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Brentuximab Vedotin

Pronunciation

(bren TUX i mab ve DOE tin)

Index Terms

  • Anti-CD30 ADC SGN-35
  • Anti-CD30 Antibody-Drug Conjugate SGN-35
  • Antibody-Drug Conjugate SGN-35
  • Brentuximab
  • SGN-35

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous [preservative free]:

Adcetris: 50 mg (1 ea) [contains polysorbate 80]

Brand Names: U.S.

  • Adcetris

Pharmacologic Category

  • Antineoplastic Agent, Anti-CD30
  • Antineoplastic Agent, Antibody Drug Conjugate
  • Antineoplastic Agent, Monoclonal Antibody

Pharmacology

Brentuximab vedotin is an antibody drug conjugate (ADC) directed at CD30 consisting of 3 components: 1) a CD30-specific chimeric IgG1 antibody cAC10; 2) a microtubule-disrupting agent, monomethylauristatin E (MMAE); and 3) a protease cleavable dipeptide linker (which covalently conjugates MMAE to cAC10). The conjugate binds to cells which express CD30, and forms a complex which is internalized within the cell and releases MMAE. MMAE binds to the tubules and disrupts the cellular microtubule network, inducing cell cycle arrest (G2/M phase) and apoptosis.

Distribution

Vdss: ADC: 6 to 10 L

Metabolism

MMAE: Minimal, primarily via oxidation by CYP3A4/5

Excretion

MMAE: Feces (~72%, primarily unchanged); urine

Time to Peak

ADC: At end of infusion; MMAE: ~1 to 3 days

Half-Life Elimination

Terminal: ADC: ~4 to 6 days

Special Populations: Renal Function Impairment

The exposure (AUC) of MMAE, a brentuximab vedotin component, was increased ~2-fold in patients with severe renal impairment receiving a 1.2 mg/kg dose.

Special Populations: Hepatic Function Impairment

The exposure (AUC) of MMAE, a brentuximab vedotin component, was increased ~2.2-fold in patients with hepatic impairment receiving a 1.2 mg/kg dose.

Use: Labeled Indications

Anaplastic large cell lymphoma (systemic): Treatment of systemic anaplastic large cell lymphoma after failure of at least 1 prior multiagent chemotherapy regimen

Hodgkin lymphoma, relapsed or refractory: Treatment of classical Hodgkin lymphoma after failure of at least 2 prior multiagent chemotherapy regimens (in patients who are not autologous hematopoietic stem cell transplant candidates) or after failure of autologous hematopoietic stem cell transplant

Hodgkin lymphoma (post-autologous hematopoietic stem cell transplantation): Treatment (maintenance therapy) of classical Hodgkin lymphoma in patients at high risk of relapse or progression as post–autologous hematopoietic stem cell transplant consolidation

Contraindications

US labeling: Concurrent use with bleomycin

Canadian labeling: Hypersensitivity to brentuximab or any component of the formulation; concurrent use with bleomycin; patients who have or have history of progressive multifocal leukoencephalopathy

Dosing: Adult

Hodgkin lymphoma, relapsed or refractory: IV: 1.8 mg/kg (maximum dose: 180 mg) every 3 weeks, continue until disease progression or unacceptable toxicities

Hodgkin lymphoma, maintenance therapy after autologous hematopoietic stem cell transplantation (HSCT): IV: 1.8 mg/kg (maximum dose: 180 mg) every 3 weeks, continue until a maximum of 16 cycles, disease progression, or unacceptable toxicity. Begin therapy within 4 to 6 weeks post HSCT or upon recovery from HSCT.

Systemic anaplastic large cell lymphoma (sALCL), refractory: IV: 1.8 mg/kg (maximum dose: 180 mg) every 3 weeks, continue until disease progression or unacceptable toxicities

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥30 mL/minute: Initial: No dosage adjustment necessary.

CrCl <30 mL/minute: Initial: Avoid use.

Dosing: Hepatic Impairment

Mild impairment (Child-Pugh class A): Initial: 1.2 mg/kg (maximum dose: 120 mg) every 3 weeks.

Moderate to severe impairment (Child-Pugh class B or C): Avoid use.

Dosing: Adjustment for Toxicity

Hematologic toxicity:

Grade 3 or 4 neutropenia: Withhold treatment until resolves to baseline or ≤ grade 2, consider growth factor support in subsequent cycles.

Recurrent grade 4 neutropenia (despite the use of growth factor support): Consider reducing the dose to 1.2 mg/kg or discontinuing treatment

Grade 3 or 4 thrombocytopenia (Canadian labeling): Monitor closely; dose delays or platelet transfusions may be considered.

Nonhematologic toxicities:

Anaphylaxis: Discontinue immediately and permanently

Infusion reaction: Interrupt infusion and administer appropriate medical intervention. Premedicate subsequent infusions with acetaminophen, an antihistamine, and/or a corticosteroid.

Peripheral neuropathy, new or worsening grade 2 or 3: Withhold treatment until improves or returns to grade 1 or baseline; then resume with dose reduced to 1.2 mg/kg

Peripheral neuropathy, grade 4: Discontinue treatment

Progressive multifocal leukoencephalopathy (PML): Withhold treatment with new-onset symptoms suggestive of PML; discontinue if PML diagnosis confirmed

Pulmonary toxicity: Withhold treatment with new-onset or worsening pulmonary symptoms during evaluation and until symptomatic improvement

Stevens-Johnson syndrome or toxic epidermal necrolysis: Discontinue and administer appropriate medical intervention

Reconstitution

Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Reconstitute each 50 mg vial with 10.5 mL sterile water for injection (SWFI), resulting in a concentration of 5 mg/mL. Direct SWFI toward the vial wall; do not direct toward the cake or powder. Swirl gently to dissolve, do not shake. Reconstituted solution should be clear to slightly opalescent without visible particles. Further dilute in at least 100 mL of either NS, D5W, or lactated Ringer’s to a final concentration of 0.4 to 1.8 mg/mL; gently invert bag to mix. Do not mix with other medications. Use within 24 hours of initial reconstitution.

Administration

Infuse over 30 minutes. Do not administer as IV push or bolus; do not mix or infuse with other medications. Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Compatibility

Stable in NS, D5W, or lactated Ringer’s; do not mix with or administer as an infusion with other products

Storage

Store intact vials refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton. Protect from light. Reconstituted solution should be diluted immediately; however, may be stored refrigerated for up to 24 hours; do not freeze. Solutions diluted for infusion should be used immediately after preparation; however, may be stored for 24 hours refrigerated (do not freeze); use within 24 hours of initial reconstitution.

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

Bleomycin: Brentuximab Vedotin may enhance the adverse/toxic effect of Bleomycin. Specifically, the risk for pulmonary toxicity may be increased. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lumacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (4% to 16%)

Central nervous system: Peripheral sensory neuropathy (2% to 56%; grade 3: 8% to 10%), fatigue (24% to 49%), pain (7% to 28%), headache (11% to 19%), insomnia (14% to 16%), dizziness (11% to 16%), peripheral motor neuropathy (4% to 23%; grade 3: 3% to 6%), chills (10% to 13%), anxiety (7% to 11%)

Dermatologic: Skin rash (27% to 31%), pruritus (12% to 19%), alopecia (13% to 14%), night sweats (9% to 12%)

Endocrine & metabolic: Weight loss (6% to 19%)

Gastrointestinal: Nausea (2% to 42%), diarrhea (20% to 36%), abdominal pain (3% to 25%), vomiting (3% to 22%), constipation (13% to 19%), decreased appetite (11% to 16%)

Hematologic & oncologic: Neutropenia (54% to 78%; grade 3: 12% to 30%; grade 4: 6% to 9%), anemia (27% to 52%; grade 3: 2% to 8%; grade 4: 4%), thrombocytopenia (16% to 41%; grade 3: 5% to 7%; grade 4: 2% to 5%), lymphadenopathy (10% to 11%)

Immunologic: Antibody development (antibrentuximab; transient: 30%; persistent: 7%)

Neuromuscular & skeletal: Arthralgia (9% to 19%), myalgia (11% to 17%), back pain (10% to 14%), muscle spasm (9% to 11%)

Respiratory: Upper respiratory tract infection (12% to 47%), cough (17% to 25%), dyspnea (13% to 19%), oropharyngeal pain (9% to 11%)

Miscellaneous: Fever (2% to 38%), infusion related reaction (12% to 15%)

1% to 10%:

Cardiovascular: Septic shock (3%), supraventricular cardiac arrhythmia (3%), pulmonary embolism (2%)

Dermatologic: Xeroderma (4% to 10%)

Genitourinary: Urinary tract infection (3%)

Hepatic: Hepatotoxicity (2%)

Neuromuscular & skeletal: Limb pain (3% to 10%)

Renal: Pyelonephritis (2%)

Respiratory: Pulmonary toxicity (5%, noninfectious), pneumonia (4%), pneumonitis (2%), pneumothorax (2%)

<1% (Limited to important or life-threatening): Anaphylaxis, febrile neutropenia, hyperglycemia, pancreatitis, progressive multifocal leukoencephalopathy, opportunistic infection, serious infection, Stevens-Johnson syndrome, tumor lysis syndrome

ALERT: U.S. Boxed Warning

Progressive multifocal leukoencephalopathy:

JC virus infection resulting in progressive multifocal leukoencephalopathy (PML) and death can occur in patients receiving brentuximab vedotin.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Grade 3 or 4 neutropenia, thrombocytopenia, and anemia may occur. Neutropenia may be severe and/or prolonged (≥1 week). Neutropenic fever also has been reported. Monitor blood counts prior to each dose; consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. May require growth factor support, dose interruption, reduction, or discontinuation.

• Dermatologic toxicity: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (some fatal). Discontinue (and begin appropriate management) if SJS or TEN occur.

• GI toxicity: Serious and fatal gastrointestinal (GI) complications (including hemorrhage, obstruction, perforation, erosion, ulcer, enterocolitis, neutropenic colitis, and ileus) have been reported. The risk for GI complications may be increased in patients with lymphoma with preexisting GI involvement. Prompt diagnostic evaluation and management should be performed if new or worsening GI symptoms occur.

• Hepatotoxicity: Serious hepatotoxicity, including fatalities, has occurred; cases were consistent with hepatocellular injury, with elevations of transaminases and/or bilirubin. Some have occurred after the initial dose or after rechallenge. The risk for hepatotoxicity may be increased with preexisting liver disease, elevated baseline liver enzymes, and concurrent medications. Monitor liver enzymes and bilirubin. Treatment delay, dose reduction, or discontinuation may be required for new, worsening, or recurrent hepatotoxicity.

• Infection: Serious infection, including opportunistic infections (eg, pneumonia, bacteremia, sepsis/septic shock) have been reported (some fatal); monitor for signs or symptoms of bacterial, fungal, or viral infections.

• Infusion reactions/anaphylaxis: Infusion reactions, including anaphylaxis have been reported. Monitor during infusion. For anaphylaxis, immediately and permanently discontinue and administer appropriate medical intervention. For infusion-related reaction, interrupt infusion and administer appropriate medical intervention; premedicate for subsequent infusions (with acetaminophen, an antihistamine, and/or a corticosteroid).

• Peripheral neuropathy: Peripheral neuropathy is common and is generally cumulative. Neuropathy is usually sensory, although motor neuropathy has also been observed. Neuropathy completely resolved in nearly half of patients; almost one-third had partial improvement. Monitor for symptoms of neuropathy (hypoesthesia, hyperesthesia, paresthesia, discomfort, burning sensation, neuropathic pain, or weakness). Dose interruption, reduction or discontinuation may be recommended for new or worsening neuropathy.

• Progressive multifocal leukoencephalopathy (PML): [US Boxed Warning]: Cases of PML and death due to JC virus infection have been reported. Immunosuppression due to prior chemotherapy treatments or underlying disease may also contribute to PML development. New-onset signs/symptoms of central nervous system abnormalities (eg, changes in mood, memory, cognition, motor incoordination and/or weakness, speech and/or visual disturbances) should receive prompt evaluation with neurology consultation, brain MRI, and lumbar puncture or brain biopsy. The time to initial symptom onset varies from treatment initiation, with some cases occurring within 3 months of initial drug exposure. Withhold treatment with new-onset symptoms suggestive of PML; discontinue if diagnosis of PML is confirmed.

• Pulmonary toxicity: Noninfectious pulmonary toxicity (eg, pneumonitis, interstitial lung disease, acute respiratory distress syndrome), some fatal, has been reported in patients receiving brentuximab vedotin. Monitor for signs/symptoms of pulmonary toxicity (eg, cough, dyspnea). Withhold treatment and perform prompt diagnostic evaluation and management for new or worsening pulmonary symptoms.

• Tumor lysis syndrome: Tumor lysis syndrome (TLS) may occur; risk of TLS is higher in patients with a high tumor burden or with rapid tumor proliferation. Monitor closely.

Disease-related concerns:

• Hepatic impairment: Avoid use in patients with moderate to severe hepatic impairment (Child-Pugh classes B and C). The frequency of grade 3/4 toxicities (and deaths) was increased in patients with moderate or severe impairment (compared to patients with normal hepatic function). A component of brentuximab vedotin, the microtubule-disrupting agent monomethylauristatin E (MMAE) is excreted hepatically. MMAE exposure is increased ~2.2-fold in patients with hepatic impairment.

• Renal impairment: Avoid use in patients with severe renal impairment (CrCl <30 mL/minute). The frequency of grade 3/4 toxicities (and deaths) was increased in patients with severe impairment (compared to patients with normal renal function). A component of brentuximab vedotin, the microtubule-disrupting agent MMAE is excreted renally; MMAE exposure is increased in patients with severe impairment.

Concurrent drug therapy issues:

• Bleomycin: Due to the risk for pulmonary injury, concurrent use with bleomycin is contraindicated. In a study comparing brentuximab combined with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) to brentuximab combined with AVD (doxorubicin, vinblastine, and dacarbazine), the occurrence of pulmonary toxicity was higher in the brentuximab/ABVD group. Pulmonary symptoms/toxicities reported with brentuximab in combination with ABVD consisted of cough, dyspnea, and interstitial infiltration/inflammation; most patients responded to corticosteroids.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Monitoring Parameters

CBC with differential prior to each dose (more frequently if clinically indicated); liver and renal function tests. Monitor for infusion reaction, tumor lysis syndrome, signs/symptoms of progressive multifocal leukoencephalopathy (PML), and for signs of neuropathy (hypoesthesia, hyperesthesia, paresthesia, discomfort, burning sensation, or neuropathic pain or weakness), dermatologic toxicity, pulmonary toxicity, GI toxicity, or infection.

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Based on the mechanism of action and on animal data, brentuximab vedotin may cause fetal harm if administered to a pregnant woman. Women of reproductive potential and men with female partners of reproductive potential should avoid pregnancy during treatment and for at least 6 months after the final dose. Brentuximab vedotin treatment may compromise fertility in males.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience joint pain, headache, nausea, vomiting, abdominal pain, constipation, diarrhea, back pain, dry skin, alopecia, muscle spasms, lack of appetite, weight loss, night sweats, insomnia, or anxiety. Have patient report immediately to prescriber signs of progressive multifocal leukoencephalopathy (confusion, depression, trouble with memory, behavioral changes, change in strength on one side, trouble speaking, change in balance, vision changes), signs of infection, signs of a severe pulmonary disorder (lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse), signs of a pancreas problem (pancreatitis; severe abdominal pain, severe back pain, severe nausea, vomiting), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), enlarged lymph nodes, severe dizziness, passing out, loss of strength and energy, angina, coughing up blood, burning or numbness feeling, muscle pain, swelling of arm or leg, bruising, bleeding, signs of tumor lysis syndrome (fast heartbeat or abnormal heartbeat; any passing out; trouble passing urine; muscle weakness or cramps; nausea, vomiting, diarrhea, or lack of appetite; or feel sluggish), or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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