Brentuximab vedotin, a chimeric human-murine anti-CD30 antibody conjugated with the microtubule inhibitor monomethyl auristatin E (MMAE), is an antineoplastic agent.1, 3, 4, 5, 10
Newly Diagnosed Classical Hodgkin Lymphoma
Brentuximab vedotin is used in combination with doxorubicin, vinblastine, and dacarbazine (AVD) for the treatment of previously untreated stage III or IV classical Hodgkin lymphoma (cHL).1, 26 Brentuximab vedotin is designated an orphan drug by FDA for the treatment of this cancer.13 In adults with previously untreated stage III or IV cHL, combination therapy with brentuximab vedotin and AVD substantially reduced the risk of progression, death, or, in those who did not achieve a complete response, receipt of subsequent anticancer therapy compared with combination therapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).1
Efficacy of brentuximab vedotin in combination with AVD for previously untreated stage III or IV cHL is based principally on the results of an open-label, randomized phase 3 study (ECHELON-1) in 1334 patients with previously untreated advanced cHL.1, 26 The primary measure of efficacy was progression-free survival (based on time to disease progression, death, or receipt of subsequent anticancer therapy following failure to achieve complete response) as assessed by an independent review facility.1, 26 The median age of patients was 36 years; 84% of patients were white, 64% had stage IV disease, and 62% had extranodal involvement at diagnosis.1, 26
In this study, patients were randomized in a 1:1 ratio to receive therapy with brentuximab vedotin in combination with AVD (brentuximab vedotin-AVD) or ABVD alone.1, 26 Patients in the brentuximab vedotin-AVD group received brentuximab vedotin 1.2 mg/kg by IV infusion over 30 minutes in combination with IV doxorubicin hydrochloride 25 mg/m2, IV vinblastine sulfate 6 mg/m2, and IV dacarbazine 375 mg/m2 on days 1 and 15 of each 28-day cycle for a maximum of 6 cycles.1, 26 Patients in the ABVD group received the same dosages of doxorubicin hydrochloride, vinblastine sulfate, and dacarbazine with the addition of IV bleomycin 10 units/m2 on days 1 and 15 of each 28-day cycle for a maximum of 6 cycles.1, 26
At a median follow-up of 24.6 months, median progression-free survival had not been reached in either group; however, the risk of disease progression, death, or receipt of subsequent anticancer therapy following failure to achieve complete response was reduced by 23% in patients receiving brentuximab vedotin-AVD compared with those receiving ABVD alone.1, 26 Disease progression, death, or receipt of subsequent anticancer therapy following failure to achieve complete response occurred in 14, 3, or 1%, respectively, of patients receiving brentuximab vedotin-AVD and 15, 3, or 3%, respectively, of those receiving ABVD alone.1, 26 Subsequent anticancer therapy consisted of salvage chemotherapy (71%) and radiation therapy (29%).26 At the time of analysis, overall survival was not substantially different between the treatment groups.1 Complete response was achieved in 73% of patients receiving brentuximab vedotin-AVD and 70% of those receiving ABVD alone.1 Results of a subgroup analysis based on relevant baseline patient and disease characteristics suggested lack of a progression-free survival benefit for brentuximab vedotin-AVD compared with ABVD alone in patients 60 years of age or older and in those without extranodal involvement.26
Brentuximab vedotin is used as single-agent consolidation therapy for cHL in patients at high risk of relapse or progression following autologous stem cell transplantation.1, 29, 30 Brentuximab vedotin is designated an orphan drug by FDA for the treatment of this cancer.13 In adults with cHL at high risk of relapse or progression following autologous stem cell transplantation, consolidation therapy with brentuximab vedotin substantially prolonged median progression-free survival compared with placebo.1, 29, 30
Efficacy of brentuximab vedotin as consolidation therapy for cHL in patients at high risk of relapse or progression following autologous stem cell transplantation is based principally on the results of a randomized, double-blind, placebo-controlled phase 3 study (AETHERA) in 329 patients with relapsed or refractory cHL (i.e., disease progression within 12 months or, in those with extranodal involvement, at 12 or more months following first-line therapy).1, 29 Patients were enrolled in the study if they achieved a complete or partial response or had stable disease following their most recent pre-stem cell transplantation salvage therapy.1, 29 The primary measure of efficacy was progression-free survival as assessed by an independent review facility.1, 29 The median age of patients was 32 years; the patients had received a median of 2 prior systemic therapies for their disease.1 In this study, patients were randomized in a 1:1 ratio to receive brentuximab vedotin (1.8 mg/kg by IV infusion over 30 minutes) or placebo every 3 weeks for a maximum of 16 cycles; treatment was initiated 30-45 days after autologous stem cell transplantation.1, 29 At a median follow-up of 22 months, median progression-free survival was prolonged in brentuximab vedotin-treated patients compared with placebo recipients (at least 42.9 versus 24.1 months; hazard ratio: 0.57).1 At the time of analysis, overall survival was not substantially different between the treatment groups.1 At a follow-up of 5 years, median progression-free survival for brentuximab vedotin-treated patients had not been reached and was 15.8 months in those receiving placebo; however, 5-year progression-free survival rate was 59% in patients receiving brentuximab vedotin and 41% in those receiving placebo.30
Relapsed Classical Hodgkin Lymphoma
Brentuximab vedotin is used as a single agent for the treatment of cHL following failure of autologous stem cell transplantation or following failure of 2 or more multiple-agent chemotherapy regimens in patients who are not candidates for autologous stem cell transplantation.1, 24, 27 Brentuximab vedotin is designated an orphan drug by FDA for the treatment of this cancer.13 This indication is based on objective response rate in a noncomparative, open-label study in patients with relapsed cHL.1
Efficacy of brentuximab vedotin for cHL following failure of autologous stem cell transplantation or following failure of 2 or more multiple-agent chemotherapy regimens in patients who are not candidates for autologous stem cell transplantation is based principally on the results of an open-label, noncomparative, phase 2 study in 102 patients with Hodgkin lymphoma who relapsed following autologous stem cell transplantation.1, 6, 20, 24 The primary measure of efficacy was objective response rate (complete plus partial responses).1, 6, 17 The median age of patients was 31 years; the patients had received a median of 5 prior therapies for their disease.1, 6 In this study, all patients received brentuximab vedotin (1.8 mg/kg IV every 3 weeks) for a maximum of 16 cycles or until disease progression or unacceptable toxicity occurred.6, 17 At the time of interim analysis, objective response rate was 73%; 32% of patients receiving the drug achieved a complete response.1 At the time of analysis, the median duration of response for all responders was 6.7 months (range: 1.3-21.9 months); the median duration of response was 20.5 months for patients achieving a complete response but only 3.5 months for those achieving a partial response.1, 20 Complete response rates at the time of final analysis (at a median follow-up of 35.1 months) remained similar to the interim results.27 At the time of final analysis, median overall survival and progression-free survival were 40.5 and 9.3 months, respectively; estimated 5-year overall survival and progression-free survival rates were 41 and 22%, respectively.27
Previously Untreated Systemic Anaplastic Large Cell Lymphoma or other Peripheral T-cell Lymphomas
Brentuximab vedotin is used in combination with cyclophosphamide, doxorubicin, and prednisone (CHP) for the treatment of previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-positive peripheral T-cell lymphomas (PTCLs), including angioimmunoblastic T-cell lymphoma (AITL) and PTCL not otherwise specified (PTCL-NOS).1, 31 Brentuximab vedotin is designated an orphan drug by FDA for the treatment of these cancers.13 In adults with previously untreated sALCL or other CD30-positive PTCLs, brentuximab vedotin in combination with CHP prolonged progression-free survival and overall survival compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).1, 31
Efficacy of brentuximab vedotin in combination with CHP for previously untreated sALCL or other CD30-positive PTCLs is based principally on the results of a double-blind, double-dummy, active-controlled, randomized phase 3 study (ECHELON-2) in 452 patients with previously untreated CD30-positive (defined as CD30 expression of at least 10% per immunohistochemistry) PTCL.1, 31 The primary measure of efficacy was progression-free survival (based on time to disease progression, death, or receipt of subsequent systemic chemotherapy for the treatment of residual or progressive disease) as assessed by a blinded independent review facility.1, 31
In this study, patients were randomized in a 1:1 ratio to receive therapy with brentuximab vedotin in combination with CHP (brentuximab vedotin-CHP) or CHOP alone.1, 31 Patients in the brentuximab vedotin-CHP group received brentuximab vedotin 1.8 mg/kg by IV infusion over 30 minutes on day 1 in combination with IV cyclophosphamide 750 mg/m2 on day 1, IV doxorubicin hydrochloride 50 mg/m2 on day 1, and oral prednisone 100 mg on days 1-5 of each 21-day cycle for up to 6-8 cycles.1, 31 Patients in the CHOP group received the same dosages of cyclophosphamide, doxorubicin hydrochloride, and prednisone with the addition of IV vincristine sulfate 1.4 mg/m2 on day 1 of each 21-day cycle for up to 6-8 cycles.1, 31
The median age of patients enrolled in this study was 58 years; 78% of the patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, 81% had stage III or IV disease, and 63% had a baseline International Prognostic Index score of 2 or 3.1, 31 Most patients (70%) enrolled in the study had sALCL; 16% had PTCL-NOS, 12% had AITL, 2% had adult T-cell leukemia/lymphoma, and less than 1% had enteropathy-associated T-cell lymphoma.1, 31 Approximately one-half (48%) of patients with sALCL had anaplastic lymphoma kinase (ALK)-negative disease.1, 31 This study excluded patients with primary cutaneous CD30-positive T-cell lymphoproliferative disorders and lymphomas.1
Overall, patients receiving brentuximab vedotin-CHP had longer median progression-free survival (48.2 versus 20.8 months; hazard ratio: 0.71), higher objective response rates (83 versus 72%), and higher complete response rates (68 versus 56%) compared with those receiving CHOP alone.1, 31 In the subset of patients with sALCL, those receiving brentuximab vedotin-CHP also had longer median progression-free survival compared with those receiving CHOP alone (55.7 versus 54.2 months; hazard ratio: 0.59).1 In the overall study population at a median follow-up of 41.9 months for those receiving brentuximab vedotin-CHP and 42.2 months for those receiving CHOP, median overall survival had not been reached in either group; however, overall survival appeared to be prolonged in patients receiving brentuximab vedotin-CHP compared with those receiving CHOP alone.1 Results of a subgroup analysis (based on age, sex, ECOG performance status, International Prognostic Index score, disease stage, histologic subtype) suggested lack of progression-free survival and overall survival benefits for brentuximab vedotin-CHP compared with CHOP alone in patients with an International Prognostic Index score of 4 or 5 or ECOG performance status score of 2; a progression-free survival benefit for brentuximab vedotin-CHP compared with CHOP alone also was not apparent in the subgroup of patients with AITL or stage I or II disease.31
Relapsed Systemic Anaplastic Large Cell Lymphoma
Brentuximab vedotin is used as a single agent for the treatment of sALCL following failure of 1 or more multiple-agent chemotherapy regimens;1, 25, 28 brentuximab vedotin is designated an orphan drug by FDA for the treatment of this cancer.13 This indication is based on objective response rate in a noncomparative, open-label, phase 2 study in patients with relapsed sALCL.1, 21, 28
This noncomparative, open-label study included 58 patients with sALCL who relapsed following prior therapy.1, 7, 21, 25, 28 The primary measure of efficacy was objective response rate (complete plus partial responses).1, 16 The median age of patients was 52 years; the patients had received a median of 2 prior therapies, 26% of the patients had received prior autologous stem cell transplantation for their disease, and 72% of the patients had ALK-negative disease, which is associated with a worse prognosis.1, 3, 7, 21 In this study, all patients received brentuximab vedotin (1.8 mg/kg IV every 3 weeks) for a maximum of 16 cycles or until disease progression or unacceptable toxicity occurred.7, 16
At the time of interim analysis, the objective response rate was 86%; 57% of patients receiving the drug achieved a complete response.1, 25 At the time of analysis, the median duration of response for all responders was 12.6 months (range: 0.1-15.9 months); the median duration of response was 13.2 months for patients achieving a complete response but only 2.1 months for those achieving a partial response.1, 21 Objective response rates at the time of final analysis (at a median follow-up of 58.4 months) remained similar to the interim results; 66% of patients receiving the drug achieved a complete response.28 At the time of final analysis, the median duration of response for all responders was 25.6 months.28 Although median overall survival had not been reached at the time of final analysis, median progression-free survival was 20 months and estimated 5-year overall survival and progression-free survival rates were 60 and 39%, respectively.28 Subgroup analysis suggested that objective response rates were similar in patients with ALK-negative or ALK-positive disease (88 or 81%, respectively).28
Relapsed Primary Cutaneous T-cell Lymphoma or Mycosis Fungoides
Brentuximab vedotin is used as a single agent for the treatment of primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-positive mycosis fungoides previously treated with systemic therapy.1, 23 Brentuximab vedotin is designated an orphan drug by FDA for the treatment of these conditions.13 In patients with previously treated CD30-positive pcALCL or mycosis fungoides, durable response rates were higher in patients receiving brentuximab vedotin compared with those receiving standard chemotherapy.1, 23
Efficacy of brentuximab vedotin for the treatment of pcALCL or CD30-positive mycosis fungoides previously treated with systemic therapy is based principally on the results of an open-label, multicenter, randomized phase 3 study (ALCANZA) in 131 patients with previously treated CD30-positive (defined as CD30 expression of at least 10% on at least one skin biopsy specimen) pcALCL or mycosis fungoides.1, 23 Patients were eligible for this study if they had pcALCL previously treated with systemic therapy or radiation therapy or mycosis fungoides previously treated with systemic therapy.1, 23 The primary measure of efficacy was durable response rate (complete plus partial responses lasting at least 4 months) as assessed by an independent review facility according to global response scoring.1, 23
In this study, patients were randomized in a 1:1 ratio to receive therapy with brentuximab vedotin 1.8 mg/kg by IV infusion over 30 minutes on day 1 of each 21-day cycle for a maximum of 16 cycles or investigator's choice of standard chemotherapy (methotrexate 5-50 mg orally once weekly or bexarotene 300 mg/m2 orally once daily) for a maximum of 48 weeks.1, 23 The median age of patients was 60 years; 85% of patients were white, 63% had stage I or II disease, and 13% had stage IV disease.1 Patients enrolled in the study had received a median of 4 prior therapies, including a median of 1 skin-directed therapy and 2 systemic therapies.1, 23
At a median follow-up of 22.9 months, the durable response rate was 56.3% in patients receiving brentuximab vedotin compared with 12.5% in those receiving standard chemotherapy.1, 23 The objective response rate was 67.2% in patients receiving brentuximab vedotin and 20.3% in those receiving standard chemotherapy; complete responses were achieved in 15.6 and 1.6% of patients receiving these respective treatments.1 Patients receiving brentuximab vedotin also had longer median progression-free survival (16.7 versus 3.5 months) and event-free survival (9.4 versus 2.3 months) compared with those receiving standard chemotherapy.1, 23 Results of a subgroup analysis based on relevant baseline patient and disease characteristics suggested that the effect of brentuximab vedotin on durable response rate and progression-free survival was consistent across all subgroups.23
Because brentuximab vedotin may cause neutropenia, the manufacturer states that complete blood cell (CBC) counts should be obtained prior to each dose; more frequent monitoring should be considered in patients with evidence of grade 3 or 4 neutropenia.1
Primary prophylaxis with a granulocyte colony-stimulating factor (G-CSF) is recommended for patients receiving brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine (AVD) or cyclophosphamide, doxorubicin, and prednisone (CHP) beginning with cycle 1.1
Patients who experience an infusion-related reaction to brentuximab vedotin should receive a premedication regimen (e.g., a corticosteroid, an antihistamine, and acetaminophen) prior to each subsequent dose of the drug.1
Clinicians should consult the respective manufacturers' labelings or published protocols for information on the dosage, method of administration, and administration sequence of other antineoplastic agents used in combination regimens.1
Procedures for proper handling (e.g., use of gloves or protective clothing) and disposal of antineoplastic agents should be followed.1, 19
Brentuximab vedotin is administered by IV infusion over 30 minutes.1
Unreconstituted brentuximab vedotin powder for injection should be stored in unopened vials at 2-8°C.1 Unopened vials should be retained in the original package for protection from light.1
Prior to administration, commercially available brentuximab vedotin powder for injection must be reconstituted and diluted using proper aseptic technique.1 The powder is reconstituted by adding 10.5 mL of sterile water for injection to a vial labeled as containing 50 mg of the drug to provide a solution containing 5 mg/mL.1 The diluent should be directed toward the wall of the vial and not directly at the brentuximab vedotin cake or powder.1 The vial should be gently swirled and inspected visually for particulate matter and discoloration prior to dilution and administration.1 The resulting solution should not be shaken.1 The solution should be clear to slightly opalescent, colorless, and free of visible particulates.1 The reconstituted brentuximab vedotin solution may be diluted immediately or stored at 2-8°C for use within 24 hours,1 and should be protected from direct sunlight until time of use.19 The reconstituted solution should not be frozen.1
For preparation of the final diluted brentuximab vedotin solution for infusion, the required amount of reconstituted brentuximab vedotin solution should be injected into an infusion bag containing a minimum volume of 100 mL of 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer's injection to produce a final solution with brentuximab vedotin concentration of 0.4-1.8 mg/mL.1 The final diluted brentuximab vedotin solution for infusion should be mixed by gentle inversion.1 The solution may be infused immediately or stored at 2-8°C and used within 24 hours following reconstitution; the solution for infusion should not be frozen and should be protected from direct sunlight until use.1, 19 Any partially used vials should be discarded.1 Brentuximab vedotin should not be admixed with any other drug, nor should any other drug be administered simultaneously in the same IV line with brentuximab vedotin infusion.1
In patients who weigh 100 kg or less, dosage of brentuximab vedotin should be based on actual body weight;19 however, in patients who weigh more than 100 kg, dosage should be calculated based on a weight of 100 kg.1
Combination Therapy for Previously Untreated Classical Hodgkin Lymphoma
When used in combination with doxorubicin, vinblastine, and dacarbazine (AVD) for the treatment of previously untreated stage III or IV classical Hodgkin lymphoma (cHL), the recommended adult dosage of brentuximab vedotin is 1.2 mg/kg (up to a maximum dose of 120 mg) administered as a 30-minute IV infusion on days 1 and 15 of each 28-day cycle.1, 26 Therapy should be continued for up to 6 cycles or until disease progression or unacceptable toxicity occurs.1, 26 In the ECHELON-1 study, brentuximab vedotin was administered approximately 1 hour after administration of the AVD regimen.26
Consolidation Therapy for Classical Hodgkin Lymphoma
For consolidation therapy as a single agent in patients with cHL at high risk of relapse or progression following autologous stem cell transplantation, the recommended adult dosage of brentuximab vedotin is 1.8 mg/kg (up to a maximum dose of 180 mg) administered as a 30-minute IV infusion every 3 weeks.1 Therapy should be continued for up to 16 cycles or until disease progression or unacceptable toxicity occurs.1 Brentuximab vedotin should be initiated upon recovery from or within 4-6 weeks following autologous stem cell transplantation.1
Monotherapy for Relapsed Classical Hodgkin Lymphoma
For the treatment of cHL following failure of autologous stem cell transplantation or following failure of 2 or more multiple-agent chemotherapy regimens in patients who are not autologous stem cell transplantation candidates, the recommended adult dosage of brentuximab vedotin is 1.8 mg/kg (up to a maximum dose of 180 mg) administered as a 30-minute IV infusion every 3 weeks.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Combination Therapy for Previously Untreated Peripheral T-cell Lymphoma
When used in combination with cyclophosphamide, doxorubicin, and prednisone (CHP) for the treatment of previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-positive peripheral T-cell lymphomas (PTCLs), including angioimmunoblastic T-cell lymphoma (AITL) and PTCL not otherwise specified (PTCL-NOS), the recommended adult dosage of brentuximab vedotin is 1.8 mg/kg (up to a maximum dose of 180 mg) administered as a 30-minute IV infusion on day 1 of each 21-day cycle.1 Therapy should be continued for 6-8 cycles.1
In the ECHELON-2 study, 70 or 18% of patients received 6 or 8 cycles, respectively, of brentuximab vedotin in combination with CHP.1
Monotherapy for Relapsed Peripheral T-cell Lymphoma
For the treatment of sALCL following failure of 1 or more multiple-agent chemotherapy regimens, the recommended adult dosage of brentuximab vedotin is 1.8 mg/kg (up to a maximum dose of 180 mg) administered as a 30-minute IV infusion every 3 weeks.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
For the treatment of primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-positive mycosis fungoides previously treated with systemic therapy, the recommended adult dosage of brentuximab vedotin is 1.8 mg/kg (up to a maximum dose of 180 mg) administered as a 30-minute IV infusion every 3 weeks.1 Therapy should be continued for up to 16 cycles or until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
Dosing interruption and/or dosage reduction or discontinuance of brentuximab vedotin therapy may be necessary based on severity of an adverse effect as described in Tables 1, 2, and 3.1
Toxicity | Dosage Modifications Relapsed cHL, Consolidation Therapy for cHL, Relapsed sALCL, or Relapsed pcALCL or Mycosis Fungoides (Initial Dosage = 1.8 mg/kg every 3 weeks) |
|---|---|
Peripheral neuropathy: New or worsening Grade 2 or 3 | Interrupt brentuximab vedotin; when toxicity resolves to grade 1 or baseline, resume at reduced dosage of 1.2 mg/kg (maximum 120 mg) every 3 weeks |
Peripheral neuropathy: Grade 4 | Discontinue brentuximab vedotin |
Neutropenia: Grade 3 or 4 | Interrupt brentuximab vedotin; when toxicity improves to grade 2 or less or to baseline, resume at same dosa consider G-CSF use during subsequent cycles |
Neutropenia: Recurrent Grade 4 (despite G-CSF use) | Consider drug discontinuance or dosage reduction (i.e., reduced brentuximab vedotin dosage of 1.2 mg/kg [maximum 120 mg] every 3 weeks) |
Toxicity | Dosage Modification Previously Untreated cHL (Initial Dosage = 1.2 mg/kg every 2 weeks) |
|---|---|
Peripheral neuropathy: Grade 2 | Reduce brentuximab vedotin dosage to 0.9 mg/kg (maximum 90 mg) every 2 weeks |
Peripheral neuropathy: Grade 3 | Consider dosage modification of concomitant neurotoxic drugs and interrupt brentuximab vedotin; when toxicity improves to grade 2 or less, resume brentuximab vedotin at reduced dosage of 0.9 mg/kg (maximum 90 mg) every 2 weeks |
Peripheral neuropathy: Grade 4 | Discontinue brentuximab vedotin |
Neutropenia: Grade 3 or 4 (patient not receiving primary G-CSF prophylaxis) | Administer G-CSF during subsequent cycles |
Toxicity | Dosage Modification Previously Untreated sALCL or Other PTCL (Initial Dosage = 1.8 mg/kg every 3 weeks) |
|---|---|
Peripheral Sensory Neuropathy: Grade 2 | Continue same dosage |
Peripheral Sensory Neuropathy: Grade 3 | Reduce brentuximab vedotin dosage to 1.2 mg/kg (maximum 120 mg) every 3 weeks |
Peripheral Sensory Neuropathy: Grade 4 | Discontinue brentuximab vedotin |
Peripheral Motor Neuropathy: Grade 2 | Reduce brentuximab vedotin dosage to 1.2 mg/kg (maximum 120 mg) every 3 weeks |
Peripheral Motor Neuropathy: Grade 3 or 4 | Discontinue brentuximab vedotin |
Neutropenia: Grade 3 or 4 (patient not receiving primary G-CSF prophylaxis) | Administer G-CSF during subsequent cycles |
For patients with mild hepatic impairment (Child-Pugh class A), the manufacturer recommends a reduced dosage of brentuximab vedotin.1 When the usual recommended dosage is 1.2 mg/kg every 2 weeks, the manufacturer recommends that patients with mild hepatic impairment (Child-Pugh class A) receive an initial brentuximab vedotin dosage of 0.9 mg/kg (up to a maximum dose of 90 mg) every 2 weeks.1 When the usual recommended dosage is 1.8 mg/kg every 3 weeks, the manufacturer recommends that patients with mild hepatic impairment (Child-Pugh class A) receive an initial brentuximab vedotin dosage of 1.2 mg/kg (up to a maximum dose of 120 mg) every 3 weeks.1 Use of brentuximab vedotin in patients with moderate or severe hepatic impairment (Child-Pugh class B or C) should be avoided.1
No dosage adjustment is necessary in patients with mild or moderate renal impairment (creatinine clearance of 30-80 mL/minute).1 Use of brentuximab vedotin in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) should be avoided.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Progressive Multifocal Leukoencephalopathy
JC virus infection causing progressive multifocal leukoencephalopathy (PML), sometimes fatal, has been reported in patients receiving brentuximab vedotin.1, 15 Other factors that might increase the risk for PML include prior therapies and underlying disease that may cause immunosuppression.1 Signs and symptoms of PML may develop over several weeks or months; some cases have occurred within 3 months of initiation of brentuximab vedotin.1, 15
The possible diagnosis of PML should be considered in any patient receiving brentuximab vedotin who experiences new neurologic manifestations suggestive of PML (e.g., changes in mood or behavior, confusion, changes in thinking, memory loss, vision changes, changes in speech or walking, decreased strength or weakness on one side of the body).1, 15 If PML is suspected, the drug should be withheld.1 If PML is confirmed, brentuximab vedotin should be permanently discontinued.1
Other Warnings and Precautions
Peripheral neuropathy has been reported in patients receiving brentuximab vedotin.1 Brentuximab vedotin mainly causes sensory neuropathy, but motor neuropathy also has been reported.1
In clinical studies evaluating single-agent brentuximab vedotin, peripheral neuropathy occurred in 62% of patients receiving the drug.1 The median time to onset of peripheral neuropathy was 3 months (range: 0-12 months), and the median time to resolution or improvement of any grade was 5 months.1 Peripheral neuropathy was managed with treatment delays, drug discontinuance, and/or dosage reductions;24, 25 62% of patients had complete resolution, 24% had partial improvement, and 14% had no improvement.1
In the ECHELON-1 study evaluating brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine (AVD), peripheral neuropathy occurred in 67% of patients receiving brentuximab vedotin in combination with AVD.1 The median time to onset of peripheral neuropathy was 2 months (range: 0-7 months).1 The median time to resolution or improvement of any grade was 2 months; however, the median time to resolution or improvement increased with severity.1 Among patients who experienced peripheral neuropathy, 43% of patients had complete resolution, 24% had partial improvement, and 33% had no improvement.1
In the ECHELON-2 study evaluating brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (CHP), new or worsening peripheral neuropathy occurred in 52% of patients receiving brentuximab vedotin in combination with CHP; sensory or motor neuropathy occurred in 94 or 16%, respectively, of these patients.1 The median time to onset of peripheral neuropathy was 2 months (range: less than 1 month to 5 months), and the median time to resolution or improvement of any grade was 4 months.1 Among patients who experienced peripheral neuropathy, 50% of patients had complete resolution, 12% had partial improvement, and 38% had no improvement.1
Patients receiving brentuximab vedotin should be monitored for manifestations of neuropathy (e.g., hypoesthesia, hyperesthesia, paresthesia, discomfort, burning sensation, neuropathic pain, weakness).1 Dosage reduction, treatment delay, or drug discontinuance may be required in patients who experience new or worsening neuropathic symptoms.1
Infusion-related reactions, including anaphylaxis, have been reported in patients receiving brentuximab vedotin.1 In clinical studies evaluating single-agent brentuximab vedotin, infusion-related reactions, including chills, nausea, dyspnea, pruritus, pyrexia, and/or cough, occurred in 13% of patients receiving the drug; grade 3 infusion-related reactions were reported in 5 of these patients.1 In the ECHELON-1 study evaluating brentuximab vedotin in combination with AVD, infusion-related reactions occurred in 57 of 662 patients (9%) receiving brentuximab vedotin in combination with AVD; grade 3 infusion-related reactions were reported in 3 of these patients.1 In the ECHELON-2 study evaluating brentuximab vedotin in combination with CHP, infusion-related reactions occurred in 10 of 223 patients (4%) receiving brentuximab vedotin in combination with CHP; grade 3 or greater infusion-related reactions were reported in 2 of these patients.1 Patients should be monitored during infusions of the drug for manifestations of infusion-related reactions.1
In patients experiencing infusion-related reactions, the brentuximab vedotin infusion should be interrupted and appropriate therapy should be instituted.1 The drug should be immediately and permanently discontinued in patients who experience anaphylaxis.1 The manufacturer states that patients who experience an infusion-related reaction to brentuximab vedotin should be premedicated (e.g., with a corticosteroid, an antihistamine, and acetaminophen) prior to each subsequent dose of the drug.1
Severe and prolonged (lasting 1 week or longer) neutropenia and grade 3 or 4 anemia or thrombocytopenia may occur.1 Febrile neutropenia, sometimes fatal, also has been reported in patients receiving brentuximab vedotin.1 Complete blood cell (CBC) counts should be monitored prior to each dose of brentuximab vedotin; if grade 3 or 4 neutropenia occurs, more frequent monitoring should be considered.1 Patients should be monitored for fever.1 The manufacturer recommends primary prophylaxis with a granulocyte colony-stimulating factor (G-CSF) for patients receiving brentuximab vedotin in combination with chemotherapy for classical Hodgkin lymphoma (cHL) or previously untreated peripheral T-cell lymphomas (PTCL).1 In patients who develop grade 3 or 4 neutropenia, temporary interruption of therapy, dosage reduction, drug discontinuance, or, in those who did not receive primary G-CSF prophylaxis, use of a G-CSF may be required.1
Serious infections and opportunistic infections, such as pneumonia, bacteremia, and sepsis/septic shock, sometimes fatal, have been reported in patients receiving brentuximab vedotin.1
Patients receiving brentuximab vedotin should be monitored closely for signs and symptoms of bacterial, fungal, or viral infections.1
Tumor lysis syndrome may occur following rapid lysis of malignant cells.1 The risk of tumor lysis syndrome is increased in patients with a large tumor burden; such patients should be monitored closely and appropriate precautions should be taken.1
Hepatotoxicity (i.e., findings suggestive of hepatocellular injury, including elevations in aminotransferases [ALT or AST] or bilirubin concentrations), sometimes serious or fatal, has been reported following initiation of or rechallenge with brentuximab vedotin.1 Patients with preexisting hepatic disease or elevations in liver enzymes at baseline and those receiving other potentially hepatotoxic drugs may be at greater risk for developing treatment-related hepatotoxicity.1
Liver function tests should be monitored during therapy.1 In patients presenting with new, worsening, or recurrent hepatotoxicity, temporary interruption of therapy, dosage reduction, or drug discontinuance may be required.1
Concomitant use of brentuximab vedotin and bleomycin may increase the risk of pulmonary toxicity; such concomitant use is contraindicated.1, 15 In a clinical trial, the incidence of noninfectious pulmonary reactions (e.g., cough, dyspnea, interstitial infiltration, inflammation) in patients receiving brentuximab vedotin in combination with chemotherapy containing bleomycin (40%) was higher than the historical incidence of pulmonary reactions in patients receiving bleomycin-based regimens (e.g., doxorubicin, bleomycin, vinblastine, and dacarbazine [ABVD]) (10-25%).1, 15 Most patients responded to corticosteroid therapy.1 In the ECHELON-1 study evaluating brentuximab vedotin in combination with AVD, noninfectious pulmonary reactions (i.e., pulmonary infiltration, pneumonitis, interstitial lung disease) occurred in 12 of 662 patients (2%) receiving brentuximab vedotin in combination with AVD.1 In the ECHELON-2 study evaluating brentuximab vedotin in combination with CHP, noninfectious pneumonitis occurred in 5 of 223 patients (2%) receiving brentuximab vedotin in combination with CHP.1 In the AETHERA study evaluating single-agent brentuximab vedotin, pulmonary toxicity occurred in 5% of patients receiving the drug compared with 3% of placebo recipients.1
Patients receiving brentuximab vedotin should be monitored for signs or symptoms of pulmonary toxicity (e.g., cough, dyspnea).1 In patients presenting with new or progressive pulmonary symptoms, brentuximab vedotin should be withheld pending results of clinical investigation and until symptoms resolve.1
Serious or fatal cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients receiving brentuximab vedotin.1 If Stevens-Johnson syndrome or toxic epidermal necrolysis occurs, brentuximab vedotin should be discontinued and appropriate treatment should be provided.1
GI complications (i.e., acute pancreatitis; GI perforation, hemorrhage, erosion, or ulcer; intestinal obstruction; enterocolitis; neutropenic colitis; ileus), sometimes fatal or serious, have been reported in patients receiving brentuximab vedotin.1 Patients with preexisting lymphoma-related GI involvement may be at greater risk for developing treatment-related GI perforation.1
In patients presenting with new or progressive GI symptoms (e.g., severe abdominal pain), prompt diagnostic evaluation should be performed and appropriate therapy should be instituted.1
Serious or fatal episodes of hyperglycemia, including new-onset hyperglycemia, exacerbation of preexisting diabetes mellitus, and ketoacidosis, have been reported in patients receiving brentuximab vedotin.1 In clinical studies evaluating single-agent brentuximab vedotin, hyperglycemia occurred in 8% of patients receiving the drug and was grade 3 or 4 in 6% of those receiving the drug.1 The median time to onset of hyperglycemia was 1 month (range: 0-10 months).1 Hyperglycemia occurred more frequently in patients with high body mass index or preexisting diabetes mellitus.1 Serum glucose concentrations should be monitored in patients receiving brentuximab vedotin; if hyperglycemia occurs, antidiabetic agents should be administered as clinically indicated.1
Fetal/Neonatal Morbidity and Mortality
Brentuximab vedotin may cause fetal harm in humans based on its mechanism of action and animal findings; the drug has been shown to be embryotoxic, fetotoxic, and teratogenic in animals.1 Available data on use of brentuximab vedotin in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes.1 Reproduction studies in rats revealed post-implantation loss, early resorption, decreased number of live fetuses, umbilical hernia, and malrotated hindlimbs at exposure levels similar to those achieved with the maximum recommended human dosage of brentuximab vedotin (1.8 mg/kg every 3 weeks).1
Pregnancy should be avoided during brentuximab vedotin therapy.1 The manufacturer recommends confirmation of pregnancy status prior to initiation of brentuximab vedotin, and women of reproductive potential and men who are partners of such women should use effective methods of contraception while receiving the drug and for at least 6 months after the drug is discontinued.1 If brentuximab vedotin is used during pregnancy or if the patient or the patient's partner becomes pregnant during therapy, the patient should be apprised of the potential fetal hazard.1
Antibodies to brentuximab vedotin have been detected in patients receiving the drug; the clinical relevance of such antibodies is not known.1 In phase 2 clinical trials evaluating brentuximab vedotin in patients with cHL or sALCL, testing for anti-brentuximab vedotin antibodies was performed every 3 weeks using a sensitive electrochemiluminescent immunoassay; test results were persistently (at more than 2 time points) or transiently (at 1 or 2 postbaseline time points) positive in approximately 7 or 30%, respectively, of patients.1 A higher incidence of infusion-related reactions was observed in patients who persistently tested positive for anti-brentuximab vedotin antibodies.1 Neutralizing antibodies were detected in 62% of patients who tested positive (either transiently or persistently) for anti-brentuximab vedotin antibodies.1
Results of animal studies suggest that brentuximab vedotin may impair male fertility.1
Brentuximab vedotin may cause fetal harm if administered to pregnant women based on animal findings.1
It is not known whether brentuximab vedotin is distributed into milk in humans; because of the potential for serious adverse reactions to brentuximab vedotin in nursing infants, women should be advised to discontinue nursing during brentuximab vedotin therapy.1 The effects of the drug on nursing infants or on the production of milk are unknown.1
Safety and efficacy of brentuximab vedotin have not been established in pediatric patients.1
The ECHELON-1 study did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients with previously untreated stage III or IV cHL receiving brentuximab vedotin in combination with AVD respond differently than younger adults; however, febrile neutropenia occurred more frequently in geriatric patients (39 versus 17%).1
In the ECHELON-2 study, 31% of patients with previously untreated CD30-positive PTCL receiving brentuximab vedotin in combination with CHP were 65 years of age or older.1 Grade 3 or greater adverse effects (74 versus 62%) and serious adverse effects (49 versus 33%) occurred more frequently in geriatric patients compared with younger adults.1 In this study, geriatric patients were at greater risk for developing febrile neutropenia compared with younger adults (29 versus 14%).1
Clinical studies evaluating single-agent brentuximab vedotin for relapsed cHL, cHL following autologous stem cell transplantation, and relapsed systemic anaplastic large cell lymphoma (sALCL) did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults.1
In the ALCANZA study, 42% of patients with relapsed primary cutaneous ALCL (pcALCL) or CD30-positive mycosis fungoides receiving single-agent brentuximab vedotin were 65 years of age or older.1 No overall differences in safety and efficacy were observed between these geriatric patients and younger adults.1
Following administration of brentuximab vedotin (1.2 mg/kg), systemic exposure of the microtubule disrupting component (monomethyl auristatin E [MMAE]) of the drug was increased by approximately 2.3-fold in individuals with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C, respectively) compared with individuals with normal hepatic function.1 Dosage adjustment is required in patients with mild hepatic impairment.1 Brentuximab vedotin should be avoided in patients with moderate or severe hepatic impairment since an increased incidence of grade 3 or greater adverse effects, including fatalities, has been observed in such patients compared with those with normal hepatic function.1
Following administration of brentuximab vedotin (1.2 mg/kg), systemic exposure of the microtubule disrupting component (MMAE) of the drug in individuals with mild to moderate renal impairment (creatinine clearance 30-80 mL/minute) was similar to that in individuals with normal renal function; systemic exposure of MMAE was approximately twofold higher in those with severe renal impairment (creatinine clearance less than 30 mL/minute).1 No dosage adjustment is required in patients with mild or moderate renal impairment.1 Brentuximab vedotin should be avoided in patients with severe renal impairment since an increased incidence of grade 3 or greater adverse effects, including fatalities, has been observed in such patients compared with those with normal renal function.1
Adverse effects reported in 10% or more of patients with previously untreated stage III or IV cHL receiving brentuximab vedotin in combination with AVD in the ECHELON-1 study include anemia,1 neutropenia,1, 26 peripheral sensory neuropathy,1, 26 constipation,1, 26 vomiting,1, 26 fatigue,26 diarrhea,1, 26 pyrexia,1, 26 abdominal pain,1, 26 decreased weight,1 stomatitis,1, 26 febrile neutropenia,1 bone pain,1 insomnia,1 decreased appetite,1 back pain,1 rash,1 dyspnea,1 peripheral motor neuropathy,1 and elevated concentrations of alanine aminotransferase (ALT).1
Adverse effects reported in 10% or more of patients with cHL at high risk for relapse or progression following autologous stem cell transplantation receiving brentuximab vedotin consolidation therapy in the AETHERA study include neutropenia,1, 29 peripheral sensory neuropathy,1, 29 thrombocytopenia,1 anemia,1 upper respiratory tract infection,1, 29 fatigue,1, 29 peripheral motor neuropathy,1, 29 nausea,1, 29 cough,1, 29 diarrhea,1, 29 decreased weight,1, 29 pyrexia,1, 29 arthralgia,1, 29 vomiting,1, 29 abdominal pain,1, 29 constipation,1, 29 dyspnea,1, 29 decreased appetite,1, 29 pruritus,1, 29 headache,1, 29 muscle spasms,1, 29 myalgia,1, 29 and chills.1, 29
Adverse effects reported in 10% or more of patients with relapsed cHL receiving brentuximab vedotin as a single agent include neutropenia,1, 5, 7 peripheral sensory neuropathy,1, 5, 6, 7 fatigue,1, 5, 6, 7 upper respiratory tract infection,1 nausea,1, 5, 6, 7 diarrhea,1, 5, 7 anemia,1 pyrexia,1, 5, 7 thrombocytopenia,1 rash,1 abdominal pain,1 vomiting,1 arthralgia/myalgia,1 headache,1 pruritus,1 constipation,1 cough,1 peripheral motor neuropathy,1 back pain,1 insomnia,1 alopecia,1 chills,1 dyspnea,1 night sweats,1 anxiety,1 decreased appetite,1 dizziness,1 lymphadenopathy,1 oropharyngeal pain,1 and extremity pain.1
Adverse effects reported in 10% or more of patients with previously untreated CD30-positive PTCL receiving brentuximab vedotin in combination with CHP in the ECHELON-2 study include anemia,1, 31 neutropenia,1, 31 peripheral neuropathy,1, 31 lymphopenia,1 nausea,1, 31 diarrhea,1, 31 fatigue/asthenia,1, 31 mucositis,1 constipation,1, 31 alopecia,1, 31 pyrexia,1, 31 vomiting,1, 31 febrile neutropenia,1 abdominal pain,1 decreased appetite,1 thrombocytopenia,1 rash,1 edema,1 dyspnea,1 headache,1 upper respiratory tract infection,1 cough,1 dizziness,31 hypokalemia,1 decreased weight,1 insomnia,1 and myalgia.1
Adverse effects reported in 10% or more of patients with relapsed sALCL receiving brentuximab vedotin as a single agent include neutropenia,1 peripheral sensory neuropathy,1 anemia,1 fatigue,1 nausea,1 pyrexia,1 rash,1 diarrhea,1 pain,1 constipation,1 dyspnea,1 pruritus,1 cough,1 vomiting,1 decreased appetite,1 dizziness,1 headache,1 insomnia,1 myalgia,1 peripheral edema,1 thrombocytopenia,1 alopecia,1 decreased weight,1 chills,1 upper respiratory tract infection,1 back pain,1 dry skin,1 extremity pain,1 lymphadenopathy,1 and muscle spasms.1
Adverse effects reported in 10% or more of patients with relapsed pcALCL or CD30-positive mycosis fungoides receiving brentuximab vedotin as a single agent in the ALCANZA study include anemia,1 peripheral sensory neuropathy,1, 23 nausea,1, 23 diarrhea,1, 23 fatigue/asthenia,1, 23 neutropenia,1 pruritus,1, 23 pyrexia,1, 23 vomiting,1, 23 alopecia,1, 23 decreased appetite,1, 23 thrombocytopenia,1 arthralgia,1, 23 myalgia,1, 23 dyspnea,1, 23 peripheral edema,1, 23 and rash.1, 23
In vitro studies indicate that monomethyl auristatin E (MMAE), the microtubule-disrupting component of brentuximab vedotin, is a substrate and an inhibitor of cytochrome P-450 (CYP) isoenzymes 3A4/5.1 In vitro studies also indicate that MMAE does not inhibit other CYP isoenzymes and does not induce major CYP isoenzymes.1 MMAE is a substrate of P-glycoprotein (P-gp) and is not an inhibitor of P-gp.1
Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of brentuximab vedotin with potent inhibitors of CYP3A4 may result in increased systemic exposure of MMAE and possible adverse effects.1 When the potent CYP3A4 inhibitor ketoconazole (400 mg once daily from day 19 of cycle 1 to day 21 of cycle 2) was administered concomitantly with brentuximab vedotin (1.2 mg/kg on day 1 of each cycle), the systemic exposure of MMAE was increased by approximately 34%.1, 19 The manufacturer states that patients receiving brentuximab vedotin concomitantly with potent CYP3A4 inhibitors should be closely monitored for adverse effects.1
When the potent CYP3A4 inducer rifampin (600 mg once daily from day 14 of cycle 1 to day 21 of cycle 2) was administered concomitantly with brentuximab vedotin (1.8 mg/kg on day 1 of each cycle), the systemic exposure of MMAE was decreased by approximately 46%.1, 19 However, dosage adjustment is not necessary.22 Clinically important effects on MMAE concentrations are not expected when other inducers of CYP3A4 (i.e., carbamazepine, dexamethasone, phenobarbital, phenytoin) are used concomitantly with brentuximab vedotin.19, 22
Drugs Metabolized by Hepatic Microsomal Enzymes
Brentuximab vedotin is not expected to alter the systemic exposure of drugs that are metabolized by CYP3A4.1 When the CYP3A4 substrate midazolam was administered 2 days after brentuximab vedotin (at approximately peak MMAE concentrations), systemic exposure of midazolam was unchanged.1, 19
MMAE is not likely to displace or be displaced by other highly protein-bound drugs.1
The incidence of noninfectious pulmonary reactions (e.g., cough, dyspnea, interstitial infiltration, inflammation) in patients receiving brentuximab vedotin in combination with chemotherapy containing bleomycin was higher than the historical incidence of pulmonary reactions in patients receiving bleomycin-based regimens.1, 15 Concomitant use of brentuximab vedotin and bleomycin is contraindicated.1, 15
Brentuximab vedotin, an anti-CD30 antibody-drug conjugate, is an antineoplastic agent.1, 3, 4, 5 The anti-CD30 antibody, a chimeric human-murine IgG1 immunoglobulin, is conjugated with the microtubule inhibitor monomethyl auristatin E (MMAE), a synthetic analog of dolastatin 10, a naturally occurring product isolated from the sea hare Dolabella auriculara .1, 3, 10 A dipeptide bond covalently links MMAE to the antibody component;1, 3, 4 on average, 4 molecules of MMAE are attached to each antibody molecule.1, 4, 10 The antibody portion of brentuximab vedotin binds specifically to antigen CD30, a membrane glycoprotein and member of the tumor necrosis factor (TNF) family that is expressed on malignant cells in approximately 98% of Hodgkin lymphoma cases.1, 3, 4, 5, 8, 9, 10 The CD30 antigen also is expressed in other hematologic malignancies, including anaplastic large cell lymphoma and T-cell lymphoma, but has limited expression in normal tissue.1, 4, 5, 8, 9, 10 Following binding of the antibody portion of brentuximab vedotin to antigen CD30, the resultant complex is internalized by the cell.1, 4, 5 MMAE is released via proteolytic cleavage of the dipeptide bond and binds to tubulin, resulting in cell cycle arrest, apoptosis, and antibody-dependent cellular phagocytosis (ADCP).1, 3, 4, 5, 10
The pharmacokinetic profile of brentuximab vedotin in combination with chemotherapy is similar to that of single-agent brentuximab vedotin.1 Areas under the serum concentration-time curve (AUCs) of the antibody-drug conjugate and free MMAE are approximately dose proportional over the brentuximab vedotin single-dose range of 1.2-2.7 mg/kg.1, 5, 10, 11, 12, 22 Peak MMAE concentrations are achieved about 1-3 days following an IV dose of brentuximab vedotin.1, 5, 10 When brentuximab vedotin 1.8 mg/kg is administered IV every 3 weeks, steady-state concentrations of the antibody-drug conjugate and MMAE are reached within 21 days; minimal systemic accumulation of the antibody-drug conjugate occurs.1, 11 When brentuximab vedotin 1.2 mg/kg is administered IV every 2 weeks, steady-state concentrations of the antibody-drug conjugate and MMAE are reached within 56 days; the accumulation ratio of the antibody-drug conjugate is 1.27-fold.1 Following multiple doses of brentuximab vedotin, systemic exposure of MMAE is decreased to about 50-80% of the exposure achieved following the initial dose.1, 22 In vitro, MMAE is 68-82% bound to plasma proteins.1 A small fraction of free MMAE is metabolized, mainly via oxidation by the cytochrome P-450 (CYP) 3A4/5 isoenzyme.1 Elimination of MMAE appears to be limited by the rate of release from the antibody-drug conjugate.1 Following administration of a single 1.8-mg/kg dose of brentuximab vedotin, approximately 24% of the total administered dose of MMAE is excreted over a 1-week period in feces (72%) and to a lesser extent in urine, mainly as unchanged drug.1 The terminal half-lives of the antibody-drug conjugate and MMAE are 4-6 and 3-4 days, respectively.1, 5, 10
Risk of progressive multifocal leukoencephalopathy (PML).1 Importance of patients, family, and caregivers being alert to and immediately reporting emergence of signs and symptoms suggestive of PML (e.g., changes in mood, unusual changes in behavior, confusion, changes in thinking, memory loss, vision changes, changes in speech or walking, decreased strength or weakness on one side of the body).1, 15
Risk of infusion-related reactions.1 Importance of reporting signs and symptoms of such reactions, including fever, chills, rash, or breathing difficulty, that occur within 24 hours of an infusion of the drug.1
Risk of peripheral neuropathy.1 Importance of informing clinician of new or worsening symptoms of peripheral neuropathy (e.g., tingling or numbness of the hands or feet, any muscle weakness).1
Risk of neutropenia.1 Importance of informing clinician of fever or other signs and symptoms of infection (e.g., chills, cough, painful urination).1
Risk of hepatotoxicity.1 Importance of informing clinician if signs and symptoms of liver damage (e.g., jaundice, fatigue, dark urine, abdominal pain [particularly in the right upper quadrant], lack of appetite) occur.1
Risk of pulmonary reactions.1 Importance of informing clinician if signs and symptoms of pulmonary reactions (e.g., cough, dyspnea) occur.1
Risk of acute pancreatitis.1 Importance of informing clinician of severe abdominal pain.1
Risk of adverse GI effects.1 Importance of informing clinician if severe abdominal pain, chills, fever, nausea, vomiting, or diarrhea occurs.1
Risk of hyperglycemia.1 Importance of learning how to recognize symptoms of hyperglycemia.1
Risk of fetal harm.1 Necessity of advising women of reproductive potential and men who are partners of such women that they should use an effective method of contraception while receiving the antibody-drug conjugate and for at least 6 months after the last dose.1 Importance of women informing clinicians if they are or plan to become pregnant.1 If pregnancy occurs, advise pregnant women of potential risk to the fetus.1
Importance of advising women to avoid breast-feeding while receiving brentuximab vedotin therapy.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Importance of informing patients of other important precautionary information.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IV infusion only | 50 mg |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions December 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Seattle Genetics, Inc. Adcetris® (brentuximab vedotin) for injection prescribing information. Bothell, WA; 2019 Oct.
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5. Younes A, Bartlett NL, Leonard JP et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med . 2010; 363:1812-21. [PubMed 21047225]
6. Chen R, Gopal AK, Smith SE et al. Results of a pivotal phase 2 study of brentuximab vedotin (SGN-35) in patients with relapsed or refractory Hodgkin lymphoma. Blood . 2010; 116 (American Society of Hematology Annual Meeting Abstracts):Abstract No. 283. [Web]
7. Shustov AR, Advani R, Brice P et al. Complete remissions with brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large cell lymphoma. Blood . 2010; 116 (American Society of Hematology Annual Meeting Abstracts):Abstract No. 961. [Web]
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10. Furtado M, Rule S. Emerging pharmacotherapy for relapsed or refractory Hodgkin's lymphoma: Focus on brentuximab vedotin. Clin Med Insights Oncol. 2012; 6:31-9. [Web]
11. Anon. Brentuximab vedotin. Drugs R & D . 2011; 11:85-95. [Web]
12. Fanale M, Bartlett NL, Forero-Torres A et al. The antibody-drug conjugate brentuximab vedotin (SGN-35) induced multiple objective responses in patients with relapsed or refractory CD30-positive lymphomas in a phase 1 weekly dosing study. Blood . 2009; 114 (American Society of Hematology Annual Meeting Abstracts):Abstract No. 2731. [Web]
13. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2019 May 29. [Web]
15. US Food and Drug Administration. FDA drug safety communication: New boxed warning and contraindication for Adcetris (brentuximab vedotin). Rockville, MD; 2012 Jan 13. From FDA website. [Web]
16. US Food and Drug Administration. Oncologic Drugs Advisory Committee Meeting. Bethesda, MD; 2011 Jul 14. From FDA website. [Web]
17. US Food and Drug Administration. Oncologic Drugs Advisory Committee Meeting. Bethesda, MD; 2011 Jul 14. From FDA website. [Web]
19. Seattle Genetics, Inc., Bothell, WA: Personal communication.
20. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125388Orig1s000: Medical review(s). From FDA website. [Web]
21. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125399Orig1s000: Medical review(s). From FDA website. [Web]
22. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125388Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. [Web]
23. Prince HM, Kim YH, Horwitz SM et al. Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet . 2017; 390:555-566. [PubMed 28600132]
24. Younes A, Gopal AK, Smith SE et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol . 2012; 30:2183-9. [PubMed 22454421]
25. Pro B, Advani R, Brice P et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol . 2012; 30:2190-6. [PubMed 22614995]
26. Connors JM, Jurczak W, Straus DJ et al. Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma. N Engl J Med . 2018; 378:331-344. [PubMed 29224502]
27. Chen R, Gopal AK, Smith SE et al. Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma. Blood . 2016; 128:1562-6. [PubMed 27432875]
28. Pro B, Advani R, Brice P et al. Five-year results of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma. Blood . 2017; 130:2709-2717. [PubMed 28974506]
29. Moskowitz CH, Nademanee A, Masszi T et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet . 2015; 385:1853-62. [PubMed 25796459]
30. Moskowitz CH, Walewski J, Nademanee A et al. Five-year PFS from the AETHERA trial of brentuximab vedotin for Hodgkin lymphoma at high risk of progression or relapse. Blood . 2018; 132:2639-2642. [PubMed 30266774]
31. Horwitz S, O'Connor OA, Pro B et al. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet . 2019; 393:229-240. [PubMed 30522922]