brentuximab vedotin

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brentuximab vedotin

Adcetris

Pharmacologic class: CD30-directed antibody-drug conjugate

Therapeutic class: Antineoplastic

Pregnancy risk category D

FDA Box Warning

• John Cunningham virus (JCV) infection resulting in progressive multifocal leukoencephalopathy (PML) and death has been reported in patients treated with brentuximab vedotin.

Action

Brentuximab vedotin antibody is a chimeric IgG1 directed against CD30. The small molecule MMAE is a micro-tubule-disrupting agent. MMAE is covalently attached to the antibody via a linker. Nonclinical data suggest that the anticancer activity of brentuximab vedotin is due to the binding of the antibody-drug conjugate (ADC) to CD30-expressing cells, followed by internalization of the ADC CD30 complex, and the release of MMAE via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, subsequently inducing cell-cycle arrest and apoptotic death of the cells.

Availability

Powder for reconstitution for injection, lyophilized: 50-mg single-use vial

Indications and dosages

Hodgkin's lymphoma after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who aren't ASCT candidates; systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen

Adults: 1.8 mg/kg I.V. infusion over 30 minutes q 3 weeks; continue treatment until a maximum of 16 cycles, disease progression, or unacceptable toxicity occurs. Calculate dosage for patients weighing more than 100 kg (220 lb) based on a weight of 100 kg.

Dosage adjustment

• Neutropenia

• Peripheral neuropathy

Contraindications

• Concurrent use of bleomycin

Precautions

Use cautiously in:

• renal or hepatic impairment

• neutropenia, peripheral neuropathy, tumor lysis syndrome, Stevens-Johnson syndrome

• elderly patients (safety and efficacy not established)

• pregnant or breastfeeding patients

• children (safety and efficacy not established).

Administration

• Follow facility policy for handling, preparing, and administering carcinogenic, mutagenic, and teratogenic drugs.

Don't administer by I.V. push or bolus.

Obtain CBC with differential before each dose. Withhold drug for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower. Be aware that growth factor support should be considered for subsequent cycles in patients who experience Grade 3 or 4 neutropenia. In patients with recurrent Grade 4 neutropenia despite the use of growth factors, consider discontinuation or dosage reduction.

• Reconstitute each 50-mg vial with 10.5 ml sterile water for injection, to yield a single-use solution containing 5 mg/ml. Direct stream toward wall of vial and not directly at powder. Gently swirl vial to aid dissolution. Don't shake.

• Reconstituted solution should be clear to slightly opalescent, colorless, and free of visible particulates.

• Following reconstitution, dilute immediately into infusion bag, or store solution at 2° to 8° C (36° to 46° F) and use within 24 hours of reconstitution. Don't freeze. Discard unused portion.

• Immediately add reconstituted solution to infusion bag containing a minimum volume of 100 ml to achieve a final concentration of 0.4 to 1.8 mg/ml in 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer's injection. Gently invert bag to mix solution. Following dilution, infuse solution immediately, or store solution at 2° to 8° C and use within 24 hours of reconstitution. Don't freeze.

• Don't mix drug with, or administer as an infusion with, other drug products.

Manage neuropathy by using combination of dose delay and dosage reduction as prescribed. For new or worsening Grade 2 or 3 neuropathy, withhold dose until neuropathy improves to Grade 1 or baseline; then restart at dosage prescribed. For Grade 4 peripheral neuropathy, discontinue drug.

If infusion reaction occurs, stop infusion and initiate appropriate medical management. If anaphylaxis occurs, discontinue infusion immediately and initiate appropriate medical management.

If Stevens-Johnson syndrome occurs, discontinue drug and initiate appropriate medical therapy.

Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of CNS abnormalities. Evaluation of PML includes, but isn't limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Withhold drug if PML is suspected; discontinue drug if PML is confirmed.

Adverse reactions

CNS: headache, dizziness, insomnia, anxiety, peripheral sensory neuropathy, peripheral motor neuropathy, fatigue

EENT: oropharyngeal pain

GI: nausea, vomiting, diarrhea, constipation, abdominal pain

Hematologic: neutropenia, anemia, thrombocytopenia

Musculoskeletal: arthralgia, myalgia, back pain, extremity pain, muscle spasms

Respiratory: upper respiratory tract infection, cough, dyspnea

Skin: rash, pruritus, alopecia, dry skin, Stevens-Johnson syndrome

Other: pyrexia, lymphadenopathy, chills, pain, peripheral edema, night sweats, decreased appetite, decreased weight, tumor lysis syndrome, sepsis, infusion reactions and anaphylaxis

Interactions

Drug-drug. Strong CYP3A4 inducers (such as rifampin): reduced MMAE exposure

Strong CYP3A4 inhibitors (such as ketoconazole): increased MMAE exposure and risk of adverse reactions

Patient monitoring

• Monitor renal and hepatic function tests closely.

• Monitor CBC with differential.

Continue to closely monitor patient for infusion reaction and take appropriate measures.

• Monitor patient for neuropathy and manage appropriately.

Be aware that concurrent use of bleomycin increases risk of pulmonary toxicity. Watch for cough, dyspnea, and other serious respiratory problems, such as interstitial infiltration or inflammation.

Be aware that patients with rapidly proliferating tumor and high tumor burden are at risk for tumor lysis syndrome; closely monitor these patients for hyperphosphatemia, hypocalcemia, hyperuricemia, hyperkalemia, and acute renal failure and take appropriate measures.

Continue to closely monitor neurologic function for signs and symptoms of PML (such as paresis, cognitive impairment, and problems with coordination).

Continue to closely monitor patients for signs and symptoms of Stevens-Johnson syndrome (such as hives, red or purple skin, rash, blisters).

Patient teaching

Instruct patient to immediately contact prescriber if signs and symptoms of infusion reactions (including fever, chills, rash, or breathing problems) occur within 24 hours of infusion.

Instruct patient to immediately contact prescriber if neurologic signs or symptoms of PML occur (such as problems with coordination, decreased strength or weakness, confusion, or problems thinking).

Instruct patient to immediately seek medical attention if hives, red or purple skin, rash, or blisters occur.

• Advise patient to report numbness or tingling of the hands or feet.

• Advise patient to contact prescriber if a fever (temperature of 38° C [100.5° F] or greater) or other evidence of potential infection (such as chills, cough, or pain on urination) develops.

• Counsel female patient of childbearing age to avoid pregnancy and breastfeeding while receiving this drug.

• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs mentioned above.

References in periodicals archive ?
and Takeda Pharmaceutical Company Limited today announced the final data of the ADCETRIS (brentuximab vedotin) monotherapy pivotal Phase 2 clinical trial in relapsed or refractory classical Hodgkin lymphoma were published in the journal Blood.
M2 PHARMA-February 20, 2015-Seattle Genetics submits supplemental biologics license application for phase III trial of Adcetris
M2 EQUITYBITES-August 22, 2011-Seattle Genetics awarded FDA accelerated approval of ADCETRIS for Hodgkin lymphoma and systemic anaplastic large cell lymphoma(C)2011 M2 COMMUNICATIONS http://www.
The pivotal, single-arm trial, which supported the FDA approval in 2011 of ADCETRIS for this indication, was conducted in 102 relapsed or refractory classical Hodgkin lymphoma patients who had previously received an autologous stem cell transplant (ASCT) to assess the efficacy and safety of single-agent ADCETRIS.
Takeda Pharmaceutical Company Limited today announced that the European Commission (EC) has extended the current conditional marketing authorization of ADCETRIS (brentuximab vedotin) and approved ADCETRIS for the treatment of adult patients with CD30+ Hodgkin lymphoma at increased risk of relapse or progression following autologous stem cell transplant (ASCT).
M2 PHARMA-February 5, 2013-Seattle Genetics to launch ADCETRIS in Canada(C)2013 M2 COMMUNICATIONS
Seattle Genetics commercializes ADCETRIS (brentuximab vedotin) for the treatment of several types of CD30-expressing lymphomas.
The European Commission has extended the current conditional marketing authorization of Adcetris (brentuximab vedotin) and approved Adcetris for the treatment of adult patients with CD30-positive cutaneous T-cell lymphoma after at least one prior systemic therapy, Osaka, Japan-based R and D-driven pharmaceutical company Takeda Pharmaceutical Company Ltd.