2C9 poor metabolisers (< 5% of the population) and who take medicinal products that are moderate or strong inhibitors of CYP2C8 and/or CYP3A4 due to the risk of increased exposure of etrasimod.

For additional details, see section 4.5 of the SmPC.

Beta blockers and calcium channel blockers

The initiation of a beta blocker with stable treatment of etrasimod has not been studied. The effect of co-administration of etrasimod and a calcium channel blocker has not been studied.

Caution is recommended for patients receiving medicinal products that slow heart rate or atrioventricular conduction because of the potential additive effects on lowering heart rate, as stated in the "Special Warnings" section.

Anti-arrhythmic medicinal products, QT prolonging medicinal products, medicinal products that may decrease heart rate

Etrasimod has not been studied in patients taking QT prolonging medicinal products.

Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) anti-arrhythmic medicinal products have been associated with cases of Torsades de Pointes in patients with bradycardia. If treatment with etrasimod is considered in patients on Class Ia or Class III anti-arrhythmic medicinal products, as well as in patients on QT prolonging medicinal products, advice from a cardiologist should be sought.

Anti-neoplastic, immune-modulating, or non-corticosteroid immunosuppressive therapies

Etrasimod has not been studied in combination with anti-neoplastic, immune-modulating, or non-corticosteroid immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune system effects during such therapy and in the weeks following administration

Oral contraceptives

No clinically significant differences in the pharmacokinetics and pharmacodynamics of an oral contraceptive containing 30 mcg ethinyl oestradiol and 150 mcg levonorgestrel were observed when co-administered with etrasimod.

Special warnings and precautions

Bradyarrhythmia and atrioventricular conduction delays

1)Treatment initiation with etrasimod

Prior to treatment initiation, an electrocardiogram (ECG) should be obtained in all patients to assess for pre-existing cardiac abnormalities. In patients with certain pre-existing conditions, first dose monitoring is recommended as described below. When reinitiating treatment after an interruption of 7 or more consecutive days, consideration may be given to repeating the baseline ECG and/or monitoring depending on the results of the first evaluation, change in patient characteristics, and duration of interruption.

Initiation of etrasimod may result in a transient decrease in heart rate and AV conduction delays.

Caution should be applied when etrasimod is initiated in patients receiving treatment with a beta-blocker because of the potential additive effects on lowering heart rate. Similar caution should be applied if patients receive calcium channel blockers, QT prolonging medicinal products, Class Ia and Class III anti-arrhythmic substances, since co-administration of these substances with etrasimod may lead to additive effects.

Temporary interruption of the beta-blocker treatment may be needed prior to initiation of etrasimod, depending on the resting heart rate before initiation of etrasimod.

If interruption is deemed necessary, treatment with a beta-blocker can be reinitiated depending on the time of reaching the baseline heart rate. Beta-blocker treatment can be initiated in patients receiving stable doses of etrasimod.

Cardiologist advice should be obtained before initiation of etrasimod to determine overall benefit risk and the most appropriate monitoring strategy in patients with the following conditions:

• Significant QT prolongation (QTcF ≥ 450 msec in males, ≥ 470 msec in females).

• Arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic medicinal products.

• Unstable ischaemic heart disease, history of cardiac arrest, cerebrovascular disease (occurring more than 6 months prior to treatment initiation), or uncontrolled hypertension.

• History of symptomatic bradycardia, recurrent cardiogenic syncope, or severe untreated sleep apnoea.

2) First dose monitoring in patients with certain pre-existing cardiac conditions

Due to the risk of transient decreases in heart rate with the initiation of etrasimod, 4-hour monitoring for signs and symptoms of symptomatic bradycardia after the first dose is recommended in patients with resting heart rate < 50 bpm, second-degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure.

Patients should be monitored with hourly pulse and blood pressure measurement during this 4-hour period. An ECG prior to and at the end of this 4-hour period is recommended. Additional monitoring is recommended in patients, if at the end of 4-hour period:

• Heart rate is < 45 bpm.

• Heart rate is the lowest value post dose, suggesting that the maximum decrease in heart rate may not have occurred yet.

• ECG shows evidence of a new onset second-degree or higher AV block.

• QTc interval is ≥ 500 msec.

In these cases, appropriate management should be initiated, and observation should continue until the symptoms/findings have resolved. If medical treatment is required, monitoring should be continued overnight, and a 4-hour monitoring period should be repeated after the second dose of etrasimod.

Infections

Risk of infections

Etrasimod causes a mean reduction in peripheral blood lymphocyte count ranging from 43 to 55% of baseline values over 52 weeks because of reversible sequestration of lymphocytes in lymphoid tissues.Therefore, there may be an increase of susceptibility to infections.

Before initiating treatment, a recent complete blood count (CBC), including lymphocyte count (i.e., within the last 6 months or after discontinuation of prior UC therapy), should be obtained.

Assessments of CBC are also recommended periodically during treatment. Absolute lymphocyte counts < 0.2 x 10⁹/L, if confirmed, should lead to interruption of etrasimod therapy until the level reaches > 0.5 x 10⁹/L when re-initiation of etrasimod can be considered.

The initiation of etrasimod in patients with any active infection should be delayed until the infection is resolved.

If a patient develops a serious infection, interruption of etrasimod should be considered.

As residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, may persist up to 2 weeks after discontinuation of etrasimod, vigilance for infection should be continued throughout this period.

Progressive multifocal leukoencephalopathy (PML)

PML has been reported in multiple sclerosis patients treated with sphingosine-1-phosphate (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 (e.g., 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). If PML is suspected, treatment with etrasimod should be suspended until PML has been excluded by an appropriate diagnostic evaluation.
If PML is confirmed, treatment with etrasimod should be discontinued.

Prior and concomitant treatment with anti-neoplastic, immune-modulating, or non-corticosteroid immunosuppressive therapies

In clinical studies, patients who received etrasimod were not to receive concomitant treatment with anti-neoplastic, immune-modulating, or non-corticosteroid immunosuppressive therapies used for the treatment of UC. Therefore, caution should be used during co-administration of these drugs with etrasimod. In clinical studies, concomitant use of corticosteroids was allowed; however, long-term data on concomitant use of etrasimod and corticosteroids are limited.

When switching to etrasimod from immunosuppressive therapies, the duration of effects and mechanism of action should be considered to avoid unintended additive immune system effects. An appropriate washout period may need to be applied.

Vaccinations

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 immunisations are required, these should be administered at least 4 weeks prior to initiation of etrasimod. The use of live attenuated vaccines during and for at least 2 weeks after treatment with etrasimod should be avoided.

It is recommended to update immunisations in agreement with current immunisation guidelines prior to initiating etrasimod therapy.

Liver injury

Elevations of aminotransferases may occur in patients receiving etrasimod. Recent transaminase and bilirubin levels (i.e., within last 6 months) should be available before initiation of treatment with etrasimod.

In the absence of clinical symptoms, liver transaminases and bilirubin levels should be monitored at months 1, 3, 6, 9, and 12 on therapy and periodically thereafter.

Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine, should have hepatic enzymes checked and etrasimod discontinued if significant liver injury is confirmed.

Resumption of therapy will be dependent on whether another cause of liver injury is determined and on the benefits to patient of resuming etrasimod therapy versus the risks of recurrence of liver dysfunction. Caution should be exercised in patients with a history of significant liver disease.

Increased blood pressure

In clinical studies, hypertension was more frequently reported in patients treated with etrasimod than in patients treated with placebo. Blood pressure should be monitored during treatment.

Women of childbearing potential

Based on animal studies, etrasimod may cause foetal harm. Due to the risk to the foetus, etrasimod is contraindicated during pregnancy and in women of childbearing potential not using effective contraception. Before initiation of treatment, women must have a negative pregnancy test, and must use effective contraception during treatment and for at least 14 days after treatment discontinuation.

Macular oedema

S1P receptor modulators, including etrasimod, have been associated with an increased risk of macular oedema. Macular oedema with or without visual symptoms has been reported in 0.3% of patients treated with Velsipity.

Patients with a history of diabetes mellitus, uveitis, and/or underlying/co-existing retinal disease, are at increased risk of macular oedema during etrasimod therapy. It is recommended that these patients undergo an ophthalmic evaluation prior to treatment initiation with etrasimod and have follow-up evaluations while receiving therapy.

In patients without the risk factors above, an ophthalmic evaluation of the fundus, including the macula, is recommended within 3-4 months after starting etrasimod treatment (cases reported with etrasimod occurred within this timeframe) and at any time if there is a change in vision while taking etrasimod.

Patients who present with visual symptoms of macular oedema should be evaluated and, if confirmed, treatment with etrasimod should be discontinued. A decision on whether etrasimod should be re-initiated after resolution needs to take into account the potential benefits and risks for the individual patient.

Malignancies

Cases of malignancies (including cutaneous malignancies) have been reported in patients treated with S1P receptor modulators. If a suspicious skin lesion is observed, it should be promptly evaluated.

Patients should be cautioned against exposure to sunlight without protection. These patients should not receive concomitant phototherapy with UV-B-radiation or PUVA-photochemotherapy.

Posterior reversible encephalopathy syndrome (PRES)

Rare cases of PRES have been reported in patients receiving S1P receptor modulators. Should an etrasimod-treated patient develop any neurological or psychiatric symptoms/signs (e.g., cognitive deficits, behavioural 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 ischaemic stroke or cerebral haemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, treatment with etrasimod should be discontinued.

Respiratory effects

Reductions in absolute forced expiratory volume over 1 second (FEV₁) and forced vital capacity (FVC) were observed in patients treated with S1P receptor modulators, including etrasimod. Etrasimod should be used with caution in patients with severe respiratory disease (e.g., pulmonary fibrosis, asthma, and chronic obstructive pulmonary disease).