Adcetris

— THERAPEUTIC DISORDERS TREATED —
  • Leukemias, lymphomas, and other hematologic cancers
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Adcetris Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Brentuximab vedotin 50mg/vial; lyophilized pwd for IV infusion after reconstitution and dilution; preservative-free.

    Pharmacological Class

    CD30-directed antibody-drug conjugate.

    How Supplied

    Single-use vial—1

    How Supplied

    Adcetris (brentuximab vedotin) for Injection is supplied as a sterile, white to off-white preservative-free lyophilized cake or powder in individually-boxed single-dose vials containing 50 mg of brentuximab vedotin.

    Storage

    Store vial at 2° to 8°C (36° to 46°F) in the original carton to protect from light.

    Manufacturer

    Seagen, Inc.

    Generic Availability

    NO

    Adcetris Indications

    Indications

    Adults with previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine. Pediatric patients aged ≥2yrs with previously untreated high risk cHL, in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide. Adults with cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplant (auto-HSCT) consolidation. Adults with cHL after failure of auto-HSCT or after failure of ≥2 prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates. Adults with previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone. Adults with sALCL after failure of ≥1 prior multi-agent chemotherapy regimen. Adults with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.

    Adcetris Dosage and Administration

    Adult

    Give by IV infusion over 30mins. Premedicate patients with prior infusion-related reaction with APAP, antihistamine, and corticosteroid for subsequent doses. Untreated Stage III/IV (initiate G-CSF starting with Cycle 1): 1.2mg/kg up to max 120mg/dose every 2 weeks; continue until max 12 doses, disease progression or unacceptable toxicity. Untreated sALCL or PTCL: 1.8mg/kg up to max 180mg/dose every 3 weeks with each cycle of chemotherapy for 6–8 doses; for PTCL: initiate G-CSF starting with Cycle 1. Others: 1.8mg/kg up to max 180mg/dose every 3 weeks; continue until disease progression or unacceptable toxicity. cHL consolidation: initiate within 4–6 weeks post-auto-HSCT or upon recovery from auto-HSCT; max 16 cycles. MF or pcALCL: max 16 cycles. Mild hepatic impairment (Child-Pugh A): (untreated Stage III/IV): 0.9mg/kg up to max 90mg every 2 weeks; (others): 1.2mg/kg up to 120mg every 3 weeks. Dose modifications: see full labeling.

    Adult

    Give by IV infusion over 30mins. Premedicate patients with prior infusion-related reaction with APAP, antihistamine, and corticosteroid for subsequent doses. 

    • Previously Untreated Stage III or IV Classical Hodgkin Lymphoma (cHL): 1.2mg/kg up to max 120mg/dose every 2 weeks; continue until max 12 doses, disease progression or unacceptable toxicity. Initiate G-CSF starting with Cycle 1.

    • cHL Consolidation: 1.8mg/kg up to max 180mg/dose every 3 weeks; continue until a maximum of 16 cycles, disease progression, or unacceptable toxicity. Initiate Adcetris within 4–6 weeks post-auto-HSCT or upon recovery from auto-HSCT.

    • Relapsed cHL: 1.8mg/kg up to max 180mg/dose every 3 weeks; continue until a disease progression or unacceptable toxicity.

    • Previously Untreated Systemic ALCL (sALCL) or Other CD30-Expressing Peripheral T-Cell Lymphomas (PTCL): 1.8mg/kg up to max 180mg/dose every 3 weeks with each cycle of chemotherapy for 6–8 doses. For PTCL: initiate G-CSF starting with Cycle 1. For previously untreated sALCL: maximum of 16 cycles.

    • Relapsed Systemic ALCL: 1.8mg/kg up to max 180mg/dose every 3 weeks; continue until a disease progression or unacceptable toxicity.

    • Relapsed Primary Cutaneous ALCL or CD30-expressing Mycosis Fungoides (MF): 1.8mg/kg up to max 180mg/dose every 3 weeks; continue until a maximum of 16 cycles, disease progression, or unacceptable toxicity.

    Children

    <2yrs (high risk cHL) and <18yrs (all other indications): not established. Give by IV infusion over 30mins. Premedicate patients with prior infusion-related reaction with APAP, antihistamine, and corticosteroid for subsequent doses. ≥2yrs: High risk cHL (initiate G-CSF starting with Cycle 1): 1.8mg/kg up to max 180mg every 3 weeks with each cycle of chemotherapy for max 5 doses. Mild hepatic impairment (Child-Pugh A): 1.2mg/kg up to 120mg every 3 weeks. Dose modifications: see full labeling.

    Children

    <2yrs (high risk cHL) and <18yrs (all other indications): not established. Give by IV infusion over 30mins. Premedicate patients with prior infusion-related reaction with APAP, antihistamine, and corticosteroid for subsequent doses. 

    • Pediatric patients 2 years of age and older with previously untreated high risk classical Hodgkin Lymphoma: 1.8 mg/kg up to a maximum of 180 mg every 3 weeks with each cycle of chemotherapy for a maximum of 5 doses. 

    Renal Impairment

    Avoid use in patients with severe renal impairment (CrCL <30 mL/min).

    Hepatic Impairment

    Avoid use in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.

    Other Modifications

    Females and Males of Reproductive Potential

    • Pregnancy Testing: Verify the pregnancy status of females of reproductive potential prior to initiating Adcetris.

    • Contraception: Advise females of reproductive potential to avoid pregnancy during and for 6 months after the last dose. Advise males with female sexual partners of reproductive potential should use effective contraception during and for 6 months after the last dose.

    Adcetris Contraindications

    Contraindications

    Concomitant bleomycin.

    Adcetris Boxed Warnings

    Boxed Warning

    Progressive multifocal leukoencephalopathy (PML).

    Boxed Warning

    Progressive multifocal leukoencephalopathy (PML)

    • JC virus infection resulting in PML and death can occur in patients receiving Adcetris.

    Adcetris Warnings/Precautions

    Warnings/Precautions

    Risk of JC virus infection. Monitor for progressive multifocal leukoencephalopathy (PML); withhold dose if suspected and discontinue if confirmed. Monitor for neuropathy; delay, change dose, or discontinue if new or worsening symptoms occur. Monitor for infusion-related reactions; permanently discontinue and treat if anaphylaxis occurs. Monitor CBCs prior to each dose and frequently for fever or Grade 3 or 4 neutropenia; delay, reduce, discontinue dose or consider G-CSF prophylaxis if develops. Increased risk of tumor lysis syndrome in rapidly proliferating tumor/high tumor burden patients; monitor closely. Monitor for emergence of bacterial, fungal, or viral infections. Monitor for pulmonary toxicity; if symptoms occur, withhold dose during evaluation and until improvement. Monitor serum glucose; if hyperglycemia develops, treat as clinically indicated. Monitor liver enzymes and bilirubin; delay, change dose, or discontinue if hepatotoxicity occurs. Severe renal impairment (CrCl <30mL/min) or moderate or severe hepatic (Child-Pugh B/C) impairment: avoid. Discontinue if serious skin reactions (eg, SJS, TEN) occur. GI complications: evaluate and treat if new or worsening GI symptoms develop. Embryo-fetal toxicity. Advise females and males of reproductive potential to use effective contraception during and for ≥6 months after final dose. Pregnancy: exclude status prior to initiation. Nursing mothers: not recommended.

    Warnings/Precautions

    Peripheral Neuropathy

    • Monitor for symptoms of neuropathy (e.g., hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness).

    • May require a delay, change in dose, or discontinuation of Adcetris if patients experience new or worsening peripheral neuropathy. 

    Anaphylaxis and Infusion Reactions

    • Monitor during infusion.

    • If anaphylaxis occurs, immediately and permanently discontinue administration of Adcetris and administer appropriate medical therapy.

    • If an infusion-related reaction occurs, interrupt infusion and institute appropriate medical management.

    Hematologic Toxicities

    • Fatal and serious cases of febrile neutropenia have been reported.

    • Start primary prophylaxis with G-CSF beginning with Cycle 1 for adult patients who receive Adcetris in combination with chemotherapy for previously untreated Stage III or IV cHL or previously untreated PTCL, and pediatric patients who receive Adcetris in combination with chemotherapy for previously untreated high risk cHL.

    • Monitor CBCs prior to each dose of Adcetris. Monitor more frequently for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent Adcetris doses (see Other Modifications).

    Serious Infections and Opportunistic Infections

    • Monitor closely during for the emergence of possible bacterial, fungal, or viral infections. 

    Tumor Lysis Syndrome

    • Increased risk of tumor lysis syndrome in patients with rapidly proliferating tumor and high tumor burden. Monitor closely and take appropriate measures.

    Increased Toxicity in the Presence of Severe Renal Impairment

    • Avoid the use of Adcetris in patients with severe renal impairment (CrCL <30 mL/min).

    Increased Toxicity in the Presence of Moderate or Severe Hepatic Impairment

    • Avoid the use of Adcetris in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.

    Hepatotoxicity

    • Increased risk of hepatotoxicity in patients with preexisting liver disease, elevated baseline liver enzymes, and concomitant medications.

    • Monitor liver enzymes and bilirubin. Patients experiencing new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of Adcetris. 

    Progressive Multifocal Leukoencephalopathy (PML)

    • Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. 

    • Hold Adcetris dosing for any suspected case of PML and discontinue Adcetris dosing if a diagnosis of PML is confirmed.

    Pulmonary Toxicity

    • Monitor patients for signs and symptoms of pulmonary toxicity, including cough and dyspnea. 

    • Hold Adcetris dosing during evaluation and until symptomatic improvement if new or worsening pulmonary symptoms occur.

    Serious Dermatologic Reactions 

    • Discontinue Adcetris and administer appropriate medical therapy if Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) occur.

    Gastrointestinal Complications 

    • Fatal and serious events of acute pancreatitis have been reported.

    • Perform a prompt diagnostic evaluation and treat appropriately if new or worsening GI symptoms occur, including severe abdominal pain.

    Hyperglycemia

    • Monitor serum glucose and if hyperglycemia develops, administer anti-hyperglycemic medications as clinically indicated. 

    Embryo-Fetal Toxicity

    • Advise females of reproductive potential to avoid pregnancy during Adcetris treatment and for 6 months after the last dose of Adcetris. Advise a pregnant woman of the potential risk to the fetus.

    Pregnancy Considerations

    Can cause fetal harm. The available data on Adcetris use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Advise pregnant women of the potential risk to a fetus.

    Nursing Mother Considerations

    Risk Summary

    • There is no information regarding the presence of brentuximab vedotin in human milk, the effects on the breastfed child, or the effects on milk production.

    • Advise patients that breastfeeding is not recommended during treatment.

    Pediatric Considerations

    The safety and effectiveness of Adcetris have been established in pediatric patients age 2 and older with previously untreated high risk classical Hodgkin lymphoma in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide. The safety and efficacy of Adcetris have not been established for this indication in patients younger than 2 years. 

    The safety and effectiveness of Adcetris have not been established in pediatric patients for all other indications.

    Renal Impairment Considerations

    Avoid use in patients with severe renal impairment (CrCL <30 mL/min).

    Hepatic Impairment Considerations

    Avoid use in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential

    • Pregnancy Testing: Verify the pregnancy status of females of reproductive potential prior to initiating Adcetris.

    • Contraception: Advise females of reproductive potential to avoid pregnancy during and for 6 months after the last dose. Advise males with female sexual partners of reproductive potential should use effective contraception during and for 6 months after the last dose.

    Adcetris Pharmacokinetics

    Absorption

     

     

    Distribution

    In humans, the mean steady state volume of distribution was approximately 6–10 L for ADC.

    In vitro, the binding of MMAE to human plasma proteins ranged from 68–82%. MMAE is not likely to displace or to be displaced by highly protein-bound drugs. 

    Metabolism

    A small fraction of MMAE released from brentuximab vedotin is metabolized. In vitro data indicate that the MMAE metabolism that occurs is primarily via oxidation by CYP3A4/5. 

    Elimination

    ADC elimination exhibited a multi-exponential decline with a half-life of ~4 to 6 days. MMAE elimination exhibited a mono-exponential decline with a half-life of ~3 to 4 days. Elimination of MMAE appeared to be limited by its rate of release from ADC. 

    After a single dose of 1.8 mg/kg of Adcetris in patients, ~24% of the total MMAE administered was recovered in both urine and feces over a 1-week period, ~72% of which was recovered in the feces, and the majority was excreted unchanged.  

    Adcetris Interactions

    Interactions

    See Contraindications. Potentiated by strong CYP3A4 inhibitors (eg, ketoconazole); monitor closely. May be antagonized by potent CYP3A4 inducers (eg, rifampin).

    Adcetris Adverse Reactions

    Adverse Reactions

    Peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper RTI, pyrexia, constipation, vomiting, alopecia, decreased weight, abdominal pain, anemia, stomatitis, lymphopenia, mucositis, thrombocytopenia, febrile neutropenia.

    Adcetris Clinical Trials

    Clinical Trials

    Classical Hodgkin Lymphoma

    Randomized Clinical Trial in Previously Untreated Stage III or IV classical Hodgkin Lymphoma (Study 5: ECHELON-1, NCT01712490) 

    Adcetris in combination with chemotherapy was evaluated in 1334 total patients with previously untreated Stage III or IV cHL in a randomized, open-label, 2-arm, multicenter trial. Patients were randomly assigned 1:1 to receive either Adcetris + AVD (adriamycin, vinblastine, dacarbazine) or ABVD (adriamycin, bleomycin, vinblastine, dacarbazine).

    Results showed that the trial met its primary endpoint with Adcetris + AVD achieving a statistically significant improvement in modified progression-free survival (PFS) vs ABVD control (hazard ratio [HR] 0.77, 95% CI, 0.60-0.98; P =.035), corresponding to a 23% reduction in the risk of progression, death or need for additional anti-cancer therapy in patients without complete response (CR) after frontline treatment. 

    Overall survival (OS), a key secondary endpoint, favored Adcetris + AVD in an interim analysis but the difference was not significant (HR 0.72, 95% CI, 0.44-1.17; P =.19). The CR rate was 73% in the Adcetris + AVD arm vs 70% in the ABVD arm. 

     

    Randomized Clinical Trial in Previously Untreated High Risk classical Hodgkin Lymphoma (Study 7, AHOD1331, NCT02166463) 

    Adcetris in combination with chemotherapy was evaluated in 600 pediatric patients (2 to <22 years of age) with previously untreated high risk cHL in a randomized, open-label, actively controlled trial. Patients were randomly assigned 1:1 to receive either Adcetris plus AVEPC (doxorubicin [A], vincristine [V], etoposide [E], prednisone [P], cyclophosphamide[C]) or A + B (bleomycin) + V + E + P + C (ABVE-PC) for up to 5 cycles. 

    Results showed treatment with brentuximab vedotin + AVEPC reduced the risk of disease progression or relapse, second malignancy, or death (primary endpoint) by 59% when compared with ABVE-PC (hazard ratio, 0.41 [95% CI, 0.25-0.67]; P =.0002).

     

    Randomized Placebo-Controlled Clinical Trial in classical Hodgkin Lymphoma Post-AutoHSCT Consolidation (Study 3: AETHERA, NCT01100502) 

    The efficacy of Adcetris was evaluated in 329 patients with cHL at high risk of relapse or disease progression post-auto-HSCT in a randomized, double-blind, placebo-controlled clinical trial. Patients were randomly assigned 1:1 to receive placebo or Adcetris 1.8 mg/kg intravenously over 30 minutes every 3 weeks for up to 16 cycles, beginning 30-45 days post-auto-HSCT. The primary endpoint was progression-free survival (PFS) determined by an independent review facility (IRF).

    Results showed that treatment with Adcetris achieved a statistically significant improvement in IRF-assessed PFS vs placebo (stratified hazard ratio, 0.57 [95% CI, 0.40-0.81]; P =.001). The median PFS was 42.9+ months (95% CI, 30.4-42.9+) for the Adcetris arm and 24.1 months (95% CI, 11.5 - Not estimable).

     

    Clinical Trial in Relapsed classical Hodgkin Lymphoma (Study 1, NCT00848926) 

    The efficacy of Adcetris was evaluated in 102 patients with cHL who relapsed after autologous hematopoietic stem cell transplantation in one open-label, single-arm, multicenter trial. Patients were treated with 1.8 mg/kg of Adcetris IV over 30 minutes every 3 weeks. Patients had received a median of 5 prior therapies including autologous hematopoietic stem cell transplantation.

    Results showed an ORR of 73% (95% CI, 65-83), of which 32% of patients achieved complete response and 40% achieved partial response.The median duration of response was 6.7 months (95% CI, 4-14.8)

     

    Systemic Anaplastic Large Cell Lymphoma and Other CD30-Expressing Peripheral T-Cell Lymphomas

    Randomized Clinical Trial in Previously Untreated Systemic Anaplastic Large Cell Lymphoma or Other CD30-Expressing Peripheral T-Cell Lymphomas (Study 6: ECHELON-2, NCT01777152)

    The efficacy of Adcetris in combination with chemotherapy was evaluated in 452 adults with previously untreated, CD30-expressing PTCL in a multicenter, randomized, double-blind, double-dummy, actively controlled trial. Patients were randomly assigned 1:1 to receive either Adcetris + CHP (cyclophosphamide, doxorubicin, and prednisone) or CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone).

    Results showed PFS was significantly longer (hazard ratio [HR] 0.71 (95% CI, 0.54-0.93; P =.011) in the Adcetris arm (median 48.2 months vs 20.8 months with CHOP). Overall survival (HR 0.66 [95% CI, 0.46, 0.95; P =.024]) and overall response rates (83% vs 72% with CHOP; P =.003) were also significantly better in the Adcetris arm.

     

    Systemic Anaplastic Large Cell Lymphoma 

    Clinical Trial in Relapsed sALCL (Study 2, NCT00866047) 

    The efficacy of ADCETRIS was evaluated in 58 patients with relapsed sALCL in one open-label, single-arm, multicenter trial. The trial included patients who had sALCL that were relapsed after prior therapy. Patients received 1.8 mg/kg of Adcetris IV over 30 minutes every 3 weeks. 

    Results showed an ORR of 86% (95% CI, 77-95), of which 57% of patients achieved complete response (95% CI, 44-70) and 29% achieved partial response (95% CI, 18-41). The median duration of response was 12.6 months.

     

    Primary Cutaneous Anaplastic Large Cell Lymphoma and CD30-Expressing Mycosis Fungoides

    Randomized Clinical Trial in Primary Cutaneous Anaplastic Large Cell Lymphoma and CD30-expressing Mycosis Fungoides (Study 4: ALCANZA, NCT01578499)

    The efficacy of Adcetris was evaluated in 131 patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or mycosis fungoides (MF) requiring systemic therapy in ALCANZA, a randomized, open-label, multicenter clinical trial. Patients were randomly assigned 1:1 to receive Adcetris 1.8 mg/kg IV over 30 minutes every 3 weeks or physician’s choice of methotrexate (5 to 50 mg orally weekly) or bexarotene (300 mg/m2 orally daily).

    The primary endpoint was achieved with Adcetris-treated patients showing a highly statistically significant improvement in objective response rate lasting ≥4 months (ORR4) vs. the control group (56.3% vs. 12.5%; P <.001). 

    Major secondary endpoints, such as ORR (67.2% vs. 20.3%), complete response rate (15.6% vs. 1.6%; P =.0066), and progression-free survival (16.7 months vs. 3.5 months; hazard ratio [HR] 0.270, 95% CI: 0.169, 0.430; P <.001) were all highly statistically significant favoring the Adcetris group over the control group. 

    Adcetris Note

    Not Applicable

    Adcetris Patient Counseling

    Patient Counseling

    Peripheral Neuropathy

    • Advise patients that Adcetris can cause a peripheral neuropathy.

    Fever/Neutropenia

    • Advise patients to contact their health care provider if a fever of 100.5°F or greater or other evidence of potential infection such as chills, cough, or pain on urination develops.

    Infusion Reactions

    • Advise patients to contact their health care provider if they experience signs and symptoms of infusion reactions including fever, chills, rash, or breathing problems within 24 hours of infusion.  

    Hepatotoxicity

    • Advise patients to report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.

    Progressive Multifocal Leukoencephalopathy 

    • Instruct patients receiving Adcetris to immediately report if they have any of the following neurological, cognitive, or behavioral signs and symptoms or if anyone close to them notices these signs and symptoms.

    Pulmonary Toxicity

    • Instruct patients to report symptoms that may indicate pulmonary toxicity, including cough or shortness of breath.

    Acute Pancreatitis

    • Advise patients to contact their health care provider if they develop severe abdominal pain.

    Gastrointestinal Complications 

    • Advise patients to contact their health care provider if they develop severe abdominal pain, chills, fever, nausea, vomiting, or diarrhea.

    Hyperglycemia

    • Educate patients about the risk of hyperglycemia and how to recognize associated symptoms.  

    Females and Males of Reproductive Potential 

    • Adcetris can cause fetal harm. Advise women receiving Adcetris to avoid pregnancy during Adcetris treatment and for 6 months after the last dose of Adcetris. 

    • Advise males with female sexual partners of reproductive potential to use effective contraception during and for 6 months after the last dose. Advise patients to report pregnancy immediately.

    Lactation

    • Advise patients to avoid breastfeeding while receiving Adcetris.

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