For adult patients with moderately to severely active UC or CD when other therapies have not worked well enough or cannot be tolerated.
LONG‑TERM SAFETY PROFILE
- vs. Placebo
Clinical trials evaluated safety in more than 3300 patients (UC and CD)1
- Open Label
5-year analysis, which included an open-label continuation study (UC and CD), has demonstrated consistent results across safety parameters2
- Safety Data from the VARSITY Trial
Study was not designed to assess safety differences
UC TRIALS I & II AND
CD TRIALS I & III
SELECT ADVERSE EVENTS1
ADVERSE EVENTS BASED ON UC TRIALS I AND II, CD TRIALS I AND III1
- Infection rates with Entyvio were 0.85 per patient-year vs. 0.7 for placebo
- Infections consisted primarily of nasopharyngitis, upper respiratory tract infection, sinusitis, and urinary tract infection
- 2% of patients discontinued Entyvio due to infections
- Serious infection rates with Entyvio were 0.07 per patient-year vs. 0.06 for placebo
- Serious infections included anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis, and cytomegaloviral colitis
- The rate of detectable anti-vedolizumab antibodies at any time during the 52 weeks of continuous treatment with Entyvio was 4% (56 of 1434 patients)
- The frequency of antibodies detected in patients who received Entyvio was 13% at 24 weeks after the last dose of study drug
- 9 of 56 patients were persistently positive (at 2 or more study visits) for anti-vedolizumab antibody, and 33 of 56 patients developed neutralizing antibodies to vedolizumab
- Among 8 out of these 9 subjects, 6 had undetectable vedolizumab concentrations, and 2 had reduced vedolizumab concentrations. None of the 9 subjects with persistently positive anti-vedolizumab antibody achieved clinical remission at Weeks 6 or 52 in the controlled trials
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)
- Although unlikely, a risk of PML cannot be ruled out:
- PML, a rare and often fatal opportunistic infection of the central nervous system (CNS), has been reported with systemic immunosuppressants, including another integrin receptor antagonist. PML is caused by the John Cunningham (JC) virus and typically only occurs in patients who are immunocompromised
- 1 case of PML in an Entyvio-treated patient with multiple contributory factors has been reported in the postmarketing setting (e.g., human immunodeficiency virus [HIV] infection with a CD4 count of 300 cells/mm3 and prior and concomitant immunosuppression)
- Entyvio should be discontinued in patients with jaundice or other evidence of significant liver injury
- 3 patients reported serious adverse reactions of hepatitis with Entyvio; 1 additional case of serious hepatitis was seen in the open-label trial
- These adverse reactions occurred following 2 to 5 Entyvio doses; however, it is unclear if the reactions indicated drug-induced or autoimmune etiology
- There have been reports of elevations of transaminase and/or bilirubin in patients receiving Entyvio
- All patients recovered following discontinuation of therapy with or without treatment with corticosteroids
- Malignancies (excluding dysplasia and basal cell carcinoma) were in 0.4% (6 of 1434) of patients treated with Entyvio and in 0.3% (1 of 297) of patients treated with placebo
- The number of malignancies in clinical trials was small; however, long-term exposure was limited
- Adverse reactions were reported in 52% of patients treated with Entyvio (N=1434) and 45% of patients treated with placebo (N=297)
- Over 52 weeks, 7% of patients treated with Entyvio experienced serious adverse reactions compared to 4% treated with placebo
INFUSION‑RELATED REACTIONS (IRRS) AND HYPERSENSITIVITY REACTIONS
- 4% of patients treated with Entyvio (N=1434) experienced an IRR vs 3% of patients on placebo (N=297)
- 1 case of anaphylaxis (1 of 1434 patients treated with Entyvio) was reported by a CD patient during the second infusion (symptoms reported were dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate) and was managed with discontinuation of infusion and treatment with antihistamine and IV hydrocortisone
- Most frequently observed IRRs were nausea, headache, pruritus, dizziness, fatigue, infusion-related reaction, pyrexia, urticaria, and vomiting. These reactions generally occurred within the first two hours after the infusion and resolved with no treatment or following antihistamine and/or IV hydrocortisone treatment
5-YEAR SAFETY DATA IN UC AND CD2,6
- Safety data from 6 trials were analyzed (two phase 2 and four phase 3 studies conducted from May 2007 to June 2013)
- The overall safety population was defined as all patients (N=2932) who received 1 or more doses of the study drug (Entyvio or placebo) in at least 1 of the 6 studies
MEDIAN PLACEBO EXPOSURE OF 42 DAYS, RANGE 1-72 DAYS
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- Integrated analyses were performed separately for each indication (UC or CD)
- For patients who participated in multiple studies, all safety data during Entyvio exposure were combined
- For GEMINI LTS, an interim data cut through June 27, 2013, was used
- Patients randomized to placebo in GEMINI I, GEMINI II, or GEMINI III and who enrolled into GEMINI LTS received open-label Entyvio in that study. Thus, Entyvio-exposed patients may also have been exposed to placebo
- For each AE, the PYs were truncated after a patient experienced the AE, and each AE was counted only once per patient
- Patients who were randomized to placebo and then rolled over into an open-label study could contribute to events in either the placebo or Entyvio group, depending on when they experienced the AE
- PYs were calculated accordingly for placebo or Entyvio for each AE
- The limitation of the analyses is the disproportionate PYs of follow-up for placebo compared with vedolizumab. Statistical comparisons were not performed between the 2 groups
- When the number of events=0, the 95% CI was calculated based on the rule of 3 (ie, [0, 3/total PYs] x 100)
* Patients (US and ex-US) participated in the GEMINI I, GEMINI II, GEMINI III, GEMINI LTS, C13002, and C13004 studies. Patients in the C13004 study who rolled over to GEMINI LTS are included.
AE = adverse event; CI = confidence interval; LTS = long-term safety; mo = month; PY = patient‑year.
Exposure-adjusted incidence rates
of any AE, any GI AE, and any SAE
rates of any infection for
Entyvio and placebo groups
† Includes patients from all 6 studies.
‡ Includes patients from GEMINI I, GEMINI II, and GEMINI III.
§ Includes all MedDRA-preferred terms listed under the “Infections and Infestations” system organ class.
‖ Serious infections of interest, including clostridial infections, sepsis, tuberculosis, and Listeria meningitis were reported for between 1 and 15 patients (≤0.6%). All clostridial infections occurred in Entyvio-exposed patients.
GI = gastrointestinal; MedDRA = Medical Dictionary for Regulatory Activities; SAE = serious adverse event.
Prolonged exposure to Entyvio did not increase the frequency of AEs or SAEs, including GI SAEs
- Safety was assessed in the overall safety population from Months 0-≥48. For Months 0-<3, any AE and SAE rates were 64% and 9% (n=2830), for Months 3-<6, 56% and 8% (n=2718), for Months 6-<12, 60% and 10% (n=2432), for Months 12-<18, 59% and 8% (n=1632), for Months 18-<24, 56% and 5% (n=1288), for Months 24-<36, 65% and 9% (n=1030), for Months 36-<48, 40% and 5% (n=551), and for ≥48 months, 33% and 2% (n=61), respectively
- Across the 6 studies, 23 hepatobiliary events were reported in 22 Entyvio-treated patients; no cases were observed among placebo-exposed patients
- Five of the hepatic events were considered serious
- Patients exposed to Entyvio or placebo had similar low exposure-adjusted incidence rates of liver enzyme abnormalities (2.1/100 patient-years for Entyvio vs 2.8/100 patient-years for placebo)
- No liver enzyme abnormalities led to study drug discontinuation
- During the phase 3 studies, all malignancies occurred in 18 patients receiving Entyvio (6 patients in the placebo-controlled trials and 12 patients receiving open-label Entyvio) and 1 patient receiving placebo
- Among patients who received Entyvio during the induction phase and placebo during the maintenance phase, a greater percentage of patients were anti-vedolizumab antibody-positive (18%) without concomitant immunosuppressive use at baseline compared with those with baseline immunosuppressive use (3%). Based on data from the GEMINI LTS study, the immunogenicity rate did not appear to increase over time
ADVERSE EVENTS OBSERVED IN THE VARSITY STUDY
Safety Was Evaluated in 383 Patients: No New Safety Signals Were Observed for Entyvio3-5
STUDY WAS NOT DESIGNED TO ASSESS SAFETY DIFFERENCES
ADVERSE EVENTS IN SAFETY POPULATION
- The most frequent AEs* for adalimumab and Entyvio were as follows: ≥1 TEAE, 35.8% and 32.9%; ulcerative colitis, 16.3% and 11.5%; nasopharyngitis, 7.8% and 7.0%; headache, 5.4% and 7.0%; anemia, 6.7% and 5.2%; abdominal pain, 5.2% and 4.7%; upper respiratory tract infection, 4.4% and 5.2%
* Adverse events that occurred during the trial period. Trial period was the time from the first dose of a trial drug and up to 126 days after the last dose.
† Adverse events were classified according to the Medical Dictionary for Regulatory Activities System Organ Class categorization and preferred terms (version 21.0). The safety population was defined as all patients who received at least one dose of the study drug.
‡ No cases of progressive multifocal leukoencephalopathy.
§ Not related to Entyvio.
‖ Updated to include final 68-week safety follow-up.
AE = adverse event; TEAE = treatment-emergent adverse event.
Important Safety Information
- ENTYVIO (vedolizumab) for injection is contraindicated in patients who have had a known serious or severe hypersensitivity reaction to ENTYVIO or any of its excipients.
- Infusion-related reactions and hypersensitivity reactions including anaphylaxis, dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate have been reported. These reactions may occur with the first or subsequent infusions and may vary in their time of onset from during infusion or up to several hours post-infusion. If anaphylaxis or other serious infusion-related or hypersensitivity reactions occur, discontinue administration of ENTYVIO immediately and initiate appropriate treatment.
- Patients treated with ENTYVIO are at increased risk for developing infections. Serious infections have been reported in patients treated with ENTYVIO, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis, and cytomegaloviral colitis. ENTYVIO is not recommended in patients with active, severe infections until the infections are controlled. Consider withholding ENTYVIO in patients who develop a severe infection while on treatment with ENTYVIO. Exercise caution in patients with a history of recurring severe infections. Consider screening for tuberculosis (TB) according to the local practice.
- Progressive multifocal leukoencephalopathy (PML), a rare and often fatal opportunistic infection of the central nervous system (CNS), has been reported with systemic immunosuppressants, including another integrin receptor antagonist. PML is caused by the John Cunningham (JC) virus and typically only occurs in patients who are immunocompromised. One case of PML in an ENTYVIO-treated patient with multiple contributory factors has been reported in the post marketing setting (e.g., human immunodeficiency virus [HIV] infection with a CD4 count of 300 cells/mm3 and prior and concomitant immunosuppression). Although unlikely, a risk of PML cannot be ruled out. Monitor patients for any new or worsening neurological signs or symptoms. Typical signs and 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 suspected, withhold dosing with ENTYVIO and refer to a neurologist; if confirmed, discontinue ENTYVIO dosing permanently.
- There have been reports of elevations of transaminase and/or bilirubin in patients receiving ENTYVIO. ENTYVIO should be discontinued in patients with jaundice or other evidence of significant liver injury.
- Prior to initiating treatment with ENTYVIO, all patients should be brought up to date with all immunizations according to current immunization guidelines. Patients receiving ENTYVIO may receive non-live vaccines and may receive live vaccines if the benefits outweigh the risks.
- Most common adverse reactions (incidence ≥3% and ≥1% higher than placebo): nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain, and pain in extremities.
Adult Ulcerative Colitis (UC)
ENTYVIO (vedolizumab) is indicated in adults for the treatment of moderately to severely active UC.
Adult Crohn's Disease (CD)
ENTYVIO (vedolizumab) is indicated in adults for the treatment of moderately to severely active CD.
- Entyvio (vedolizumab) prescribing information. Takeda Pharmaceuticals.
- Colombel JF, Sands BE, Rutgeerts P, et al. Gut. 2017;66(5):839-851.
- Data on file. Takeda Pharmaceuticals.
- Sands BE, Peyrin-Biroulet L, Loftus EV Jr, et al. N Engl J Med. 2019;381(13):1215-1226.
- Sands BE, Peyrin-Biroulet L, Loftus EV Jr, et al. N Engl J Med. 2019;381(13):1215-1226. (supplemental appendix).
- Colombel JF, Sands BE, Rutgeerts P, et al. Gut. 2017;66(5):839-851. (supplemental appendix).