ENTYVIO (vedolizumab) is indicated for:
•inducing and maintaining clinical response,•inducing and maintaining clinical remission,•improving the endoscopic appearance of the mucosa, and •achieving corticosteroid-free remissionin adult patients with moderately to severely active ulcerative colitis who he had an inadequate response with, lost response to, or were intolerant to a tumor necrosis factor (TNF) blocker or immunomodulator; or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids.
1.2 Adult Crohn's DiseaseENTYVIO (vedolizumab) is indicated for:
•achieving clinical response,•achieving clinical remission, and•achieving corticosteroid-free remissionin adult patients with moderately to severely active Crohn's disease who he had an inadequate response with, lost response to, or were intolerant to a tumor necrosis factor (TNF) blocker or immunomodulator; or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids.
2.1 Important Preparation And Administration Instructions Administer ENTYVIO as an intrenous infusion over 30 minutes. Do not administer as an intrenous push or bolus. Reconstitute ENTYVIO lyophilized powder with Sterile Water for Injection and dilute in 250 mL of sterile 0.9% Sodium Chloride Injection or sterile Lactated Ringer's Injection prior to administration [see Dosage and Administration (2.4)].After the infusion is complete, flush with 30 mL of sterile 0.9% Sodium Chloride Injection or sterile Lactated Ringer's Injection.ENTYVIO should be administered by a healthcare professional prepared to manage hypersensitivity reactions including anaphylaxis, if they occur [see Warnings and Precautions (5.1)]. Appropriate monitoring and medical support measures should be ailable for immediate use. Observe patients during infusion and until the infusion is complete. 2.2 Prior To Administration Of Entyvio Prior to initiating treatment with ENTYVIO, all patients should be brought up to date with all immunizations according to current immunization guidelines. 2.3 Dosage In Adults With Ulcerative Colitis Or Crohn's DiseaseThe recommended dosage of ENTYVIO in adults with ulcerative colitis or Crohn's disease is 300 mg administered by intrenous infusion at zero, two and six weeks and then every eight weeks thereafter.
Discontinue therapy in patients who show no evidence of therapeutic benefit by Week 14.
2.4 Reconstitution And Dilution InstructionsReconstitution Instructions
Remove the flip-off cap from the single-dose vial and wipe with alcohol swab. Reconstitute ENTYVIO vial containing lyophilized powder with 4.8 mL of Sterile Water for injection at room temperature (20° to 25°C [68° to 77°F]), using a syringe with a 21- to 25- gauge needle.Insert the syringe needle into the vial through the center of the stopper and direct the stream of Sterile Water for Injection to the glass wall of the vial to oid excessive foaming.Gently swirl the vial for at least 15 seconds to dissolve the lyophilized powder. Do not vigorously shake or invert.Allow the solution to sit for up to 20 minutes at room temperature to allow for reconstitution and for any foam to settle; the vial can be swirled and inspected for dissolution during this time. If not fully dissolved after 20 minutes, allow another 10 minutes for dissolution. Do not use the vial if the drug product is not dissolved within 30 minutes.Visually inspect the reconstituted ENTYVIO solution for particulate matter and discoloration prior to dilution. Solution should be clear or opalescent, colorless to light brownish yellow and free of visible particulates. Do not administer reconstituted solution showing uncharacteristic color or containing particulates.Once dissolved, gently invert vial three times.Immediately, withdraw 5 mL (300 mg) of reconstituted ENTYVIO solution using a syringe with a 21- to 25- gauge needle. Discard any remaining portion of the reconstituted solution in the vial.Dilution Instructions
Add the 5 mL (300 mg) of reconstituted ENTYVIO solution to 250 mL of sterile 0.9% Sodium Chloride Injection or Lactated Ringer's Injection and gently mix the infusion bag. Do not add other medicinal products to the prepared infusion solution or intrenous infusion set. Once reconstituted and diluted, use the infusion solution as soon as possible.
Discard any unused portion of the infusion solution.
Storage
Specific storage conditions and timing for the reconstituted solution in vial and diluted solution in the infusion bag are outlined in Table 1.
Do not freeze the reconstituted solution in the vial or the diluted solution in the infusion bag.
Table 1: Storage InstructionsStorage ConditionRefrigeration(2° to 8°C [36° to 46°F])Room temperature(20° to 25°C [68° to 77°F])Reconstituted Solution (in Sterile Water for Injection inside vial)8 hoursUse immediately after reconstitutionDiluted Solution (in 0.9% Sodium Chloride Injection)24 hoursThis time assumes the reconstituted solution is immediately diluted in the 0.9% Sodium Chloride Injection or Lactated Ringer's Injection and held in the infusion bag only. Any time that the reconstituted solution was held in vial should be subtracted from the time the solution may be held in the infusion bag.
,This period may include up to 12 hours at room temperature (20° to 25°C [68° to 77°F]).
12 hoursDiluted Solution (in Lactated Ringer's Injection)6 hoursUse immediately after dilutionThe combined storage time of reconstituted ENTYVIO solution in the vial and the diluted solution in the infusion bag with 0.9% Sodium Chloride Injection is a total of 12 hours at room temperature (20° to 25°C [68° to 77°F]) or 24 hours refrigerated (2° to 8°C [36° to 46°F]). This combined storage time may include up to eight hours of the reconstituted solution in the vial at 2° to 8°C.
The combined storage time of reconstituted ENTYVIO solution in the vial and the diluted solution in the infusion bag with Lactated Ringer's Injection is a total of six hours refrigerated (2° to 8°C [36° to 46°F]).
3 Dosage Forms And StrengthsFor injection: 300 mg of vedolizumab as a white to off-white lyophilized cake in a single-dose vial for reconstitution.
4 ContraindicationsENTYVIO is contraindicated in patients who he had a known serious or severe hypersensitivity reaction to ENTYVIO or any of its excipients (such as dyspnea, bronchospasm, urticaria, flushing, rash and increased heart rate) [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
5.1 Infusion-Related Reactions And Hypersensitivity ReactionsIn UC Trials I and II and CD Trials I and III, hypersensitivity reactions occurred including a case of anaphylaxis (one out of 1434 patients [0.07%]) [see Adverse Reactions (6.1)]. Allergic reactions including dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate he also been observed. The majority were mild to moderate in severity as assessed by the investigator. Experience with other biologic medications suggests that hypersensitivity reactions and anaphylaxis to ENTYVIO may vary in their time of onset from during infusion or immediately post-infusion to occurring up to several hours post-infusion.
If anaphylaxis or other serious allergic reactions occur, discontinue administration of ENTYVIO immediately and initiate appropriate treatment (e.g., epinephrine and antihistamines).
5.2 InfectionsPatients treated with ENTYVIO are at increased risk for developing infections [see Adverse Reactions (6.1)]. The most commonly reported infections in clinical trials occurring at a rate greater on ENTYVIO than placebo involved the upper respiratory and nasal mucosa (e.g., nasopharyngitis, upper respiratory tract infection). Serious infections he also 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 treatment in patients who develop a severe infection while on treatment with ENTYVIO. Exercise caution when considering the use of ENTYVIO in patients with a history of recurring severe infections. Consider screening for tuberculosis (TB) according to the local practice. For progressive multifocal leukoencephalopathy (PML), see Warnings and Precautions (5.3).
5.3 Progressive Multifocal LeukoencephalopathyAnother integrin receptor antagonist has been associated with progressive multifocal leukoencephalopathy (PML), a rare and often fatal opportunistic infection of the central nervous system (CNS). PML is caused by the John Cunningham (JC) virus and typically only occurs in patients who are immunocompromised.
In ENTYVIO clinical trials, patients were actively monitored for PML with frequent and regular screenings, and evaluations of any new, unexplained neurological symptoms, as necessary. While zero cases of PML were identified among patients with at least 24 months of exposure, a risk of PML cannot be ruled out. No claims of comparative safety to other integrin receptor antagonists can be made based on this data.
Monitor patients on ENTYVIO for any new onset, or worsening, of neurological signs and 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. The progression of deficits usually leads to death or severe disability over weeks or months. If PML is suspected, withhold dosing with ENTYVIO and refer to a neurologist; if confirmed, discontinue dosing permanently.
5.4 Liver InjuryThere he been reports of elevations of transaminase and/or bilirubin in patients receiving ENTYVIO. In general, the combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients. ENTYVIO should be discontinued in patients with jaundice or other evidence of significant liver injury [see Adverse Reactions (6.1)].
5.5 Live And Oral VaccinesPrior to initiating treatment with ENTYVIO, all patients should be brought up to date with all immunizations according to current immunization guidelines [see Dosage and Administration (2.2)]. Patients receiving ENTYVIO may receive non-live vaccines (e.g., influenza vaccine injection) and may receive live vaccines if the benefits outweigh the risks. There are no data on the secondary transmission of infection by live vaccines in patients receiving ENTYVIO [see Adverse Reactions (6.1)].
6 Adverse ReactionsThe following topics are also discussed in detail in the Warnings and Precautions section:
•Infusion-Related Reactions and Hypersensitivity Reactions [see Warnings and Precautions (5.1)]•Infections [see Warnings and Precautions (5.2)]•Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.3)]•Liver Injury [see Warnings and Precautions (5.4)] 6.1 Clinical Trials ExperienceBecause 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 practice.
The data described below reflect exposure to ENTYVIO in 3,326 patients and healthy volunteers in clinical trials, including 1,396 exposed for greater than one year, and 835 exposed for greater than two years.
The safety data described in Table 2 are derived from four controlled Phase 3 trials (UC Trials I and II, and CD Trials I and III); data from patients receiving open-label ENTYVIO treatment at Weeks 0 and 2 (prior to entry into UC Trial II and CD Trial III) and from Weeks 6 to 52 (non-responders at Week 6 of UC Trial I and CD Trial I) are included [see Clinical Studies (14.1 and 14.2)].
In these trials, 1,434 patients received ENTYVIO 300 mg for up to 52 weeks, and 297 patients received placebo for up to 52 weeks. Of these, 769 patients had ulcerative colitis and 962 patients had Crohn's disease. Patients were exposed for a mean duration of 259 days (UC Trials I and II) and 247 days (CD Trials I and III).
Adverse reactions were reported in 52% of patients treated with ENTYVIO and 45% of patients treated with placebo (UC Trials I and II: 49% with ENTYVIO and 37% with placebo; CD Trials I and III: 55% with ENTYVIO and 47% with placebo). Serious adverse reactions were reported in 7% of patients treated with ENTYVIO compared to 4% of patients treated with placebo (UC Trials I and II: 8% with ENTYVIO and 7% with placebo; CD Trials I and III: 12% with ENTYVIO and 9%, with placebo).
The most common adverse reactions (reported by ≥3% of patients treated with ENTYVIO in the UC Trials I and II and CD Trials I and III combined group and ≥1% higher than in combined placebo group) were nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain and pain in extremities (Table 2).
Table 2. Adverse Reactions in ≥3% of ENTYVIO-treated Patients and ≥1% Higher than in Placebo (UC Trials I and IIData from patients receiving open-label ENTYVIO treatment at Weeks 0 and 2 (prior to entry into UC Trial II and CD Trial III) and from Weeks 6 to 52 (non-responders at Week 6 of UC Trial I and CD Trial I) are included.
and CD Trials I and III) Adverse ReactionENTYVIO
Patients who received ENTYVIO for up to 52 weeks.
(N=1434)Placebo
Patients who received placebo for up to 52 weeks.
(N=297) Nasopharyngitis13%
7%
Headache12%
11%
Arthralgia12%
10%
Nausea9%
8%
Pyrexia9%
7%
Upper respiratory tract infection7%
6%
Fatigue6%
3%
Cough5%
3%
Bronchitis4%
3%
Influenza4%
2%
Back pain4%
3%
Rash3%
2%
Pruritus3%
1%
Sinusitis3%
1%
Oropharyngeal pain3%
1%
Pain in extremities3%
1%
Safety data for patients (n=279) in UC Trials I and II and CD Trials I and III who received ENTYVIO at Weeks 0 and 2 and were then randomized to placebo at Week 6 for up to 52 weeks, and for patients (n=416) in CD Trial II, a 10 week Crohn's disease trial, are similar to those listed in Table 2.
Infusion-Related Reactions and Hypersensitivity Reactions
Serious infusion-related reactions and hypersensitivity reactions including anaphylaxis he been reported following ENTYVIO administration in clinical trials [see Warnings and Precautions (5.1)]. In UC Trials I and II and Crohn's Trials I and III, one case of anaphylaxis [one out of 1434 patients treated with ENTYVIO (0.07%)] was reported by a Crohn's disease 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 intrenous hydrocortisone.
In UC Trials I and II and CD Trials I and III, 4% of patients treated with ENTYVIO and 3% of patients treated with placebo experienced an infusion-related reaction (IRR). The most frequently observed IRR in the patients treated with ENTYVIO (reported more than twice) were nausea, headache, pruritus, dizziness, fatigue, infusion-related reaction, pyrexia, urticaria and vomiting (each of these adverse reactions occurred in