Velsipity

/ Pfizer

The recommended dose is 2 mg etrasimod taken once daily.
It is recommended that etrasimod be administered with food for the first 3 days to attenuate potential transient heart rate lowering effects related to initiation of treatment. Etrasimod can then be taken with or without food.
See prescribing information for full details.

Treatment of patients 16 years of age and older 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.

* Hypersensitivity to the active substance or to any of the excipients.
* Immunodeficient state.
* 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.
* Pregnancy and in women of childbearing potential not using effective contraception

Bradyarrhythmia and atrioventricular conduction delays
Treatment initiation with etrasimod
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. 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.
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.
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 (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:
• 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. Etrasimod may, therefore, increase the 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.
Progressive multifocal leukoencephalopathy (PML)
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. If PML is confirmed, treatment with etrasimod should be discontinued.
Liver injury
Elevations of aminotransferases may occur in patients receiving etrasimod. 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).
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 with etrasimod and managed appropriately.
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 this medical product.
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.
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.
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.
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 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.
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).
See prescribing information for full details.

Very common: Lymphopenia
Common: Urinary tract infection, lower respiratory tract infection, Neutropenia, Hypercholesterolaemia, Headache, dizziness, Visual impairment, Bradycardia, Hypertension, Hepatic enzyme increased.
See prescribing information for full details.

Effect of inhibitors of CYP2C8, CYP2C9, and CYP3A4 on etrasimod
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.
Effect of inducers of CYP2C8, CYP2C9, and CYP3A4 on etrasimod
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.
Effect of CYP2C9 polymorphism
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.
Anti-arrhythmic 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.
Vaccination
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.
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. 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.

Women of childbearing potential/Contraception in females
This medical product 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.
Pregnancy: There is a limited amount of data from the use of etrasimod in pregnant women. 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, this medical product is contraindicated during pregnancy.
Etrasimod should be stopped at least 14 days before a pregnancy is planned
Lactation: 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.

In patients with overdose of etrasimod, signs and symptoms of bradycardia should be monitored, which may include overnight monitoring. Regular measurements of heart rate, blood pressure, and ECGs should be performed. There is no specific antidote to etrasimod available. The decrease in heart rate induced by etrasimod can be reversed by parenteral atropine.