Entyvio^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Takeda Pharma A/S (Denmark)

Manufactured By

Patheon Italia, S.P.A. (Italy)

Or

Takeda Pharmaceutical Company Limited (Japan)

Packaging and Quality Control Release

DELPHARM NOVARA, S.r.l. (Italy)

Or

TAKEDA AUSTRIA, GmbH (Austria)

ATC Code

L04AA33 (Vedolizumab)

Active Substance

Vedolizumab (Rec.INN registered by WHO)

Dosage Form

Entyvio®

Lyophilisate for preparation of concentrate for preparation of solution for infusion 300 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of concentrate for preparation of solution for infusion in the form of a powder or porous mass of white or almost white color; reconstituted solution – from colorless to brownish-yellow, transparent or opalescent solution.

Excipients: L-histidine – 22.95 mg, L-histidine hydrochloride monohydrate – 21.4 mg, L-arginine hydrochloride – 131.65 mg, sucrose – 500 mg, polysorbate 80 – 3 mg.*

* the amount of active and excipients is indicated without a 10.4% overfill.

Glass vials (type I) with a volume of 20 ml (1) in a cardboard stand – cardboard packs with first-opening control.

Clinical-Pharmacological Group

Immunosuppressive drug – monoclonal antibodies

Pharmacotherapeutic Group

Immunosuppressive agent – monoclonal antibodies

Pharmacological Action

An immunosuppressive biological agent with selective action on the intestine. It is a humanized monoclonal IgG₁ antibody that specifically binds to the α₄β₇ integrin and selectively blocks the interaction of the α₄β₇ integrin with mucosal addressin cell adhesion molecule-1 (MAdCAM-1), but not with vascular cell adhesion molecule-1 (VCAM-1). MAdCAM-1 is predominantly expressed mainly on intestinal endothelial cells and plays a leading role in the migration of T-helper lymphocytes that cause the chronic inflammatory process characteristic of ulcerative colitis and Crohn’s disease, in which gastrointestinal tissues are affected.

Disruption of this molecular interaction prevents the transmigration of intestinal T-lymphocytes across the vascular endothelium into the parenchymal tissue in non-human primates and induces a reversible threefold increase in the content of these cells in the peripheral blood. The murine precursor of vedolizumab reduced gastrointestinal inflammation in colitis in cotton-top tamarins, which are an experimental model of ulcerative colitis. Vedolizumab does not bind to α₄β₁– and α_Eβ₇-integrins and does not suppress their function.

Vedolizumab suppressed the immune response to gastrointestinal antigen stimulation in healthy volunteers.

In clinical studies, patients were administered Vedolizumab at doses ranging from 2 to 10 mg/kg and more than 95% saturation of α₄β₇ receptors on circulating lymphocyte subtypes involved in immune surveillance in the gut was observed.

Pharmacokinetics

Pharmacokinetic studies of vedolizumab with single and multiple administration were conducted in healthy volunteers and patients with severe or moderately severe active ulcerative colitis or Crohn’s disease.

In patients receiving 300 mg of vedolizumab via 30-minute IV infusion at weeks 0 and 2, the mean serum concentration at week 6 was 27.9 µg/ml (standard deviation ±15.51) in patients with ulcerative colitis and 26.8 µg/ml (standard deviation ±17.45) in patients with Crohn’s disease. Starting from week 6, patients were administered Vedolizumab at doses of 300 mg every 8 weeks or every 4 weeks. In patients with ulcerative colitis, the mean serum C_ss was 11.2 µg/ml (standard deviation ±7.24) and 38.3 µg/ml (standard deviation ±24.43), respectively. In patients with Crohn’s disease, the mean serum C_ss was 13 µg/ml (standard deviation ±9.08) and 34.8 µg/ml (standard deviation ±22.55), respectively.

Vedolizumab exhibited linear pharmacokinetic properties at serum concentrations above 1 µg/ml.

The V_d of vedolizumab is about 5 L. Vedolizumab is predominantly located in the serum and is not distributed to peripheral tissues.

The total clearance of vedolizumab is approximately 0.157 L/day, and the serum T_1/2 is 25 days. The exact route of elimination of vedolizumab has not been established. The results of population pharmacokinetic analyses suggest that low albumin levels, increased body weight, a history of treatment with TNF inhibitor drugs, and the presence of antibodies to vedolizumab may contribute to increased clearance of vedolizumab, but the degree of impact of these factors is not considered clinically relevant. Dosing of vedolizumab based on body weight is not justified.

Indications

Moderately severe or severe active ulcerative colitis: patients with inadequate response, treatment failure (or loss of efficacy) or intolerance to one or more standard therapy drugs; with unsatisfactory response, loss of response or intolerance to one or more TNFα inhibitors.

Moderately severe or severe active Crohn’s disease: patients with inadequate response, treatment failure (or loss of efficacy) or intolerance to one or more standard therapy drugs; with unsatisfactory response, loss of response or intolerance to one or more TNFα inhibitors.

ICD codes

Dosage Regimen

Administer as an intravenous infusion over 30 minutes.

The single dose is 300 mg.

For induction therapy in ulcerative colitis and Crohn’s disease, administer at weeks 0, 2, and 6.

For maintenance therapy, administer 300 mg every 8 weeks.

Consider a dosing interval of every 4 weeks for patients who subsequently lose response.

Do not administer as an intravenous push or bolus.

Reconstitute the lyophilisate with 4.8 mL of Sterile Water for Injection.

Gently swirl the vial for at least 15 seconds to dissolve; do not shake or agitate vigorously.

Allow the reconstituted solution to stand for up to 20 minutes; it may remain at room temperature.

Visually inspect the solution for particulate matter and discoloration prior to dilution and administration.

Withdraw 5 mL from the vial and further dilute in 250 mL of 0.9% Sodium Chloride Injection.

Use the diluted solution immediately; if not used immediately, store refrigerated for up to 24 hours.

Do not freeze the reconstituted or diluted solution.

Monitor patients during the infusion and for at least 2 hours post-infusion for the first two doses.

Subsequent infusions require monitoring for approximately 1 hour post-infusion.

Discontinue the infusion immediately if a severe hypersensitivity reaction occurs.

Adverse Reactions

Infections and parasitic diseases very common – nasopharyngitis; common – bronchitis, gastroenteritis, upper respiratory tract infections, influenza, sinusitis, pharyngitis; uncommon – respiratory tract infections, vulvovaginal candidiasis, oral candidiasis.

Nervous system disorders very common – headache; common – paresthesia.

Cardiovascular system disorders common – arterial hypertension.

Respiratory system disorders: common – oropharyngeal pain, nasal congestion, cough.

Gastrointestinal system disorders common – anal abscess, anal fissure, nausea, dyspepsia, constipation, abdominal distension, flatulence, hemorrhoids.

Skin and subcutaneous tissue disorders common – rash, pruritus, eczema, erythema, night sweats, acne; uncommon – folliculitis.

Musculoskeletal and connective tissue disorders very common – arthralgia; common – muscle spasms, back pain, muscle weakness, fatigue, pain in extremity.

General disorders and administration site conditions common – pyrexia; uncommon – infusion reactions (including pain and irritation at the infusion site), chills associated with infusion reaction, feeling cold.

Contraindications

Active form of severe infectious diseases, such as tuberculosis, sepsis, CMV infection, listeriosis and opportunistic infections, such as progressive multifocal leukoencephalopathy; children under 18 years of age; hypersensitivity to vedolizumab.

Use in Pregnancy and Lactation

No studies have been conducted on the use of vedolizumab in pregnant women. The use of vedolizumab during pregnancy is permissible only if the potential benefit clearly outweighs the presumed risk, both for the mother and the fetus. Women of reproductive age are strongly advised to use appropriate contraceptive measures to prevent pregnancy during treatment with vedolizumab. Contraceptive use should be continued for at least 18 weeks after the last administration of the drug.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age

Geriatric Use

The drug is approved for use in elderly patients

Special Precautions

Emergency assistance means should be available during the infusion. Patients should be under close observation during the infusion and after its completion for 2 hours for the first 2 infusions and approximately 1 hour for subsequent infusions.

Treatment with vedolizumab should not be prescribed to patients with active forms of severe infections until the infections are brought under control. The possibility of discontinuing the course of treatment should also be considered in patients who develop a severe infection during a long course of treatment with vedolizumab.

Caution is required when using vedolizumab in patients with controlled severe chronic infections or a history of recurrent severe infections. Patients should be carefully monitored for infections before, during, and after completion of the course of treatment.

Before starting treatment, patients should be screened for tuberculosis in accordance with established standards. If latent tuberculosis is detected, treatment for tuberculosis must be carried out before using vedolizumab in accordance with local recommendations. If tuberculosis is detected in patients already undergoing treatment, Vedolizumab should be discontinued until the tuberculosis infection is cured.

Patients with ulcerative colitis and Crohn’s disease have an increased risk of developing malignancies.

Before starting treatment with vedolizumab, it is recommended to vaccinate all patients in accordance with current immunization guidelines. Administration of live and non-live vaccines simultaneously with vedolizumab is allowed only if the benefit of use significantly outweighs the risk.

In some patients, induction of remission in Crohn’s disease may take up to 14 weeks. The reasons for this phenomenon are not yet fully understood and may be related to the drug’s mechanism of action. This should be taken into account, especially in patients with severe active disease at baseline who have not yet been treated with TNFα inhibitors.

There is evidence that the use of vedolizumab without concomitant corticosteroid treatment may be less effective in achieving induction of remission in Crohn’s disease compared to patients already receiving concomitant corticosteroid therapy (regardless of concomitant use of immunomodulators).

Effect on ability to drive vehicles and operate machinery

Caution should be exercised when driving vehicles and working with mechanisms requiring increased attention and quick reactions, because Vedolizumab may sometimes cause dizziness.

Drug Interactions

In patients previously treated with natalizumab, the interval before starting treatment with vedolizumab should be at least 12 weeks, if the clinical situation allows.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.