Vedolizumab

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous [preservative free]:

Entyvio: 300 mg (1 ea) [contains polysorbate 80]

Pharmacology

Mechanism of Action

Vedolizumab is a humanized monoclonal antibody that binds to the alpha4beta7 integrin and blocks the interaction of alpha4beta7 integrin with mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and inhibits the migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue. The interaction of the alpha4beta7 integrin with MAdCAM-1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of ulcerative colitis and Crohn disease.

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: 5 L

Half-Life Elimination

25 days (serum, at 300 mg dosage)

Use: Labeled Indications

Crohn disease: For achieving clinical response, remission, and corticosteroid-free remission in moderately to severely active Crohn disease in adult patients who have had an inadequate response with, lost response to, or were intolerant to a tumor necrosis factor-alpha (TNF-alpha) blocker or immunomodulator, or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids.

Ulcerative colitis: For inducing and maintaining clinical response and remission, improving endoscopic appearance of the mucosa, and achieving corticosteroid-free remission in moderately to severely active ulcerative colitis in adult patients who have had an inadequate response with, lost response to, or were intolerant to a tumor necrosis factor-alpha (TNF-alpha) blocker or immunomodulator, or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids.

Contraindications

Serious or severe hypersensitivity to vedolizumab or any component of the formulation

Canadian labeling: Additional contraindications (not in US labeling): Patients with active severe infections or opportunistic infections.

Dosage and Administration

Dosing: Adult

Note: Prior to initiating treatment, all patients should be brought up to date with all immunizations according to current immunization guidelines.

Crohn disease or ulcerative colitis: IV: 300 mg at 0, 2, and 6 weeks and then every 8 weeks thereafter. Discontinue therapy in patients who show no evidence of therapeutic benefit by week 14.

Dosing: Geriatric

Refer to adult dosing.

Reconstitution

Reconstitute with 4.8 mL of room temperature SWFI (final concentration of 60 mg/mL) using a syringe with a 21- to 25-gauge needle; direct stream of SWFI to glass wall of vial to avoid excessive foaming. Gently swirl vial for at least 15 seconds; 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. 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.

Prior to withdrawing the reconstituted vedolizumab solution from the vial for dilution, gently invert vial 3 times. Add the 5 mL (300 mg) of reconstituted vedolizumab solution to 250 mL of sterile sodium chloride 0.9% or LR and gently mix the infusion bag. Once reconstituted and diluted, use the infusion solution as soon as possible.

Administration

IV: Infuse over 30 minutes. Do not administer by IV push or bolus. Following infusion, flush with 30 mL of sterile 0.9% sodium chloride injection or LR. Observe patients during infusion (until complete) and monitor for hypersensitivity reactions; discontinue if a reaction occurs.

Storage

Refrigerate unopened vials at 2°C to 8°C (36ºF to 46ºF). Retain in original package to protect from light.

Vials reconstituted with SWFI and solutions diluted for infusion in NS or LR may be stored as follows:

Table has been converted to the following text.

Storage Condition:

Vials reconstituted with SWFI:

Refrigeration (2°C to 8°C [36ºF to 46ºF]): 8 hours

Room temperature (20°C to 25°C [68ºF to 77ºF]): Use immediately after reconstitution

Diluted solution in NS:

Refrigeration (2°C to 8°C [36ºF to 46ºF]): 24 hours^{a, b, c}

Room temperature (20°C to 25°C [68ºF to 77ºF]): 12 hours^{a, c}

Diluted solution in LR:

Refrigeration (2°C to 8°C [36ºF to 46ºF]): 6 hours^{a, d}

Room temperature (20°C to 25°C [68ºF to 77ºF]): Use immediately after dilution

^aThis time assumes the reconstituted solution is immediately diluted in NS or LR 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.

^bThis period may include up to 12 hours at room temperature (20°C to 25°C [68ºF to 77ºF]).

^cThe combined storage time of reconstituted solution in the vial and the diluted solution in the infusion bag with NS is a total of 12 hours at room temperature (20°C to 25°C [68ºF to 77ºF]) or 24 hours refrigerated (2°C to 8°C [36ºF to 46ºF]). This combined storage time may include up to 8 hours of the reconstituted solution in the vial at 2°C to 8°C (36ºF to 46ºF). Avoid freezing.

^dThe combined storage time of reconstituted solution in the vial and the diluted solution in the infusion bag with LR is a total of 6 hours refrigerated (2°C to 8°C [36ºF to 46ºF]). Avoid freezing.

Drug Interactions

Anti-TNF Agents: May enhance the adverse/toxic effect of Vedolizumab. Avoid combination

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Vedolizumab may enhance the adverse/toxic effect of Natalizumab. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Travelers' Diarrhea and Cholera Vaccine: Vedolizumab may diminish the therapeutic effect of Travelers' Diarrhea and Cholera Vaccine. Management: Administer travelers' diarrhea andl cholera vaccine prior to initiation of therapy with vedolizumab. Consider therapy modification

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

>10%:

Central nervous system: Headache (12%)

Immunologic: Antibody development (4% to 13%; neutralizing: 2%)

Neuromuscular & skeletal: Arthralgia (12%)

Respiratory: Nasopharyngitis (13%)

1% to 10%:

Central nervous system: Fatigue (6%)

Dermatologic: Pruritus (3%), skin rash (3%)

Gastrointestinal: Nausea (9%)

Hepatic: Increased serum ALT (≥3 x ULN: <2%), increased serum AST (≥3 x ULN: <2%)

Infection: Influenza (4%)

Neuromuscular & skeletal: Back pain (4%), limb pain (3%)

Respiratory: Upper respiratory tract infection (7%), cough (5%), bronchitis (4%), oropharyngeal pain (3%), sinusitis (3%)

Miscellaneous: Fever (9%), infusion related reaction (4%)

<1%: Anaphylaxis, hepatitis, hypersensitivity reaction, increased serum bilirubin, increased serum transaminases, infection (including anal abscess, sepsis, tuberculosis, salmonella sepsis, listeria meningitis, giardiasis, cytomegaloviral colitis), malignant neoplasm (excluding dysplasia and basal cell carcinoma)

Warnings/Precautions

Concerns related to adverse effects:

• Hypersensitivity reactions: Hypersensitivity reactions have been reported including anaphylaxis. Allergic reactions including dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate have also been observed. Symptom onset may vary from during the infusion, immediately post-infusion, to several hours post-infusion. If serious reactions occur, discontinue administration immediately.
• Infections: Use may be associated with an increased risk for developing infections; most commonly reported infections included upper respiratory and nasal mucosa. Serious infections have also been reported in patients treated, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis, and cytomegaloviral colitis. Therapy is not recommended in patients with uncontrolled, active, severe infections. If a patient develops a serious infection, consider discontinuing therapy. Use with caution in patients with a history of recurring severe infections. Screening for tuberculosis should be considered.
• Liver injury: Elevations of transaminase and/or bilirubin have been reported in patients receiving vedolizumab. Discontinue therapy in patients with jaundice or other evidence of significant liver injury such as fatigue, anorexia, right upper abdominal discomfort, or dark urine.
• Progressive multifocal leukoencephalopathy: Integrin receptor antagonists have been associated with progressive multifocal leukoencephalopathy (PML), a rare and often fatal opportunistic infection of the central nervous system caused by the John Cunningham (JC) virus. Monitor patients for any new onset or worsening of neurological signs and symptoms including 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. Symptoms may progress over days to weeks and can lead to death or severe disability in weeks to months. If PML is suspected withhold therapy and refer to a neurologist; if confirmed, discontinue therapy permanently.

Other warnings/precautions:

• Immunizations: Patients should be brought up to date with all immunizations according to immunization guidelines before initiating therapy. Live vaccines should not be given concurrently unless the benefits outweigh the risks; there are no data on the secondary transmission of infection by live vaccines with vedolizumab. Non-live vaccines may be given concurrently.

Monitoring Parameters

Observe patients during infusion (until complete) and monitor for hypersensitivity reactions; LFTs; tuberculosis screening according to local practice; signs/symptoms of infection; any new onset or worsening of neurological signs and symptoms

Pregnancy

Pregnancy Considerations

Vedolizumab crosses the placenta (Mahadevan 2016).

Vedolizumab is a humanized monoclonal antibody (IgG₁). Placental transfer of human IgG is dependent upon the IgG subclass, maternal serum concentrations, birth weight, and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009).

Information related to the use of vedolizumab in pregnancy is available (Bar-Gil Shitrit 2019; Julsgaard 2017; Mahadevan 2017; Moens 2019; Sheridan 2017). Based on available data, an increased risk of adverse maternal or fetal effects has not been observed following vedolizumab exposure in pregnancy.

The safety of administering live vaccines to infants exposed to vedolizumab in utero is not known. Vaccination with live vaccines (eg, rotavirus vaccine) should be avoided for the first 6 months of life if exposure to a biologic agent occurs during the third trimester of pregnancy (eg, >27 weeks' gestation) (Mahadevan 2019).

Inflammatory bowel disease is associated with adverse pregnancy outcomes including an increased risk of miscarriage, premature delivery, delivery of a low birth weight infant, and poor maternal weight gain. Management of maternal disease should be optimized prior to pregnancy. Treatment decreases disease flares, disease activity, and the incidence of adverse pregnancy outcomes (Mahadevan 2019).

When treatment for inflammatory bowel disease is needed in pregnant women, appropriate biologic therapy can be continued without interruption. Serum levels should be evaluated prior to conception and optimized to avoid subtherapeutic concentrations or high levels which may increase placental transfer. Dosing can be adjusted so delivery occurs at the lowest serum concentration. For vedolizumab, the final injection can be given 6 to 10 weeks prior to the estimated date of delivery (4 to 5 weeks before delivery if every-4-week dosing), then continued 48 hours' postpartum (Mahadevan 2019).

Treatment algorithms are available for use of biologics in female patients with Crohn disease who are planning a pregnancy (Weizman 2019).

Data collection to monitor pregnancy and infant outcomes following exposure to vedolizumab is ongoing. Health care providers are encouraged to enroll women exposed to vedolizumab during pregnancy in a pregnancy exposure registry. Information about the registry can be obtained by calling 1-877-825-3327.

Patient Education

What is this drug used for?

• It is used to treat Crohn disease.
• It is used to treat ulcerative colitis.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Back pain
• Common cold symptoms
• Joint pain
• Nausea
• Stuffy nose
• Sore throat
• Painful extremities
• Loss of strength and energy

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Infusion reaction
• Liver problems like dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes.
• Shortness of breath
• Dizziness
• Passing out
• Vision changes
• Flushing
• Fast heartbeat
• Abnormal heartbeat
• Severe headache
• Progressive multifocal leukoencephalopathy like confusion, depression, trouble with memory, behavioral changes, change in strength on one side, trouble speaking, change in balance, or vision changes.
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.