Etrasimod

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, advice from a cardiologist should be sought.

Due to the potential additive effects on heart rate, if treatment initiation with etrasimod is considered in patients on QT prolonging medicinal products, advice from a cardiologist should be sought.

The co-administration of etrasimod with steady state fluconazole (moderate CYP2C9 and CYP3A4 inhibitor) increased exposure (AUC) of etrasimod by 84%. Co-administration of etrasimod 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) (e.g., fluconazole) increases the exposure of etrasimod and is not recommended.

The co-administration of etrasimod with rifampicin (strong CYP3A4, moderate CYP2C8, and CYP2C9 inducer) decreased exposure (AUC) of etrasimod by 49%. Co-administration of etrasimod 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) (e.g., rifampicin, enzalutamide) decreases the exposure of etrasimod and is not recommended.

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.

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

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. Co-administration of etrasimod with an oral contraceptive containing ethinyl oestradiol and levonorgestrel increases AUC values of the ethinyl oestradiol and levonorgestrel by approximately 24% and 32%, respectively.

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.

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

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.

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).

Due to the potential for increased exposure of etrasimod, co-administration of etrasimod 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 is not recommended.

There is a limited amount of data from the use of etrasimod in pregnant women. Studies in animals have shown reproductive toxicity. 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. The limited human data available for etrasimod also suggest an increased risk of abnormal pregnancy outcomes. Consequently, etrasimod is contraindicated during pregnancy.

Etrasimod should be stopped at least 14 days before a pregnancy is planned. If a woman becomes pregnant during treatment, etrasimod must be immediately discontinued. Medical advice should be given regarding the risk of harmful effects to the foetus associated with treatment and follow-up examinations should be performed.

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.

Women of childbearing potential / Contraception in females

Etrasimod is contraindicated in women of childbearing potential not using effective contraception. Therefore, before initiation of treatment in women of childbearing potential, a negative pregnancy test result must be available and counselling should be provided regarding the serious risk to the foetus. Due to the time it takes to eliminate etrasimod from the body after stopping treatment, the potential risk to the foetus may persist and women of childbearing potential must use effective contraception during etrasimod treatment and for at least 14 days after treatment discontinuation.

Specific measures are also included in the Healthcare Professional checklist. These measures must be implemented before etrasimod is prescribed to female patients and during treatment.

Fertility

The effect of etrasimod on human fertility has not been evaluated. In animal studies, no adverse effects on fertility were observed.

Etrasimod has no or negligible influence on the ability to drive and use machines.

However, patients who experience dizziness after taking etrasimod should refrain from driving or using machines until the dizziness resolves.

Summary of the safety profile

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.

Description of selected adverse reactions

Bradyarrhythmia

In ELEVATE UC 52 and ELEVATE UC 12, bradycardia was reported as an AE on the day of treatment initiation in 1.5% of patients treated with etrasimod. On Day 2, bradycardia was reported as an AE in 0.4% of patients treated with etrasimod. Bradycardia was recorded more frequently on ECG monitoring.

In ELEVATE UC 52 and ELEVATE UC 12, on the day of treatment initiation, events of first- or second-degree Mobitz type I AV blocks were reported as an AE in 0.6% of patients treated with etrasimod. Events of AV block were mostly transient and asymptomatic. PR interval prolongation was recorded more frequently on ECG monitoring.

Infections

In ELEVATE UC 52 and ELEVATE UC 12, the overall rate of infections and rate of serious infections in patients treated with etrasimod was comparable to that in patients who received placebo (18.8% vs 17.7% and 0.6% vs 1.9%, respectively). Etrasimod increased the risk of urinary tract infections and lower respiratory tract infections (see Table 1).

Blood lymphocyte count and neutrophil count reduction

Etrasimod partially and reversibly blocks the capacity of lymphocytes to egress from lymphoid organs, reducing the number of lymphocytes in peripheral blood. The proportion of patients treated with etrasimod who experienced lymphocyte counts less than 0.2 × 10⁹/L was 3.5% in ELEVATE UC 52 and ELEVATE UC 12. These events did not lead to treatment discontinuation. Etrasimod caused a reversible decrease in neutrophil count; the proportion of patients treated with etrasimod who experienced neutrophil counts less than 0.5 × 10⁹/L was 0.2% in ELEVATE UC 52 and ELEVATE UC 12. These events did not lead to treatment discontinuation.

Elevated hepatic enzymes

In ELEVATE UC 52 and ELEVATE UC 12, elevations of ALT to 5-fold and 3-fold the ULN or greater occurred in 0.9% and 4.0% of patients treated with etrasimod, respectively.

The majority (75%) of patients with ALT greater than 3-fold the ULN continued treatment with etrasimod with values returning to less than 3-fold the ULN while on treatment.

Overall, the percentage of discontinuation because of elevations in hepatic enzymes was 0.4% in patients treated with etrasimod.

Hepatic enzyme increased includes events of gamma glutamyl transferase increased, alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, hepatic function abnormal, liver disorder, liver function test abnormal, and transaminases increased (see Table 1).

Increased blood pressure

In ELEVATE UC 52 and ELEVATE UC 12, patients 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. The increase was first detected after 2 weeks of treatment and remained within the specified average range in blood pressure increases throughout treatment. Hypertension was reported as an adverse reaction in 2.1% of patients treated with etrasimod. All the events were mild to moderate in severity.

Macular oedema

In ELEVATE UC 52 and ELEVATE UC 12, macular oedema was reported in 0.4% of patients treated with etrasimod.