FDA

Velsipity

Approved 12 Oct 2023OralTablet

Indications

VELSIPITY is indicated for the treatment of moderately to severely active ulcerative colitis (UC) in adults. VELSIPITY is a sphingosine 1-phosphate receptor modulator indicated for the treatment of moderately to severely active ulcerative colitis in adults. ( 1 )

Contraindications

VELSIPITY is contraindicated in patients who:

In the last 6 months, have experienced a myocardial infarction, unstable angina pectoris, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III or IV heart failure [see Warnings and Precautions (5.2) ] .
Have a history or presence of Mobitz type II second-degree or third-degree AV block, sick sinus syndrome, or sino-atrial block, unless the patient has a functioning pacemaker [see Warnings and Precautions (5.2) ] .
In the last 6 months, experienced myocardial infarction, unstable angina pectoris, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III or IV heart failure. ( 4 , 5.2 )
History or presence of Mobitz type II second-degree or third-degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial block, unless the patient has a functioning pacemaker. ( 4 , 5.2 )

Warnings and precautions

Infections : May increase the risk of infections. Obtain a complete blood count (CBC) before initiation of treatment. Monitor for infection during treatment and for 5 weeks after discontinuation. Consider interruption of treatment if a serious infection develops. Avoid use of live attenuated vaccines during and for up to 5 weeks after treatment. ( 5.1 )
Bradyarrhythmia and Atrioventricular Conduction Delays : May result in a transient decrease in heart rate and AV conduction delays. Obtain an electrocardiogram (ECG) to assess for preexisting cardiac conduction abnormalities before starting treatment. Consider cardiology consultation for conduction abnormalities or concomitant use with other drugs that decrease heart rate. ( 2.1 , 5.2 , 7 )
Liver Injury : Elevations of aminotransferases may occur. Obtain transaminase and bilirubin levels before initiating VELSIPITY. Discontinue if significant liver injury is confirmed. ( 2.1 , 5.3 )
Macular Edema : May increase the risk of macular edema. Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with VELSIPITY. Periodically conduct an evaluation of the fundus, including the macula, while on therapy and any time there is a change in vision. Consider discontinuing VELSIPITY if macular edema develops. ( 2.1 , 5.4 )

At a glance

Brand name: Velsipity
Active substance: etrasimod arginine
Route: Oral
Dosage form: Tablet
Applicant: Pfizer
Status: Prescription
FDA approval: 12 Oct 2023
Application: NDA216956-001

Contraindications

VELSIPITY is contraindicated in patients who:

In the last 6 months, have experienced a myocardial infarction, unstable angina pectoris, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III or IV heart failure [see Warnings and Precautions (5.2) ] .
Have a history or presence of Mobitz type II second-degree or third-degree AV block, sick sinus syndrome, or sino-atrial block, unless the patient has a functioning pacemaker [see Warnings and Precautions (5.2) ] .
In the last 6 months, experienced myocardial infarction, unstable angina pectoris, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III or IV heart failure. ( 4 , 5.2 )
History or presence of Mobitz type II second-degree or third-degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial block, unless the patient has a functioning pacemaker. ( 4 , 5.2 )

Warnings and precautions

Infections : May increase the risk of infections. Obtain a complete blood count (CBC) before initiation of treatment. Monitor for infection during treatment and for 5 weeks after discontinuation. Consider interruption of treatment if a serious infection develops. Avoid use of live attenuated vaccines during and for up to 5 weeks after treatment. ( 5.1 )
Bradyarrhythmia and Atrioventricular Conduction Delays : May result in a transient decrease in heart rate and AV conduction delays. Obtain an electrocardiogram (ECG) to assess for preexisting cardiac conduction abnormalities before starting treatment. Consider cardiology consultation for conduction abnormalities or concomitant use with other drugs that decrease heart rate. ( 2.1 , 5.2 , 7 )
Liver Injury : Elevations of aminotransferases may occur. Obtain transaminase and bilirubin levels before initiating VELSIPITY. Discontinue if significant liver injury is confirmed. ( 2.1 , 5.3 )
Macular Edema : May increase the risk of macular edema. Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with VELSIPITY. Periodically conduct an evaluation of the fundus, including the macula, while on therapy and any time there is a change in vision. Consider discontinuing VELSIPITY if macular edema develops. ( 2.1 , 5.4 )

Interactions

Etrasimod is primarily metabolized by CYP2C8, CYP2C9, and CYP3A4. Table 3 includes drugs with clinically important drug interactions when administered concomitantly with VELSIPITY and instructions for preventing or managing them. Consult the labeling of concomitantly used drugs to obtain further information. The effect of concomitant use of VELSIPITY with a combination of separate drugs that are moderate to strong inhibitors or inducers of either CYP2C8, CYP2C9, or CYP3A4 is unknown.

However, based on the information below, a similar clinically significant change in exposure cannot be ruled out when two or more metabolic pathways are affected. Table 3: Drugs That Affect VELSIPITY CYP-Mediated Metabolic Pathways Anti-Arrhythmic Drugs and QT Prolonging Drugs Clinical Impact A transient decrease in heart rate and AV conduction delays may occur when initiating VELSIPITY [see Warnings and Precautions (5.2) ] .

Because of the potential additive effect on heart rate, VELSIPITY may increase the risk of QT prolongation and Torsades de Pointes with concomitant use of Class Ia and Class III anti-arrhythmic drugs and QT prolonging drugs. Prevention or Management Seek the advice of a cardiologist before initiating VELSIPITY treatment with Class Ia (e.g., quinidine, procainamide), Class III anti-arrhythmic drugs (e.g., amiodarone, sotalol), or other drugs that prolong the QT interval.

Beta-Blockers or Calcium Channel Blockers Clinical Impact A transient decrease in heart rate and AV conduction delays may occur when initiating VELSIPITY [see Warnings and Precautions (5.2) ] . Concomitant use of VELSIPITY in patients receiving stable beta blocker treatment did not result in additive effects on heart rate reduction [see Clinical Pharmacology (12.2) ] . However, the risk of additive heart rate reduction following initiation of beta blocker therapy with stable VELSIPITY treatment or concomitant use with other drugs that may decrease heart rate is unknown.

Prevention or Management VELSIPITY can be initiated in patients receiving stable doses of beta blocker treatment. Seek the advice of a cardiologist before initiating a beta blocker in a patient receiving stable VELSIPITY treatment or concomitant use with other drugs that may decrease heart rate (e.g., calcium channel blockers). Anti-Neoplastic, Immune-Modulating, or Non-Corticosteroid Immunosuppressive Therapies Clinical Impact Risk of additive immune system effects with VELSIPITY VELSIPITY has not been studied in combination with anti-neoplastic, immune-modulating, or non-corticosteroid immunosuppressive therapies.

Prevention or Management Avoid concomitant administration during and in the weeks following administration of VELSIPITY. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects [see Warnings and Precautions (5.10) ] . Moderate to Strong Inhibitors of CYP2C9 and CYP3A4 Clinical Impact Increased exposure of etrasimod was observed with concomitant use with a drug that is a moderate inhibitor of CYP2C9 and a moderate inhibitor of CYP3A4 (i.e., fluconazole) [see Clinical Pharmacology (12.3) ] .

Prevention or Management Concomitant use with a drug that is a moderate to strong inhibitor of CYP2C9 and a moderate to strong inhibitor of CYP3A4 is not recommended. CYP2C9 Poor Metabolizers Using Moderate to Strong Inhibitors of CYP2C8 or CYP3A4 Clinical Impact Increased exposure of etrasimod in patients who are CYP2C9 poor metabolizers is expected with concomitant use of moderate to strong inhibitors of CYP2C8 or CYP3A4 [see Clinical Pharmacology (12.3 , 12.5) ] .

Prevention or Management Concomitant use not recommended. Rifampin Clinical Impact Concomitant use with a drug that is a combined CYP3A4 (strong), CYP2C8 (moderate) and CYP2C9 (moderate) inducer (i.e., rifampin) decreases exposure to etrasimod [see Clinical Pharmacology (12.3) ] . Prevention or Management Concomitant use not recommended. See full prescribing information for a list of clinically important drug interactions.

( 7 )

Pregnancy and breastfeeding

8.1Pregnancy Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to VELSIPITY during pregnancy. Pregnant females exposed to VELSIPITY and healthcare providers are encouraged to contact the pregnancy registry by calling 1-800-616-3791. Risk Summary Based on findings from animal studies, VELSIPITY may cause fetal harm when administered to a pregnant woman. Available data from reports of pregnancies from the clinical development program with VELSIPITY are insufficient to identify a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.

There are risks to the mother and the fetus associated with increased disease activity in women with inflammatory bowel disease during pregnancy (see Clinical Considerations ). In animal reproduction studies, administration of etrasimod during organogenesis produced adverse effects on development, including embryolethality and fetal malformations, in both rats and rabbits at maternal exposures 5 and 6 times, respectively, the exposure at the maximum recommended human dose (MRHD).

Administration of VELSIPITY to pregnant rats during organogenesis through lactation resulted in decreased pup growth and viability at maternal exposures 5 times the exposure at the MRHD, as well as impaired reproductive performance in first generation offspring, including decreased implantations and increased pre-implantation loss at maternal exposures 24 times the exposure at the MRHD (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that the risk of adverse pregnancy outcomes in women with inflammatory bowel disease is associated with increased disease activity.

Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. Data Animal Data In an embryo-fetal development study in pregnant rats, etrasimod was orally administered at 1, 2, or 4 mg/kg/day (5, 11, and 21 times the exposure at the MRHD of 2 mg, based on AUC comparison) during the period of organogenesis, from gestation day 6 to 17.

No maternal toxicity was observed up to 21 times the exposure at the MRHD. Increased post-implantation loss with a corresponding decrease in the number of viable fetuses was observed at 4 mg/kg/day (21 times the exposure at the MRHD). Etrasimod-related fetal external and/or visceral malformations were noted at all dose levels (≥5 times the exposure at the MRHD). In an embryo-fetal development study in pregnant rabbits, etrasimod was orally administered at 2, 10, or 20 mg/kg/day (0.8, 6, and 11 times the exposure at the MRHD of 2 mg, based on AUC comparison) during the period of organogenesis, from gestation day 7 to 20.

Increased post-implantation loss with a corresponding decrease in the number of viable fetuses was observed at 10 and 20 mg/kg/day (6 and 11 times the exposure at the MRHD). Etrasimod-related fetal malformations including aortic arch defects and fused sternebrae were noted at 10 and/or 20 mg/kg/day (6 and 11 times the exposure at the MRHD). There were no adverse effects on embryofetal development at 2 mg/kg/day (less than the exposure at the MRHD).

In a pre- and post-natal development study in rats, etrasimod was orally administered at 0.4, 2, or 4 mg/kg/day (2, 10, and 24 times the exposure at the MRHD of 2 mg, based on AUC comparison) throughout pregnancy and lactation, from gestation day 6 through lactation day 20. Mortality during delivery and impaired maternal performance including increased post-implantation loss, increased number of females with stillborn pups, increased number of stillborn pups per litter, decreased viability index, and/or decreased lactation index was observed at 2 and 4 mg/kg/day (10 and 24 times the exposure at the MRHD).

Etrasimod was detected in the plasma of F1 offspring, indicating exposure from the milk of the lactating dam. Decreased pup body weights were observed during the preweaning period at all dose levels (maternal exposures ≥2 times the exposure at the MRHD), and decreased pup viability was observed at 2 and 4 mg/kg/day (maternal exposures 10 and 24 times the exposure at the MRHD). Reduced fertility and reproductive performance including reduction in implantations and increased preimplantation loss in F1 offspring occurred at the highest dose tested (maternal exposures 24 times the exposure at the MRHD).

Adverse reactions

The following serious adverse reactions are described elsewhere in the labeling:

Infections [see Warnings and Precautions (5.1) ]
Bradyarrhythmia and Atrioventricular Conduction Delays [see Warnings and Precautions (5.2) ]
Liver Injury [see Warnings and Precautions (5.3) ]
Macular Edema [see Warnings and Precautions (5.4) ]
Increased Blood Pressure [see Warnings and Precautions (5.5) ]
Fetal Risk [see Warnings and Precautions (5.6) ]
Cutaneous Malignancies [see Warnings and Precautions (5.7) ]
Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.8) ]
Respiratory Effects [see Warnings and Precautions (5.9) ]
Unintended Additive Immune System Effects from Prior Treatment with Immunosuppressive or Immune-Modulating Drugs [see Warnings and Precautions (5.10) ]
Immune System Effects After Stopping VELSIPITY [see Warnings and Precautions (5.11) ] Most common adverse reactions (incidence ≥5%) are: headache, elevated liver tests, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of VELSIPITY 2 mg once daily in subjects with moderately to severely active ulcerative colitis was evaluated in two randomized, placebo-controlled studies of 52 weeks (UC-1) and 12 weeks (UC-2) duration [see Clinical Studies (14) ].

Additional safety data were obtained from a randomized, double-blind, placebo-controlled dose-finding study of 12 weeks duration (UC-3). In the 52-week study (UC-1), 433 subjects were enrolled of whom 289 received VELSIPITY 2 mg once daily. In the 12-week studies (UC-2 and UC-3), 458 subjects were enrolled of whom 288 received VELSIPITY 2 mg once daily. Table 1 summarizes the adverse reactions reported in at least 2% of subjects and at a higher rate than placebo during UC-1.

Table 1: Adverse Reactions Reported in at least 2% of subjects and at a higher rate than placebo. in Subjects with Ulcerative Colitis in a Placebo-Controlled 52-Week Study (UC-1) Adverse Reaction VELSIPITY 2 mg Once Daily N = 289 % Placebo N = 144 % Headache Headache includes related terms headache, migraine, and tension headache. 9 5 Elevated liver tests Elevated liver tests includes related terms ALT increased, AST increased, blood alkaline phosphatase increased, cholestasis, GGT increased, hepatic enzyme increased, hyperbilirubinemia, liver function test increased, and transaminases increased. 6 5 Dizziness Dizziness includes related terms dizziness, dizziness exertional, and dizziness postural. 5 2 Arthralgia 4 2 Hypertension Hypertension includes related terms hypertension, and blood pressure increased. 3 1 Urinary tract infection Urinary tract infection includes related terms urinary tract infection and cystitis. 3 2 Nausea 3 1 Hypercholesterolemia Hypercholesterolemia includes related terms hypercholesterolemia and blood cholesterol increased. 3 0 Herpes viral infection Herpes viral infection includes related terms herpes zoster, oral herpes, and herpes simplex. 2 1 Table 2 summarizes the adverse reactions reported in at least 2% of subjects and at a higher rate than placebo during UC-2 and UC-3.

Table 2: Adverse Reactions Reported in at least 2% of subjects and at a higher rate than placebo. in Subjects with Ulcerative Colitis in Placebo-Controlled 12-Week Studies (UC-2 and UC-3) Adverse Reaction VELSIPITY 2 mg Once Daily N = 288 % Study-size adjusted % for each group are based on the Mantel-Haenszel weights. Placebo N = 170 % Headache Headache includes related terms headache, migraine, and sinus headache. 6 4 Elevated liver tests Elevated liver tests includes related terms ALT increased, AST increased, blood alkaline phosphatase increased, blood bilirubin increased, cholestasis, GGT increased, hepatic enzyme increased, hepatic function abnormal, liver function test abnormal, and transaminases increased. 5 <1 Nausea 4 2 Bradycardia Bradycardia includes related terms bradycardia, sinus bradycardia, and heart rate decreased. 3 0 Urinary tract infection Urinary tract infection includes related terms urinary tract infection, cystitis, and genitourinary tract infection. 3 0 Ophthalmologic Findings In UC-1, for subjects with a baseline and follow-up examination, a decrease in visual acuity was reported in 2.6% (4/156) of subjects who received VELSIPITY and no subjects who received placebo [see Warnings and Precautions (5.4) ] .

Velsipity

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Velsipity

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

5.1Infections Risk of Infections

Interactions

Pregnancy and breastfeeding

8.1Pregnancy Pregnancy Exposure Registry

Adverse reactions

6.1Clinical Trials Experience

Composition

Official product information