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INDICATIONS and IMPORTANT SAFETY INFORMATION

BOXED WARNING

Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS.

Indications:

ADCETRIS is indicated for the treatment of:

  • Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)
  • HL in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens
  • Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen

The indications for ADCETRIS are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS.

Contraindication:

Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity.

Warnings and Precautions:

  • Peripheral neuropathy: ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Treating physicians should monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly.
  • Infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion reaction occurs, the infusion should be interrupted and appropriate medical management instituted. If anaphylaxis occurs, the infusion should be immediately and permanently discontinued and appropriate medical management instituted.
  • Neutropenia: Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions or discontinuation. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS.
  • Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome and these patients should be monitored closely and appropriate measures taken.
  • Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.
  • Stevens-Johnson syndrome: Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy.
  • Use in pregnancy: Fetal harm can occur. Pregnant women should be advised of the potential hazard to the fetus.

Adverse Reactions:

ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.

Drug Interactions:

Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions.


For additional Important Safety Information, including Boxed WARNING, please see the full Prescribing Information for ADCETRIS.

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After multiple failures,
single agent response

ADCETRIS is indicated for the treatment of:

  • Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)1
  • HL in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens1
  • Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen1

The indications for ADCETRIS are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS.1

A therapeutic alternative

73% ORR, 32% CR, and 40% PR in HL[1] 86% ORR, 57% CR, and 29% PR in sALCL[1]

ADCETRIS (brentuximab vedotin, formerly known as SGN-35) is the first approved antibody-drug conjugate (ADC) directed to CD30-expressing cells and the first therapeutic advance for HL in 30 years.2 ADCETRIS was studied as monotherapy in 160 patients in two pivotal phase 2 trials. Assessment of efficacy included objective response rate (complete remission plus partial remission) and duration of response.1

ADCETRIS induced complete and partial remissions in clinical trials1

Efficacy in relapsed patients1
  Relapsed HL
(N = 102)		 Relapsed sALCL
(N = 58)
  Median treatment duration: 27 weeks Median treatment duration: 24 weeks
  Response, %
(95% Cl)		 Duration of response
in months		 Response, %
(95% Cl)		 Duration of response
in months
  Median
(95% Cl)		 Range Median
(95% Cl)		 Range
Complete remission (CR) 32
(23-42)		 20.5
(12.0-NE*)		 1.4-21.9+ 57
(44-70)		 13.2
(10.8-NE*)		 0.7-15.9+
Partial remission (PR) 40
(32-49)		 3.5
(2.2-4.1)		 1.3-18.7 29
(18-41)		 2.1
(1.3-5.7)		 0.1-15.8+
Objective response rate (ORR) 73
(65-83)		 6.7
(4.0-14.8)		 1.3-21.9+ 86
(77-95)		 12.6
(5.7-NE*)		 0.1-15.9+

*Not estimable. +Follow-up was ongoing at the time of data submission.


  • ADCETRIS (brentuximab vedotin) demonstrated efficacy in sALCL patients with poor prognosis1
    • 72% of sALCL patients had anaplastic lymphoma kinase (ALK)-negative disease, which has a worse prognosis than ALK-positive disease1,3

ADCETRIS is the first approved CD30-directed ADC

ADC diagram

ADCETRIS is an ADC designed to target cells expressing CD301

  • CD30 is prevalent in both HL and sALCL but has limited expression in healthy tissue4-6
  • Binding of ADCETRIS (brentuximab vedotin) to CD30 on the cell surface initiates internalization of the ADC-CD30 complex1
  • Inside the cell, MMAE is released via proteolytic cleavage1
  • Binding of released MMAE to tubulin disrupts the microtubule network, inducing apoptotic cell death1
Most commonly reported (≥10%) adverse reactions1
  HL sALCL
  Total N = 102 Total N = 58
  % of patients % of patients
Adverse Reaction Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4
Blood and lymphatic system disorders            
 Neutropenia* 54 15 6 55 12 9
 Anemia* 33 8 2 52 2 -
 Thrombocytopenia* 28 7 2 16 5 5
 Lymphadenopathy 11 - - 10 - -
Nervous system disorders            
 Peripheral sensory neuropathy 52 8 - 53 10 -
 Peripheral motor neuropathy 16 4 - 7 3 -
 Headache 19 - - 16 2 -
 Dizziness 11 - - 16 - -
General disorders and administration site conditions            
 Fatigue 49 3 - 41 2 2
 Pyrexia 29 2 - 38 2 -
 Chills 13 - - 12 - -
 Pain 7 - - 28 - 5
 Edema peripheral 4 - - 16 - -
Infections and infestations            
 Upper respiratory tract infection 47 - - 12 - -
Gastrointestinal disorders            
 Nausea 42 - - 38 2 -
 Diarrhea 36 1 - 29 3 -
 Abdominal pain 25 2 1 9 2 -
 Vomiting 22 - - 17 3 -
 Constipation 16 - - 19 2 -
Skin and subcutaneous tissue disorders            
 Rash 27 - - 31 - -
 Pruritus 17 - - 19 - -
 Alopecia 13 - - 14 - -
 Night sweats 12 - - 9 - -
 Dry skin 4 - - 10 - -
Respiratory, thoracic and mediastinal disorders            
 Cough 25 - - 17 - -
 Dyspnea 13 1 - 19 2 -
 Oropharyngeal pain 11 - - 9 - -
Musculoskeletal and connective tissue disorders            
 Arthralgia 19 - - 9 - -
 Myalgia 17 - - 16 2 -
 Back pain 14 - - 10 2 -
 Pain in extremity 10 - - 10 2 2
 Muscle spasms 9 - - 10 2 -
Psychiatric disorders            
 Insomnia 14 - - 16 - -
 Anxiety 11 2 - 7 - -
Metabolism and nutrition disorders            
 Decreased appetite 11 - - 16 2 -
Investigations            
 Weight decreased 6 - - 12 3 -

*Derived from laboratory values and adverse reaction data.

  • 21% of patients discontinued therapy due to treatment-emergent adverse reactions1

Recommended dose is 1.8 mg/kg administered only as an IV infusion over 30 minutes every 3 weeks1

  • Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity1
  • The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg1
  • Do not administer as an intravenous push or bolus1
  • Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions1
  • Complete blood counts should be monitored prior to each dose of ADCETRIS (brentuximab vedotin)1

Monitoring and dose modification may help manage PN symptoms

  • 54% of patients experienced peripheral neuropathy (PN) in the pivotal trials1
  • Most PN was Grade 1 or 2—no Grade 4 PN events were observed1
  • Grade 3 PN (sensory) was reported by 8% and 10% of patients in the HL and sALCL trials, respectively1
    • 8% discontinued due to peripheral sensory neuropathy1
  • Grade 3 PN (motor) was reported by 4% and 3% of patients in the HL and sALCL trials, respectively1
    • 3% discontinued due to peripheral motor neuropathy1

Treating physicians should monitor patients for symptoms of PN and institute dose modification accordingly1

New or worsening Grade 2 or 3 Hold dose until PN improves to Grade 1 or baseline and then restart at 1.2 mg/kg
Grade 4 Discontinue ADCETRIS

Improvement or resolution of PN symptoms was observed in the majority of patients during follow-up1:

  • 49% had complete resolution
  • 51% had residual PN at time of last evaluation (31% partial improvement, 20% no improvement)

Neutropenia should be managed by dose delay and reduction1

Grade 3 or 4 Hold dose until resolution to baseline or Grade 2 or lower
Consider growth factor support for subsequent cycles
Recurrent Grade 4 despite use of growth factors Discontinue or reduce dose to 1.2 mg/kg

 

REFERENCES

1. ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics Inc; 2012. 2. Younes A. Novel treatment strategies for patients with relapsed classical Hodgkin lymphoma. Hematology Am Soc Hematol Educ Program. 2009:507-519. 3. Savage KJ, Harris NL, Vose JM, et al; International Peripheral T-Cell Lymphoma Project. ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood. 2008;111(12):5496-5504. 4. Haluska FG, Brufsky AM, Canellos GP. The cellular biology of the Reed-Sternberg cell. Blood. 1994;84(4):1005-1019. 5. Mani H, Jaffe ES. Hodgkin lymphoma: an update on its biology with new insights into classification. Clin Lymphoma Myeloma. 2009;9(3):206-216. 6. Stein H, Mason DY, Gerdes J, et al. The expression of the Hodgkin's disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood. 1985;66(4):848-858.