Treatment initiation with VELSIPITY

• Prior to treatment initiation with VELSIPITY, an 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 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 VELSIPITY may result in a transient decrease in heart rate and AV conduction delays
• Caution should be applied when VELSIPITY 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, or Class Ia and Class III anti-arrhythmic substances, since co-administration of these substances with VELSIPITY may lead to additive effects. 
  • Temporary interruption of beta-blocker treatment may be needed prior to initiation of VELSIPITY, depending on the resting heart rate before initiation of VELSIPITY. 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 VELSIPITY.

• Significant QT prolongation (QTcF ≥450 msec in males, ≥470 msec in females.
• Arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic medicinal 
• product.
• Unstable ischaemic heart disease, history of cardiac arrest, cerebrovascular disease (occurring >6 months prior to treatment initiation), or uncontrolled hypertension 
• History of symptomatic bradycardia, recurrent cardiogenic syncope, or severe untreated sleep apnoea.

• Due to the risk of transient decreases in heart rate with the initiation of VELSIPITY, 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 may be required at the end of the 4-hour monitoring period if:
    • 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

Risk of infections

• Patients should be instructed to promptly report symptoms of infection to their physician. If a patient develops a serious infection, interruption of VELSIPITY should be considered
• VELSIPITY causes a mean reduction in peripheral blood lymphocyte count ranging from 43–55% of baseline values over 52 weeks because of reversible sequestration of lymphocytes in lymphoid tissues. Therefore, VELSIPITY may increase the susceptibility to infections 
• Before initiating treatment, a recent CBC (within the last 6 months or after discontinuation of prior UC therapy) should be obtained, including lymphocyte count
  • Assessments of CBC are also recommended periodically during treatment 
  • Absolute lymphocyte counts <0.2 x 10⁹/L, if confirmed, should lead to interruption of VELSIPITY until the level reaches >0.5 x 10⁹/L when re-initiation of treatment can be considered
• The initiation of VELSIPITY in patients with any active infection should be delayed until the infection is resolved
• If a patient develops a serious infection, interruption of VELSIPITY should be considered

• PML has been reported in multiple sclerosis patients treated with 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 VELSIPITY should be suspended until PML has been excluded by an appropriate diagnostic evaluation 
  • If PML is confirmed: Treatment with VELSIPITY should be discontinued

• 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 immunisations are required, these should be administered at least 4 weeks prior to initiation of VELSIPITY
• The use of live attenuated vaccines during and for at least 2 weeks after treatment with VELSIPITY should be avoided
• It is recommended to update immunisations in agreement with current immunisation guidelines prior to initiating VELSIPITY therapy

• In clinical studies, patients who received VELSIPITY 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 VELSIPITY and corticosteroids are limited.
• 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. When switching to VELSIPITY 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.

• In clinical studies, hypertension was more frequently reported in patients treated with VELSIPITY than in patients treated with placebo
• Blood pressure should be monitored during treatment with VELSIPITY and managed appropriately

• Based on animal studies, VELSIPITY may cause foetal harm
• Due to the risk to the foetus, VELSIPITY is contraindicated during pregnancy and in women of childbearing potential not using effective contraception
• 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

• S1P receptor modulators, including VELSIPITY, 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 Velsipity. 
• Patients with a history of diabetes mellitus, uveitis, or underlying/co-existing retinal disease, are at increased risk of macular oedema during VELSIPITY therapy. It is recommended that these patients undergo an ophthalmic evaluation prior to treatment initiation with VELSIPITY 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 treatment (cases reported with Velsipity occurred within this timeframe) and at any time if there is a change in vision while taking Velsipity
• Patients who present with visual symptoms of macular oedema should be evaluated and, if confirmed, treatment with VELSIPITY should be discontinued
  • A decision on whether VELSIPITY should be reinitiated 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 VELSIPITY 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 a VELSIPITY-treated patient develop any neurological or psychiatric symptoms/ signs, any symptom/sign suggestive of an increase of intracranial pressure, or accelerated neurological deterioration, a complete physical and neurological examination should be scheduled and an MRI considered
• If PRES is suspected, treatment with VELSIPITY should be discontinued

• VELSIPITY should be used with caution in patients with severe respiratory disease (e.g. pulmonary fibrosis, asthma and chronic obstructive pulmonary disease)

• Elevations of aminotransferases may occur in patients receiving VELSIPITY. Before initiating treatment, recent transaminase and bilirubin levels (within the last 6 months) should be obtained. 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, should have hepatic enzymes checked. VELSIPITY should be discontinued if significant liver injury is confirmed