Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Brussels, Belgium
Prior to treatment initiation with etrasimod, 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 (see 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 (see sections 4.8 and 5.1).
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 (see section 4.5), since co-administration of these substances with etrasimod may lead to additive effects.
Temporary interruption of beta-blocker treatment may be needed prior to initiation of etrasimod, depending on the resting HR before initiation of etrasimod (see also section below and section 4.5). 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:
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 (see section 4.3).
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:
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.
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 (see section 5.1). Etrasimod may, therefore, increase the susceptibility to infections (see section 4.8).
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 × 109/L, if confirmed, should lead to interruption of etrasimod therapy until the level reaches >0.5 × 109/L when re-initiation of etrasimod can be considered (see section 4.2).
The initiation of etrasimod in patients with any active infection should be delayed until the infection is resolved (see section 4.3).
Patients should be instructed to promptly report symptoms of infection to their physician. Effective diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy.
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 (see section 5.1).
PML is an opportunistic viral infection of the brain caused by the John Cunningham virus (JCV) that typically occurs in patients who are immunocompromised, and that may lead 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 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. 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.
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. In clinical studies, concomitant use of corticosteroids was allowed; however, long-term data on concomitant use of etrasimod and corticosteroids are limited (see section 5.1).
Anti-neoplastic, immune-modulating, or immunosuppressive therapies (including corticosteroids) should be co-administered with caution because of the risk of additive immune system effects during such therapy (see section 4.5).
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.
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 (see section 5.1).
It is recommended to update immunisations in agreement with current immunisation guidelines prior to initiating etrasimod therapy.
Elevations of aminotransferases may occur in patients receiving etrasimod (see section 4.8). 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. Etrasimod should be discontinued if significant liver injury is confirmed (for example, alanine aminotransferase (ALT) exceeds 3-fold the upper limit of normal (ULN) and total bilirubin exceeds 2-fold the ULN).
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. Although there are no data to establish that patients with pre-existing liver disease are at increased risk of developing elevated liver function test values when taking etrasimod, caution should be exercised in patients with a history of significant liver disease.
In clinical studies, hypertension was more frequently reported in patients treated with etrasimod than in patients treated with placebo (see section 4.8). Blood pressure should be monitored during treatment with etrasimod and managed appropriately.
Based on animal studies, etrasimod may cause foetal harm (see sections 4.6 and 5.3). Due to the risk to the foetus, etrasimod is contraindicated during pregnancy and in women of childbearing potential not using effective contraception (see sections 4.3 and 4.6). Before initiation of treatment, women of childbearing potential must be informed about this risk to the foetus, must have a negative pregnancy test, and must use effective contraception during treatment and for at least 14 days after treatment discontinuation (see section 4.6).
S1P receptor modulators, including etrasimod, have been associated with an increased risk of macular oedema (see section 4.8). An ophthalmic evaluation of the fundus, including the macula, is recommended near the start of treatment in all patients and at any time if there is any change in vision while taking etrasimod.
Patients with a history of diabetes mellitus, uveitis, or underlying/co-existing retinal disease, are at increased risk of macular oedema during etrasimod therapy (see section 4.8). 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.
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.
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.
Since there is a potential risk of malignant skin growths, patients treated with etrasimod should be cautioned against exposure to sunlight without protection. These patients should not receive concomitant phototherapy with UV-B-radiation or PUVA-photochemotherapy.
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.
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 (see section 4.5).
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 (see section 4.5).
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 (see section 4.5).
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).
This medicinal product contains tartrazine (E102) which may cause allergic reactions.
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
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 (see section 4.4).
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 (see section 4.4).
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 (see section 4.4).
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 (see section 4.4).
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 (see section 4.4).
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 (see section 4.4).
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 (see section 4.4).
Vaccinations may be less effective if administered during and for up to 2 weeks after discontinuation of treatment with etrasimod. The use of live attenuated vaccine may carry the risk of infection and should therefore be avoided during etrasimod treatment and for at least 2 weeks after discontinuation of treatment with etrasimod (see section 4.4).
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.
Interaction studies have only been performed in adults.
Velsipity is contraindicated in women of childbearing potential not using effective contraception (see section 4.3). 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 (see section 4.4).
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.
There is a limited amount of data from the use of etrasimod in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). 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, Velsipity is contraindicated during pregnancy (see section 4.3).
Etrasimod should be stopped at least 14 days before a pregnancy is planned (see section 4.4). 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 (see section 5.3). A risk to newborns/infants cannot be excluded. Etrasimod should not be used during breast-feeding.
The effect of etrasimod on human fertility has not been evaluated. In animal studies, no adverse effects on fertility were observed (see section 5.3).
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 (see section 4.8).
The most common adverse reactions are lymphopenia (11%) and headache (7%).
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:
| System organ class (SOC) | Very common | Common | Uncommon |
|---|---|---|---|
| Infections and infestations | Urinary tract infectiona, lower respiratory tract infectionb | ||
| Blood and lymphatic system disorders | Lymphopeniac | Neutropenia | |
| Metabolism and nutrition disorders | Hypercholesterolaemiad | ||
| Nervous system disorders | Headache, dizziness | ||
| Eye disorders | Visual impairment | Macular oedema | |
| Cardiac disorders | Bradycardiae | Atrioventricular blockf | |
| Vascular disorders | Hypertension | ||
| Hepatobiliary disorders | Hepatic enzyme increased |
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.
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 (see section 5.1).
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 (see section 5.1).
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).
Etrasimod partially and reversibly blocks the capacity of lymphocytes to egress from lymphoid organs, reducing the number of lymphocytes in peripheral blood (see section 5.1). 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.
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).
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.
In ELEVATE UC 52 and ELEVATE UC 12, macular oedema was reported in 0.4% of patients treated with etrasimod.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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