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* Developed by:
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* Dosing Information
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=====Body as a Whole=====
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|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
|useInRenalImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.
|useInHepaticImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.
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|administration=* Oral
* Intravenous
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.
* Description
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|overdose====Acute Overdose===
====Signs and Symptoms====
* Description
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* Description
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There is limited information regarding <i>Chronic Overdose</i> of {{PAGENAME}} in the drug label.
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|PK=There is limited information regarding <i>Pharmacokinetics</i> of {{PAGENAME}} in the drug label.
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|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
==Overview==
<!--Brand Names-->
'''Brentuximab vedotin''' ([[International Nonproprietary Name|INN]], trade name '''Adcetris''') is an [[antibody-drug conjugate]] (ADC) directed to the protein [[CD30]], which is expressed in classical [[Hodgkin lymphoma]] (HL) and systemic [[anaplastic large cell lymphoma]] (sALCL).
|brandNames=* ®<ref>{{Cite web | title = | url = }}</ref>
On 28 February 2011 [[Seattle Genetics]] submitted a [[Biologics License Application]] or BLA to the [[U.S. Food and Drug Administration]] (FDA) for the use of brentuximab vedotin in relapsed or refractory Hodgkin's lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma.<ref>Fierce Biotech: [http://www.fiercebiotech.com/press-releases/seattle-genetics-submits-bla-fda-brentuximab-vedotin-relapsed-or-refractory-0?utm_medium=rss&utm_source=rss Seattle Genetics Submits BLA to FDA for brentuximab vedotin in relapsed or refractory hodgkin lymphoma and systemic ALCL]</ref>
<!--Look-Alike Drug Names-->
|lookAlike=* A® — B®<ref name="www.ismp.org">{{Cite web | last = | first = | title = http://www.ismp.org | url = http://www.ismp.org | publisher = | date = }}</ref>
The drug was granted accelerated approval by the FDA<ref>U.S. FDA: [http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm287672.htm Brentuximab Vedotin (marketed as Adcetris) Information]</ref> on August 19, 2011 for relapsed HL and relapsed sALCL and conditional [[Marketing authorization]] from the [[European Medicines Agency]] in October 2012<ref>EMA/European Medicines Agency: [http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/002455/WC500135004.pdf EPAR summary for the public for Adcetris/brentuximab vedotin]</ref> for relapsed or refractory HL and relapsed or refractory sALCL.<ref>Genetic Engineering & Biotechnology News: [http://www.genengnews.com/gen-news-highlights/seattle-genetics-antibody-drug-conjugate-receives-fda-okay-to-treat-lymphomas/81245576 Seattle Genetics’ Antibody-Drug Conjugate Receives FDA Okay to Treat Lymphomas]</ref>
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== Antibody-drug conjugates ==
Antibody-drug conjugates or ADCs represent a therapeutic application that combines the properties of [[monoclonal antibodies]] (mAbs) with the cell killing activity of cytotoxic small molecule drugs. The key components of antibody-drug conjugates include a monoclonal antibody, a stable linker<ref>ADC Review / Journal of Antibody-drug Conjugates: [http://adcreview.com/page/stable-linker-technologies Stable Linker (technologies)], May 23, 2013</ref> and a cytotoxic (anticancer) agent.<ref>ADC Review / Journal of Antibody-drug Conjugates: [http://adcreview.com/page/cytotoxic-agents Cytotoxic Agents], May 23, 2013</ref> Monoclonal antibodies are attached to biologically active drugs by chemical linkers with labile bonds. By combining the targeting of mAbs with the cancer-killing ability of cytotoxic drugs, antibody-drug conjugates allow discrimination between healthy and diseased tissue.
Brentuximab vedotin consists of the [[Chimera (protein)|chimeric]] [[monoclonal antibody]] brentuximab (cAC10, which targets the cell-membrane protein [[CD30]]) linked to cathepsin cleavable linker ([[valine]]-[[citrulline]]), [[Carbamate|para-aminobenzylcarbamate]] spacer three to five units of the [[antimitotic agent]] [[monomethyl auristatin E]] (MMAE, reflected by the 'vedotin' in the drug's name).<ref>ADC Review / Journal of Antibody-drug Conjugates: [http://adcreview.com/page/monomethyl-auristatin-e-mmae Monomethyl auristatin E (MMAE)], May 23, 2013</ref> The peptide-based linker bonds the antibody to the cytotoxic compound in a stable manner so the drug is not easily released from the antibody under physiologic conditions to help prevent toxicity to healthy cells and ensure dosage efficiency. The peptide antibody-drug bond facilitates rapid and efficient drug cleavage inside target [[tumor]] cell. The antibody cAC10 part of the drug binds to CD30 which often occurs on diseased cells but rarely on normal tissues.The antibody portion of the drug attaches to CD30 on the surface of malignant cells, delivering MMAE which is responsible for the anti-tumour activity.<ref>Seattle Genetics: [http://www.seagen.com/clinical_trials_sgn35.shtml Clinical Trials with brentuximab vedotin (SGN-35)]</ref> Once bound brentuximab vedotin is internalised by endocytosis and thus selectively uptaken by targeted cells. The vesicle containing the drug is fused with [[lysosomes]] and lysosomal cysteine proteases, particularly [[cathepsin B]] start to break down valine-citrulline linker and [[monomethyl auristatin E|MMAE]] is no longer bound to the antibody and is released directly into tumor environment.
<ref>Christos Vaklavas and Andres Forero-Torres; Safety and efficacy of brentuximab vedotin in patients with Hodgkin lymphoma or systemic anaplastic large cell lymphoma Therapeutic Advances in Hematology (August 2012) vol. 3 no. 4: 209-225[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627331/ doi: 10.1177/2040620712443076]</ref>
== Clinical trials ==
<!--Label Display Image-->
In a 2010 [[clinical trial]],<ref>{{ClinicalTrialsGov|NCT00848926|A Pivotal Open-Label Trial of Brentuximab Vedotin for Hodgkin Lymphoma}}</ref> 34% of patients with refractory Hodgkin Lymphoma achieved complete remission and another 40% had partial remission.<ref>[http://investor.seagen.com/phoenix.zhtml?c=124860&p=irol-newsArticle&ID=1504306&highlight= Seattle Genetics and Millennium Report Positive Data from Pivotal Trial of Brentuximab Vedotin (SGN-35) in Relapsed or Refractory Hodgkin Lymphoma] at 2010 Annual Meeting of the American Society of Hematology (ASH) (Corporate Press Release)</ref> Tumor reductions were achieved in 94% of patients. In ALCL, 87% of patients had tumors shrink at least 50% and 97% of patients had some tumor shrinkage.<ref>Minyanville Business News: [http://www.minyanville.com/businessmarkets/articles/seattle-genetics-biotech-sector-dendreon-immunotherapy/12/2/2010/id/31470 Is Seattle Genetics the Next Big Thing?], December 2, 2010</ref> Reports from the 55th Annual Meeting of the American Society of Hematology (2013) showed interim results<ref>{{cite journal|title=A Phase 2 Study Of Brentuximab Vedotin In Patients With Relapsed Or Refractory CD30-Positive Non-Hodgkin Lymphomas: Interim Results In Patients With DLBCL and Other B-Cell Lymphomas|journal=Blood|date=21 October 2013|volume=122|issue=21|url=http://bloodjournal.hematologylibrary.org/content/122/21/848.abstract|author1=Jeff P. Sharman|pages=848}}</ref> from a Phase II, open-label, single-arm study designed to evaluate the antitumor activity of brentuximab vedotin in relapsed or refractory CD30-positive NHL, including B-cell neoplasms. These results demonstrated that single-agent brentuximab vedotin induced a 42% objective response rate and manageable safety profile among advanced diffuse large B-cell lymphoma patients.<ref>{{ClinicalTrialsGov|NCT01421667|A Study of Brentuximab Vedotin in Relapsed or Refractory Non-Hodgkin Lymphoma}}</ref><ref>{{cite journal|journal=ADC Review / Journal of Antibody-drug Conjugates|url=http://adcreview.com/profiles/blogs/brentuximab-vedotin-shows-42-objective-response-rate-in-patients-|title=Brentuximab Vedotin Shows 42% Objective Response Rate in Patients with Relapsed or Refractory Diffuse Large B-cell Lymphoma, Study Shows|date=10 December 2013}}</ref> An ongoing phase III trial funded by Millennium Pharmaceuticals has the objective of comparing [[ABVD]] (a combination of [[chemotherapy]] drugs [[doxorubicin]], [[bleomycin]], [[vinblastine]], and [[dacarbazine]] used for treatment of [[Hodgkin lymphoma]]) and brentuximab vedotin in combination with AVD (doxorubicin, vinblastine, and dacarbazine) for treatment of [[classical Hodgkin lymphoma]]. A phase I study shows that a high number of patients using combination of brentuximab vedotin and ABVD experienced pulmonary toxic effects, however 0 patients had pulmonary toxic effects when treated with brentuximab vedotin and AVD, proving that [[bleomycin]]- brentuximab vedotin interaction caused these effects. 24 out of 25 patients treated with brentuximab vedotin and AVD achieved complete remission but further studies are required to find [[progression-free survival time]] and measure the effectiveness of this new combination therapy.<ref>Anas Younes, Joseph M. Connors, Steven I. Park, Michelle Fanale, Megan M. O'Meara, Naomi N. Hunder et al; Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study The Lancet Oncology, (December 2013) Volume 14, Issue 13, 1348 - 1356[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70501-1/abstract doi:10.1016/S1470-2045(13)70501-1]</ref> Brentuximab vedotin is also investigated as a substitute for [[vincristine]] (another mitotic inhibitor which prevents [[tubulin]] polymerization) which is used in [[non-Hodgkin lymphoma]] chemotherapy regimen [[CHOP]] (consisting of [[cyclophosphamide]], [[hydroxydaunorubicin]], [[vincristine]], [[prednisone]] or [[prednisolone]]). A phase III [[clinical trial]] is currently comparing the two combination therapies (CHOP and CHP- brentuximab vedotin) with estimated completion in December 2017<ref>A Randomized, Double-blind, Placebo-controlled, Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP) Versus CHOP in the Frontline Treatment of Patients With CD30-positive Mature T-cell Lymphomas [http://clinicaltrials.gov/show/NCT01777152 trial identifier: NCT01777152]</ref>
== Serious adverse events ==
Brentuximab vedotin was studied as monotherapy in 160 patients in two phase II trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were [[chemotherapy-induced peripheral neuropathy]] (a progressive, enduring and often irreversible tingling numbness, intense pain, and hypersensitivity to cold, beginning in the hands and feet and sometimes involving the arms and legs), [[neutropenia]] (an immune system impairment), fatigue, nausea, [[anemia]], [[upper respiratory tract infection]], diarrhea, fever, rash, [[thrombocytopenia]], cough and vomiting.<ref name="Prescribing Info">[http://www.adcetris.com/pdf/ADCETRIS_Prescribing_Information.pdf Highlights of Prescribing Information (US)/Adcetris (brentuximab vedotin) for Injection] (2012)</ref>
=== Black box warning ===
On January 13, 2012, the FDA announced that because brentuximab vedotin had been linked with two cases of [[progressive multifocal leukoencephalopathy]], they were requiring the addition of a [[Boxed_warning|black box]] warning to the drug regarding this potential risk.<ref>[http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm287710.htm Adcetris (brentuximab vedotin): Drug Safety Communication - Progressive Multifocal Leukoencephalopathy and Pulmonary Toxicity]</ref>
== Interactions ==
Patients who are receiving strong [[CYP3A4]] inhibitors concomitantly with brentuximab vedotin should be closely monitored for serious adverse events.<ref name="Prescribing Info" />
== Development and marketing collaboration ==
Brentuximab vedotin is marketed as ''Adcetris''.<ref>Onco'Zine - The International Cancer Network: [http://oncozine.com/profiles/blogs/european-medicines-agency European Medicines Agency Accepts Brentuximab Marketing Authorization Application], June 27, 2011</ref> Seattle Genetics and Millennium Pharmaceuticals/Takeda are jointly developing brentuximab vedotin. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and the Takeda Group has rights to commercialize in the rest of the world. Seattle Genetics and the Takeda Group are funding joint development costs for brentuximab vedotin on a 50:50 basis, except in Japan where the Takeda Group will be solely responsible for development costs.
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Black Box Warning
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Overview
Brentuximab vedotin is a {{{drugClass}}} that is FDA approved for the {{{indicationType}}} of {{{indication}}}. There is a Black Box Warning for this drug as shown here. Common adverse reactions include .
Adult Indications and Dosage
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There is limited information regarding Off-Label Guideline-Supported Use of Brentuximab vedotin in adult patients.
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There is limited information regarding Off-Label Non–Guideline-Supported Use of Brentuximab vedotin in adult patients.
Pediatric Indications and Dosage
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There is limited information regarding FDA-Labeled Use of Brentuximab vedotin in pediatric patients.
Off-Label Use and Dosage (Pediatric)
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There is limited information regarding Off-Label Guideline-Supported Use of Brentuximab vedotin in pediatric patients.
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There is limited information regarding Off-Label Non–Guideline-Supported Use of Brentuximab vedotin in pediatric patients.
Contraindications
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Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Brentuximab vedotin in the drug label.
Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Brentuximab vedotin in the drug label.
