Drug Information

Brentuximab vedotin

Brentuximab vedotin

Brand Names: U.S.

  • Adcetris™
Pharmacologic Category

  • Antineoplastic Agent, Monoclonal Antibody
Dosing: AdultNote: For patients weighing >100 kg, dose should be calculated using a weight of 100 kg.

Hodgkin lymphoma, refractory: I.V.: 1.8 mg/kg (maximum dose: 180 mg) every 3 weeks, continue until disease progression, unacceptable toxicities, or a maximum of 16 cycles

Systemic anaplastic large cell lymphoma, refractory: I.V.: 1.8 mg/kg (maximum dose: 180 mg) every 3 weeks, continue until disease progression, unacceptable toxicities, or a maximum of 16 cycles

Dosing: GeriatricRefer to adult dosing.

Dosing: Renal ImpairmentThere are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic ImpairmentThere are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Adjustment for ToxicityHematologic 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

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

Stevens-Johnson syndrome: Discontinue and administer appropriate medical intervention

Dosage Forms: U.S.Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, powder for reconstitution:

Adcetris™: 50 mg [contains polysorbate 80; derived from or manufactured using hamster or mouse protein]

Generic Equivalent Available: U.S.No

AdministrationInfuse over 30 minutes. Do not administer as I.V. push or bolus.

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

UseTreatment of Hodgkin lymphoma after failure of at least 2 prior chemotherapy regimens (in patients ineligible for transplant) or after stem cell transplant failure; treatment of systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 prior chemotherapy regimen

Medication Safety Issues

Sound-alike/look-alike issues:

Brentuximab may be confused with bendamustine, bevacizumab, rituximab

High alert medication:

This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Adverse Reactions Significant>10%:

Cardiovascular: Peripheral edema (4% to 16%)

Central nervous system: Fatigue (41% to 49%), fever (29% to 38%), pain (7% to 28%), headache (16% to 19%), insomnia (14% to 16%), dizziness (11% to 16%), chills (12% to 13%), anxiety (7% to 11%)

Dermatologic: Rash (27% to 31%), pruritus (17% to 19%), alopecia (13% to 14%)

Gastrointestinal: Nausea (38% to 42%), diarrhea (29% to 36%), abdominal pain (9% to 25%), vomiting (17% to 22%), constipation (16% to 19%), appetite decreased (11% to 16%), weight loss (6% to 12%)

Hematologic: Neutropenia (54% to 55%; grade 4: 6% to 9%); anemia (33% to 52%; grade 4: ≤2%), thrombocytopenia (16% to 28%; grade 4: 2% to 5%)

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Neuromuscular & skeletal: Peripheral sensory neuropathy (52% to 53%; grade 3: 8% to 10%), arthralgia (9% to 19%), myalgia (16% to 17%), peripheral motor neuropathy (7% to 16%; grade 3: 3% to 4%), back pain (10% to 14%)

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

Miscellaneous: Infusion reactions (12%), night sweats (9% to 12%), lymphadenopathy (10% to 11%)

1% to 10%:

Cardiovascular: Supraventricular arrhythmia

Dermatologic: Dry skin

Genitourinary: Urinary tract infection

Neuromuscular & skeletal: Limb pain, muscle spasms

Renal: Pyelonephritis

Respiratory: Pneumonitis, pneumothorax, pulmonary embolism

Miscellaneous: Antibrentuximab antibody formation, septic shock

<1% (Limited to important or life-threatening): Anaphylaxis, progressive multifocal leukoencephalopathy (PML), Stevens-Johnson syndrome, tachycardia, tumor lysis syndrome

ContraindicationsThere are no contraindications listed within the manufacturer’s labeling.

Warnings/Precautions Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal.

Concerns related to adverse effects:

• Bone marrow suppression: Neutropenia, thrombocytopenia and anemia may occur. Neutropenia may be prolonged (≥1 week). Monitor blood counts. May require dose delay, reduction or discontinuation.

• Infusion reactions: 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. Usually sensory neuropathy, 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. Dose interruption, reduction or discontinuation may be recommended.

• Progressive multifocal leukoencephalopathy (PML): One case (fatal) of PML has been reported; this was in a patient who had received 4 prior chemotherapy regimens.

• Stevens-Johnson syndrome: Stevens-Johnson syndrome has been observed. Discontinue and administer appropriate medical intervention.

• 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: A component of brentuximab vedotin, the microtubule-disrupting agent MMAE is excreted hepatically; the impact of hepatic impairment on MMAE pharmacokinetics is undetermined.

• Renal impairment: A component of brentuximab vedotin, the microtubule-disrupting agent MMAE is excreted renally; the impact of renal impairment on MMAE pharmacokinetics is undetermined.

BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination

Cardiac Glycosides: Antineoplastic Agents may decrease the absorption of Cardiac Glycosides. This may only affect digoxin tablets. Exceptions: Digitoxin. Risk C: Monitor therapy

Coccidioidin Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioidin Skin Test. Risk C: 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. Risk C: Monitor therapy

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

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

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

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

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

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

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

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

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

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. 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. Risk X: Avoid combination

Vitamin K Antagonists (eg, warfarin): Antineoplastic Agents may enhance the anticoagulant effect of Vitamin K Antagonists. Antineoplastic Agents may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Pregnancy Risk Factor

Drug ratings in pregnancy (US Food & Drug Administration)
Category Interpretation
A Controlled studies show no risk
Controlled studies in pregnant women fail to demonstrate a risk to the fetus in the first trimester with no evidence of risk in later trimesters. The possibility of fetal harm appears remote.
B No evidence of human risk in controlled studies
Either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester and there is no evidence of a risk in later trimesters.
C Risk cannot be ruled out
Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal effects or other) and there are no controlled studies in women, or studies in women and animals are not available. Drugs should be given only if the potential benefits justify the potential risk to the fetus.
D Positive evidence of risk
There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (eg, if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).
X Contraindicated in pregnancy
Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience, or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.
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Reproduced with permission from: Lacy CF, Armstrong LL, Goldman MP, Lance LL. Lexi-Comp Drug Information Handbook, 20th Edition. Hudson, OH: Lexi-Comp, 2011. Copyright © 2011.
Pregnancy ImplicationsEmbryo-fetal toxicities and fetal malformations were noted in animal studies. There are no adequate and well-controlled studies in pregnant women. Based on the mechanism of action, may cause fetal harm if administered during pregnancy.

LactationExcretion in breast milk unknown/not recommended

Breast-Feeding ConsiderationsAccording to the manufacturer, the decision to continue or discontinue breast-feeding during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother.

Monitoring ParametersCBC with differential prior to each dose (more frequently if clinically indicated). Monitor for infusion reaction, tumor lysis syndrome, and for signs of neuropathy (hyperesthesia, paresthesia, discomfort, burning sensation, or neuropathic pain or weakness).

Mechanism of ActionBrentuximab 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.

Pharmacodynamics/KineticsDistribution: Vdss: ADC: 6-10 L

Metabolism: MMAE: Minimal, primarily via oxidation by CYP3A4/5

Half-life elimination: Terminal: ADC: ~4-6 days

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

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

REFERENCES

  1. Chen RW, Gopal AK, Smith SE, et al, “Results From a Pivitol Phase II Study of Brentuximab Vedotin (SGN-35) in Patients With Relapsed or Refractory Hodgkin Lymphoma (HL),” J Clin Oncol, 2011, 29(15s):8031 [abstract 8031 from 2011 ASCO Annual Meeting].
  2. Pro B, Avandi R, Brice P, et al, “Durable Remissions With Brentuximab Vedotin (SG-35): Updated Results of a Phase II Study in Patients With Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma (sALCL),” J Clin Oncol, 2011, 29(15s):8032 [abstract 8032 from 2011 ASCO Annual Meeting].
  3. Younes A, Bartlett NL, Leonard JP, et al, “Brentuximab Vedotin (SGN-35) for Relapsed CD30-Positive Lymphomas,” N Engl J Med, 2010, 363(19):1812-21. [PubMed 21047225]

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