5.1 Infections

Risk of Infections

VELSIPITY causes a mean reduction in peripheral blood lymphocyte count to approximately 45% of baseline values at Week 52 because of reversible sequestration of lymphocytes in lymphoid tissues [see Clinical Pharmacology (12.2)]. VELSIPITY may, therefore, increase the susceptibility to infections. Life-threatening and rare fatal infections have been reported in association with other sphingosine 1-phosphate (S1P) receptor modulators.

Before initiating treatment, obtain a recent (i.e., within 6 months or after discontinuation of prior UC therapy) CBC, including lymphocyte count.

Delay initiation of VELSIPITY in patients with an active infection until the infection is resolved.

In UC-1, the overall rate of infections in subjects treated with VELSIPITY was 24.9% compared to 22.2% in subjects who received placebo. In pooled data from UC-2 and UC-3, the overall rate of infections in subjects treated with VELSIPITY was 14.0% compared to 11.8% in subjects who received placebo. The most common infections were urinary tract infections and herpes viral infections in UC-1, and urinary tract infections in UC-2 and UC-3 [see Adverse Reactions (6.1)].

The proportion of subjects treated with VELSIPITY who experienced lymphocyte counts less than 0.2 x 109/L was 5.5% in UC-1 and 0.6% in UC-2 and UC-3. These events did not lead to treatment discontinuation. Peripheral blood absolute lymphocyte counts returned to the normal range in 90% of subjects within 4 to 5 weeks of stopping therapy [see Clinical Pharmacology (12.2)].

Consider interruption of treatment with VELSIPITY if a patient develops a serious infection.

Because residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, may persist up to 5 weeks after discontinuation of VELSIPITY, vigilance for infection should be continued throughout this period.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically occurs in patients who are immunocompromised, and that usually leads 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 (MS) patients treated with S1P receptor modulators and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants, and duration of use). Based on data from patients with MS, longer treatment duration increases the risk of PML in patients treated with S1P receptor modulators, and the majority of PML cases have occurred in patients treated with S1P receptor modulators for at least 18 months. VELSIPITY is not indicated for the treatment of MS. Physicians should be vigilant for clinical symptoms or unexplained neurologic findings that may be suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. If PML is suspected, treatment with VELSIPITY should be suspended until PML has been excluded by an appropriate diagnostic evaluation.

If PML is confirmed, discontinue treatment with VELSIPITY.

Immune reconstitution inflammatory syndrome (IRIS) has been reported in MS patients treated with S1P receptor modulators who developed PML and subsequently discontinued treatment. IRIS presents as a clinical decline in the patient’s condition that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes on MRI. The time to onset of IRIS in patients with PML was generally within a few months after S1P receptor modulator discontinuation. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken.

Herpes Viral Infections

Herpes simplex encephalitis, varicella zoster meningitis, and localized herpes viral infections have been reported with S1P receptor modulators. In UC-1, herpes zoster was reported in 0.7% of subjects treated with VELSIPITY and in none of the subjects who received placebo. Patients without a healthcare professional-confirmed history of varicella (chickenpox), or without documentation of a full course of vaccination against varicella zoster virus (VZV), should be tested for antibodies to VZV before initiating VELSIPITY (see Vaccinations).

Cryptococcal Infection

Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with S1P receptor modulators. Physicians should be vigilant for clinical symptoms or signs of CM. Patients with symptoms or signs consistent with a cryptococcal infection should undergo prompt diagnostic evaluation and treatment. VELSIPITY treatment should be suspended until a cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.

Prior and Concomitant Treatment with Anti-neoplastic, Immune-modulating, or Non-corticosteroid Immunosuppressive Therapies

VELSIPITY has not been studied in combination with anti-neoplastic, immune-modulating, or non-corticosteroid immunosuppressive therapies. Avoid concomitant administration of these therapies with VELSIPITY and in the weeks following administration because of the risk of additive immunosuppressive effects [see Warnings and Precautions (5.10)].

Vaccinations

Patients without a healthcare professional-confirmed history of varicella (chickenpox) or without documentation of a full course of vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV before initiating VELSIPITY. A full course of VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with VELSIPITY, following which initiation of treatment with VELSIPITY should be postponed for 4 weeks to allow the full effect of vaccination to occur.

No clinical data are available on the safety and efficacy of vaccinations in patients taking VELSIPITY. Vaccinations may be less effective if administered during VELSIPITY treatment.

If live attenuated vaccine immunizations are required, administer at least 4 weeks prior to initiation of VELSIPITY. Avoid the use of live attenuated vaccines during and for 5 weeks after treatment with VELSIPITY.

Update immunizations in agreement with current immunization guidelines prior to initiating VELSIPITY therapy.

5.2 Bradyarrhythmia and Atrioventricular Conduction Delays

Initiation of VELSIPITY may result in a transient decrease in heart rate and AV conduction delays [see Clinical Pharmacology (12.2)].

Reduction in Heart Rate

Initiation of VELSIPITY may result in a transient decrease in heart rate. After the first dose of VELSIPITY 2 mg, subjects with UC experienced the greatest mean decrease from baseline in heart rate of 7.2 bpm at Hour 3 in UC-1 and Hour 2 in UC-2.

In UC-1, bradycardia was reported on the day of treatment initiation in 1% of subjects treated with VELSIPITY compared to none in subjects who received placebo. On Day 2, bradycardia was reported in 1 subject (0.3%) treated with VELSIPITY compared to none in subjects who received placebo. In UC-2 and UC-3, bradycardia was reported on the day of treatment initiation in 2.9% of subjects treated with VELSIPITY compared to none in subjects who received placebo. On Day 2, bradycardia was reported in 1 subject (0.3%) treated with VELSIPITY compared to none in subjects who received placebo. Subjects who experienced bradycardia were generally asymptomatic. Few subjects experienced symptoms, such as dizziness, and these symptoms resolved without intervention.

Atrioventricular Conduction Delays

Initiation of VELSIPITY may result in transient AV conduction delays.

On the day of treatment initiation of VELSIPITY 2 mg, first- or second-degree Mobitz type I AV blocks were observed in 0.7% of VELSIPITY-treated subjects compared to none in placebo in UC-1, and in 0.8% of VELSIPITY-treated subjects compared to none in placebo in UC-2 and UC-3. In UC-1, UC-2, and UC-3, Mobitz type II second- or third-degree AV blocks were not reported in VELSIPITY-treated subjects.

If treatment with VELSIPITY is considered, advice from a cardiologist should be sought for those individuals:

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With significant QT prolongation (QTcF ≥450 msec in males, ≥470 msec in females)

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With arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs or QT prolonging drugs [see Drug Interactions (7)]

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With unstable ischemic heart disease, Class I or II heart failure, history of cardiac arrest, cerebrovascular disease, or uncontrolled hypertension [see Contraindications (4)]

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With resting heart rate of less than 50 bpm

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With history of symptomatic bradycardia, recurrent cardiogenic syncope, or severe untreated sleep apnea

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With history of Mobitz type I second-degree AV block, unless the patient has a functioning pacemaker [see Contraindications (4)]

5.3 Liver Injury

Elevations of aminotransferases may occur in patients receiving VELSIPITY. In UC-1, elevations of alanine transaminase (ALT) greater than 3-fold the upper limit of normal (ULN) occurred in 4.5% of subjects who received VELSIPITY and 2.1% of subjects who received placebo. In UC-2 and UC-3, elevations of ALT greater than 3-fold the ULN occurred in 2.5% of subjects who received VELSIPITY and 0.5% of subjects who received placebo.

Obtain transaminase and bilirubin levels, if not recently available (i.e., within last 6 months), before initiation of VELSIPITY.

Obtain transaminases and bilirubin in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. Discontinue VELSIPITY if significant liver injury is confirmed.

5.4 Macular Edema

S1P receptor modulators, including VELSIPITY, have been associated with an increased 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.

Macular edema over an extended period of time (i.e., 6 months) can lead to permanent visual loss. Consider discontinuing VELSIPITY if macular edema develops.

5.5 Increased Blood Pressure

In UC-1 and UC-2 and UC-3, subjects treated with VELSIPITY 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 compared to <1.5 mm Hg and <1 mm Hg in subjects receiving placebo, respectively. The increase was first detected after 2 weeks of treatment and remained within the specified average range of BP increases throughout treatment. Hypertension was reported as an adverse reaction in UC-1 [see Adverse Reactions (6.1)].

Monitor blood pressure during treatment with VELSIPITY and manage appropriately.

5.6 Fetal Risk

Based on animal studies, VELSIPITY may cause fetal harm when administered to a pregnant woman. In animal reproduction studies conducted in rats and rabbits, embryofetal toxicity was observed with administration of etrasimod at clinically relevant doses. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception to avoid pregnancy during and for one week after stopping VELSIPITY [see Use in Specific Populations (8.1, 8.3)].

5.7 Cutaneous Malignancies

The risk of cutaneous malignancies (including basal cell carcinoma, squamous cell carcinoma, and melanoma) is increased in patients treated with S1P receptor modulators in controlled trials. Kaposi’s sarcoma and Merkel cell carcinoma have also been reported in patients treated with S1P receptor modulators in the postmarketing setting.

Skin examinations are recommended prior to or shortly after the start of treatment and periodically thereafter for all patients, particularly those with risk factors for skin cancer. Providers and patients are advised to monitor for suspicious skin lesions. If a suspicious skin lesion is observed, it should be promptly evaluated. As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Concomitant phototherapy with UV-B radiation or PUVA-photochemotherapy is not recommended in patients taking VELSIPITY.

5.8 Posterior Reversible Encephalopathy Syndrome

Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving S1P receptor modulators. If a patient develops any neurological or psychiatric symptoms/signs (e.g., cognitive deficits, behavioral 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 ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, discontinue treatment with VELSIPITY.

5.9 Respiratory Effects

Reductions in absolute forced expiratory volume over 1 second (FEV1) were observed in subjects treated with VELSIPITY as early as 3 months after treatment initiation. In UC-1, the decline in absolute FEV1 from baseline in subjects treated with VELSIPITY compared to placebo was 79 mL (95% CI: -152, -5) at 3 months. In UC-2, reductions in absolute FEV1 were not observed. There is insufficient information to determine the reversibility of the decrease in FEV1 after drug discontinuation. In UC-1 and UC-2, subjects with UC and asthma and/or chronic obstructive pulmonary disease were treated with VELSIPITY; however, interpretation of changes in pulmonary function test measures in this population are limited due to small sample sizes. Spirometric evaluation of respiratory function should be performed during therapy with VELSIPITY if clinically indicated.

5.10 Unintended Additive Immune System Effects from Prior Treatment with Immunosuppressive or Immune-Modulating Drugs

When switching to VELSIPITY from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects [see Drug Interactions (7)].

5.11 Immune System Effects After Stopping VELSIPITY

After stopping VELSIPITY, lymphocyte counts returned to the normal range in 90% of subjects within 4 to 5 weeks of stopping VELSIPITY [see Clinical Pharmacology (12.2)]. Use of immunosuppressants within this period may lead to an additive effect on the immune system, and therefore monitor patients receiving concomitant immunosuppressants for infectious complications up to 5 weeks after the last dose of VELSIPITY [see Drug Interactions (7)].