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  • CLASSES

    Selective Adhesion Molecule Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Monoclonal antibody that is a specific integrin receptor antagonist; given via IV infusion, dosed every 8 weeks for maintenance
    Used for the treatment of moderately to severely active ulcerative colitis and Crohn's disease in adults
    Monitor for infusion and hypersensitivity reactions and increased risk for infection

    COMMON BRAND NAMES

    Entyvio

    HOW SUPPLIED

    Entyvio Intravenous Inj Pwd F/Sol: 300mg

    DOSAGE & INDICATIONS

    For moderately to severely active ulcerative colitis to reduce signs and symptoms and to induce and maintain clinical remission in patients who have an inadequate response to conventional therapy.
    Intravenous infusion dosage
    Adults

    300 mg IV infusion administered over 30 minutes at weeks 0, 2, and 6 as induction therapy. Thereafter, a maintenance regimen of 300 mg IV is given every 8 weeks. Full response is usually observed by 6 weeks; patients who do not respond by week 14 are unlikely to respond with continued treatment and consideration should be given to discontinuing therapy in these patients.The American College of Gastroenterology strongly recommends the use of vedolizumab for the induction and maintainenace of remission in patients with moderately- to severely-active ulcerative colitis.

    For moderately to severely active Crohn's disease to reduce signs and symptoms and to induce and maintain clinical remission in patients who have an inadequate response to conventional therapy.
    Intravenous infusion dosage
    Adults

    300 mg IV infusion administered over 30 minutes at weeks 0, 2, and 6 as induction therapy. Thereafter, a maintenance regimen of 300 mg IV is given every 8 weeks. Full response is usually observed by 6 weeks; patients who do not respond by week 14 are unlikely to respond with continued treatment and consideration should be given to discontinuing therapy in these patients.The American College of Gastroenterology states that vedolizumab with or without an immunomodulator is more effective than placebo and should be considered to be used for induction of symptomatic remission in patients with moderately to severely active Crohn's disease.

    MAXIMUM DOSAGE

    Adults

    300 mg/dose IV.

    Geriatric

    300 mg/dose IV.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; use with caution. There have been reports of elevations of transaminase and/or bilirubin as well as serious adverse reactions of hepatitis in patients receiving vedolizumab. Evaluate patients with signs or symptoms of hepatic dysfunction and discontinue vedolizumab therapy if these occur.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    NOTE: Have medications for the treatment of hypersensitivity reactions available for immediate use. Discontinue vedolizumab if a severe hypersensitivity reaction occurs. A severe hypersensitivity reaction contraindicates future vedolizumab receipt.
     

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Reconstituted solution should be clear or opalescent, colorless to light brownish yellow, and free of visible particulates. Discard if discoloration or particulate matter are observed.

    Intravenous Administration

    Administer as an intravenous infusion only. Do not administer as an intravenous push or bolus.
    Prior to initial treatment, ensure patient is current on all immunizations according to immunization guidelines.
     
    Reconstitution and Dilution
    Reconstitute vial containing lyophilized powder with 4.8 mL of Sterile Water for Injection at room temperature, using a syringe with a 21 to 25 gauge needle.
    Insert the syringe needle into the vial and direct the stream of Sterile Water for Injection to the glass wall of the vial to avoid excessive foaming. 
    Gently swirl the vial for 15 seconds to dissolve the lyophilized powder. Do not shake or invert.
    Allow the solution to stand 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. Discard if product has not dissolved within 30 minutes.
    Following dissolution, gently invert vial 3 times. 
    Immediately withdraw 5 mL (300 mg) of reconstructed product using a 21 to 25 gauge needle. Discard remaining product. 
    Add the 5 mL (300 mg) of reconstituted product to 250 mL of sterile 0.9% Sodium Chloride Injection or Lactated Ringer's Injection and gently mix the infusion bag. Do not mix with other medications. Administer solution as soon as possible.
    Storage: Do not freeze the reconstituted solution in the vial or the diluted solution in the infusion bag. Storage time periods for the infusion bags assume the reconstituted solution was immediately diluted. If the reconstituted solution is not immediately diluted, subtract the time in the vial from the time the diluted solution is stored in the infusion bag.
    Reconstituted solution in Sterile Water for Injection inside vial: Use immediately after reconstitution if stored at room temperature (20 to 25 degrees C [68 to 77 degrees F]) or within 8 hours if stored under refrigeration at 2 to 8 degrees C (26 to 46 degrees F).
    Diluted solution in 0.9% Sodium Chloride Injection: Use within 12 hours if stored at room temperature or 24 hours if stored under refrigeration (refrigerated time may include up to 12 hours at room temperature).
    Diluted solution in Lactated Ringer's Injection: Use immediately after dilution if stored at room temperature or within 6 hours if stored under refrigeration.
     
    Infusion
    Do not infuse concomitantly in the same intravenous line with other agents.
    Infuse over 30 minutes. After infusion, flush line with 30 mL of sterile 0.9% Sodium Chloride Injection. Discard any unused infusion solution.

    STORAGE

    Entyvio:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze reconstituted product
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in carton until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Vedolizumab is contraindicated in a patient with a previous hypersensitivity reaction to vedolizumab. In clinical trials, hypersensitivity reactions occurred including a case of anaphylaxis. Allergic symptoms may occur at any time during infusion, immediately following infusion, or up to several hours post-infusion. Vedolizumab should be administered in a facility prepared to immediately administer medications for the treatment of hypersensitivity reactions in the event of a reaction. Discontinue vedolizumab therapy if hypersensitivity occurs.

    Hepatic disease, jaundice

    Use vedolizumab with caution in patients with a history of hepatic disease. Monitor vedolizumab patients closely for evidence of liver disfunction, including elevated hepatic enzymes, jaundice, malaise, nausea, vomiting, abdominal pain, and anorexia. Reports of elevated transaminase and/or bilirubin in patients receiving vedolizumab have occured. Elevated transaminase and bilirubin, without evidence of obstruction, is predictive of severe liver injury that may be fatal or may require a liver transplant in some patients. If hepatic dysfunction is suspected, discontinue vedolizumab therapy immediately.

    Immunosuppression, infection, sepsis, tuberculosis

    Patients treated with vedolizumab are at an increased risk of developing infections due to immunosuppression. Cases of serious infections have been reported during vedolizumab trials including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis and cytomegaloviral colitis.  Patients need to be evaluated for tuberculosis risk factors and for latent or active tuberculosis infection with a tuberculin skin test both before and during treatment.  Do not administer vedolizumab to patients with a clinically important active infection like influenza or sepsis.  Educate patients about the symptoms of infection, and closely monitor patients for signs and symptoms of an infection during and after vedolizumab treatment. Patients who develop a new infection during treatment should be closely monitored and evaluated for appropriate antimicrobial therapy. If a patient develops a serious infection or sepsis, discontinue vedolizumab.

    Progressive multifocal leukoencephalopathy

    Use vedolizumab with caution in patients with a past experience of progressive multifocal leukoencephalopathy (PML) while receiving treatment with other integrin receptor antagonists. PML is a rare and sometimes fatal opportunistic infection of the central nervous system 9CNS) caused by the John Cunningham virus. PML typically only effects immunocompromised individuals. During clinical evaluation, patients receiving vedolizumab were carefully monitored for unexplained CNS changes. Although no cases of PML were identified during studies, the risk of PML exists in patients receiving vedolizumab. Therefore, monitor patients for any new or worsening neurological signs and symptoms. Signs and symptoms associated with PML vary, are progressive over days to weeks, and include: increased weakness on one side of the body or clumsiness of limbs, visual disturbance, and changes in thinking, memory, and orientation leading to confusion and personality changes. Severe disability or death can come over weeks or months. Interrupt vedolizumab therapy if PML is suspected and refer patient to a neurologist; if confirmed, discontinue therapy without rechallange.

    Vaccination

    Vedolizumab recipients may receive vaccinations except for live or live attenuated vaccines. No data are available on the response to live vaccination or the secondary transmission of infection by live vaccines in patients receiving vedolizumab. According to the manufacturer, live vaccines may be administered concurrently with vedolizumab only if the benefits outweigh the risks.

    Infants, neonates, pregnancy

    Available pharmacovigilance data, data from the ongoing pregnancy registry, and data from published case reports and cohort studies in pregnant women have not identified a vedolizumab associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Although not always predictive of human response, animal reproduction studies revealed no fetal harm with IV administration of vedolizumab to rabbits and monkeys at dose levels 20 times the recommended human dosage. Vedolizumab administered during pregnancy could affect immune responses in the in utero exposed neonates and infants. The clinical significance of low levels of vedolizumab in the exposed infants and the safety of administering live or live-attenuated vaccines to exposed infants are unknown. A pregnancy registry has been established to monitor maternal and fetal outcomes; health care providers are encouraged to enroll pregnant women exposed to vedolizumab by calling 1-877-TAKEDA7 (1-877-825-3327).[57235] There are limited data regarding the use of vedolizumab in pregnancy; guidelines generally recommend that the pregnant patient continue their biologic treatment as prescribed. For vedolizumab, experts recommend that practitioners plan the administration of the final pregnancy dose 6 to 10 weeks before the estimated delivery date, then resume treatment postpartum. Experts also recommend the avoidance of live vaccines for 6 months following birth for in utero exposed infants.

    Breast-feeding

    There are no data on the effects of vedolizumab on the breastfed infant, or the effects on milk production. Available published literature suggests the presence of vedolizumab in human milk. The effects of local gastrointestinal exposure and expected low systemic exposure to vedolizumab on the breastfed infant are unknown. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.[57235] Experts generally recommend the continuation of biologics such as vedolizumab during lactation and do not discourage breast-feeding; breastfed infants exposed to biologic or immunomodulating treatments did not appear to have differences in infection rates or developmental milestones compared to non-exposed infants according to available data from the Pregnancy in Inflammatory bowel disease and Neonatal Outcomes (PIANO) registry. Fewer data were available for vedolizumab vs. other agents at the time of review.[64164]

    Human anti-chimeric antibody (HACA)

    Similar to other therapeutic proteins, patients treated with vedolizumab may develop human anti-chimeric antibody (HACA). In clinical evaluation, antibody formation against vedolizumab occurred in 13% of patients at 24 weeks following the last dose. During treatment, 4% of patients had detectable anti-vedolizumab antibody at any time during the 52 weeks of continuous treatment. Patients with persistently positive anti-vedolizumab antibody failed to  achieve clinical remission at weeks 6 or 52 in the controlled trials.

    ADVERSE REACTIONS

    Severe

    new primary malignancy / Delayed / 0-1.0
    anaphylactoid reactions / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known
    leukoencephalopathy / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known

    Moderate

    antibody formation / Delayed / 4.0-13.0
    dyspnea / Early / Incidence not known
    jaundice / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known

    Mild

    pharyngitis / Delayed / 13.0-13.0
    arthralgia / Delayed / 12.0-12.0
    headache / Early / 12.0-12.0
    nausea / Early / 9.0-9.0
    fever / Early / 9.0-9.0
    fatigue / Early / 6.0-6.0
    cough / Delayed / 5.0-5.0
    back pain / Delayed / 4.0-4.0
    influenza / Delayed / 4.0-4.0
    musculoskeletal pain / Early / 3.0-3.0
    sinusitis / Delayed / 3.0-3.0
    rash / Early / 3.0-3.0
    pruritus / Rapid / 3.0-3.0
    infection / Delayed / Incidence not known
    flushing / Rapid / Incidence not known

    DRUG INTERACTIONS

    Adalimumab: (Major) Vedolizumab should not be used in combination with tumor necrosis factor (TNF) modifiers because of the potential for increased risk of progressive multifocal leukoencephalopathy and other infections. Ordinarily, patients receiving chronic immunosuppressant or immunomodulatory therapy should not be treated with vedolizumab.
    Certolizumab pegol: (Major) Vedolizumab should not be used in combination with tumor necrosis factor (TNF) modifiers because of the potential for increased risk of progressive multifocal leukoencephalopathy and other infections. Ordinarily, patients receiving chronic immunosuppressant or immunomodulatory therapy should not be treated with vedolizumab.
    Etanercept: (Major) Vedolizumab should not be used in combination with tumor necrosis factor (TNF) modifiers because of the potential for increased risk of progressive multifocal leukoencephalopathy and other infections. Ordinarily, patients receiving chronic immunosuppressant or immunomodulatory therapy should not be treated with vedolizumab.
    Golimumab: (Major) Vedolizumab should not be used in combination with tumor necrosis factor (TNF) modifiers because of the potential for increased risk of progressive multifocal leukoencephalopathy and other infections. Ordinarily, patients receiving chronic immunosuppressant or immunomodulatory therapy should not be treated with vedolizumab.
    Infliximab: (Major) Vedolizumab should not be used in combination with tumor necrosis factor (TNF) modifiers because of the potential for increased risk of progressive multifocal leukoencephalopathy and other infections. Ordinarily, patients receiving chronic immunosuppressant or immunomodulatory therapy should not be treated with vedolizumab.
    Live Vaccines: (Major) Avoid administering live vaccines to vedolizumab recipients unless the benefits outweigh the risks; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving vedolizumab. Before initiation of vedolizumab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Vedolizumab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
    Natalizumab: (Major) Avoid concomitant use of vedolizumab and natalizumab. The concomitant use of vedolizumab and natalizumab may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy and other opportunistic infections, over the risk observed with use of vedolizumab alone. The safety and efficacy of vedolizumab in combination with natalizumab have not been established.
    Tumor Necrosis Factor modifiers: (Major) Vedolizumab should not be used in combination with tumor necrosis factor (TNF) modifiers because of the potential for increased risk of progressive multifocal leukoencephalopathy and other infections. Ordinarily, patients receiving chronic immunosuppressant or immunomodulatory therapy should not be treated with vedolizumab.

    PREGNANCY AND LACTATION

    Pregnancy

    Available pharmacovigilance data, data from the ongoing pregnancy registry, and data from published case reports and cohort studies in pregnant women have not identified a vedolizumab associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Although not always predictive of human response, animal reproduction studies revealed no fetal harm with IV administration of vedolizumab to rabbits and monkeys at dose levels 20 times the recommended human dosage. Vedolizumab administered during pregnancy could affect immune responses in the in utero exposed neonates and infants. The clinical significance of low levels of vedolizumab in the exposed infants and the safety of administering live or live-attenuated vaccines to exposed infants are unknown. A pregnancy registry has been established to monitor maternal and fetal outcomes; health care providers are encouraged to enroll pregnant women exposed to vedolizumab by calling 1-877-TAKEDA7 (1-877-825-3327).[57235] There are limited data regarding the use of vedolizumab in pregnancy; guidelines generally recommend that the pregnant patient continue their biologic treatment as prescribed. For vedolizumab, experts recommend that practitioners plan the administration of the final pregnancy dose 6 to 10 weeks before the estimated delivery date, then resume treatment postpartum. Experts also recommend the avoidance of live vaccines for 6 months following birth for in utero exposed infants.

    MECHANISM OF ACTION

    Vedolizumab is a humanized monoclonal antibody that specifically binds to alpha-4-beta-7 integrin and blocks the interaction between alpha-4-beta-7 integrin with mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in the gastrointestinal tract. Vedolizumab in turn inhibits the migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue. It does not, however, bind to or inhibit function of the alpha-4-beta-1 and alpha-E-beta-7 integrins and does not antagonize the interaction of alpha-4 integrins with vascular cell adhesion molecule-1 (VCAM-1). The alpha-4-beta-7 integrin is expressed on the surface of a discrete subset of memory T-lymphocytes that preferentially migrate into the gastrointestinal tract. MAdCAM-1 is mainly expressed on gut endothelial cells and plays a critical role in the homing of T-lymphocytes to gut lymph tissue. Blocking the interaction of the alpha-4-beta-7 integrin with MAdCAM-1 reduces the chronic inflammatory process present in both ulcerative colitis and Crohn’s disease.

    PHARMACOKINETICS

    Vedolizumab is administered via intravenous infusion. Vedolizumab displays both linear and non-linear pharmacokinetics. Population pharmacokinetic analyses indicated that the linear clearance was approximately 0.157 L/day, the serum half-life was approximately 25 days at 300 mg dosage, and the distribution volume was approximately 5 L. The non-linear clearance decreases with increasing concentrations. Vedolizumab was not detected in the cerebrospinal fluid of 14 healthy subjects at five weeks after a single 450 mg intravenous administration.

    Intravenous Route

    Similar pharmacokinetics were observed in ulcerative colitis and Crohn’s disease patients. Vedolizumab, when administered as a 300 mg IV infusion (over 30 minutes) on weeks 0 and 2 and then starting at week 6 every 8 weeks, had trough serum concentrations for ulcerative colitis patients as follows: 26.3 +/- 12.9 mcg/ml (n = 210, week 6) and 11.2 +/- 7.2 mcg/ml (n = 77, week 46); similarly, through concentrations for Crohn’s disease patients were as follows: 27.4 +/- 19.2mcg/ml (n = 198, week 6) and 13.0 +/- 9.1 mcg/ml (n = 72, week 46). Persistent anti-vedolizumab antibody were associated with reduced serum concentrations of vedolizumab, either to undetectable or negligible levels at weeks 6 and 52 (n = 8).