brentuximab vedotin (Adcetris)

Dosing and uses of Adcetris (brentuximab vedotin)

• Adult
• Pediatric

 

Adult dosage forms and strengths

lyophilized powder for injection

• 50mg/vial

 

Hodgkin Lymphoma

Indicated for treatment of classical Hodgkin lymphoma (HL) after failure of autologous hematopoietic stem cell transplant (auto-HSCT) or after failure of at least 2 prior multiagent chemotherapy regimens in patients who are not stem cell transplant candidates

1.8 mg/kg IV infused over 30 minutes q3Weeks; not to exceed 180 mg/dose

Continue treatment until disease progression or unacceptable toxicity

Classical HL post-auto-HSCT consolidation

• Indicated post-auto-HSCT in patients with HL at high risk for relapse or progression
• Initiate within 4–6 weeks post-auto-HSCT or upon recovery from auto-HSCT
• 1.8 mg/kg IV infused over 30 minutes q3Weeks; not to exceed 180 mg/dose
• Continue treatment until a maximum of 16 cycles, disease progression, or unacceptable toxicity

 

Systemic Anaplastic Large Cell Lymphoma

Indicated for treatment of systemic anaplastic large cell lymphoma after failure of at least one prior multiagent chemotherapy regimen

1.8 mg/kg IV infused over 30 minutes q3Weeks

If patient weighs >100 kg, calculate dose based on a weight of 100 kg

Continue treatment until disease progression or unacceptable toxicity

 

Dosage modifications

Renal impairment

• Mild or moderate (CrCl 30-80 mL/min): No dosage adjustment required
• Severe (CrCl <30 mL/min): Avoid use

Hepatic impairment

• Mild (Child-Pugh A): 1.2 mg/kg/dose; not to exceed 120 mg/dose
• Moderate or severe (Child-Pugh B or C): Avoid use

Peripheral neuropathy

• New or worsening grade 2 or 3 peripheral neuropathy: Hold dose until neuropathy improves to grade 1 or baseline, and then restart at 1.2 mg/kg
• Grade 4 peripheral neuropathy: Discontinue brentuximab vedotin

Neutropenia

• Grade 3 or 4 neutropenia: Hold dose until resolution to baseline or grade 2 or lower
• Consider growth factor support for subsequent cycles
• For recurrent grade 4 neutropenia despite use of growth factors, discontinue brentuximab vedotin or reduce dose to 1.2 mg/kg

 

Orphan Designations

CD30-positive cutaneous T-cell lymphoma including those with primary cutaneous anaplastic large cell lymphoma (pcALCL) (ie, mycosis fungoides)

Peripheral T-cell lymphoma, not otherwise specified

Angioimmunoblastic T-cell lymphoma

Diffuse large B-cell lymphoma

Adult T-cell leukemia/lymphoma

Enteropathy-associated T-cell lymphoma

Orphan sponsor

• Seattle Genetics, Inc; 21823 30th Drive Southeast, Bothell, WA 98021

 

Pediatric dosage forms and strengths

Safety and effectiveness not established

Clinical trials included only 9 pediatric patients and this number is not sufficient to determine whether they respond differently than adult patients

 

Adcetris (brentuximab vedotin) adverse (side) effects

>10%

Neutropenia (54-55%)

Peripheral sensory neuropathy (52-53%)

Anemia (33-52%)

Fatigue (41-49%)

URIs (12-47%)

Nausea (38-42%)

Pyrexia (29-38%)

Diarrhea (29-36%)

Rash (27-31%

Thrombocytopenia (16-28%)

Pain (7-28%)

Cough (17-25%)

Abdominal pain (9-25%)

Vomiting (17-22%)

Pruritus (17-19%)

Constipation (16-19%)

Headache (16-19%)

Dyspnea (13-19%)

Arthralgia (9-19%)

Myalgia (16-17%)

Insomnia (14-16%)

Dizziness (11-16%)

Peripheral motor neuropathy (7-16%)

Peripheral edema (4-16%)

Alopecia (13-14%)

Back pain (10-14%)

Chills (12-13%)

Night sweats (9-12%)

Lymphadenopathy (10-11%)

Oropharyngeal pain (9-11%)

Anxiety (7-11%)

 

1-10%

Extremity pain (10%)

Muscle spasms (9-10%)

Dry skin (4-10%)

 

Postmarketing reports

Noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and ARDS (some with fatal outcomes)

 

Warnings

Black box warnings

Progressive multifocal leukoencephalopathy

• JC virus infection resulting in PML and death can occur; cases of progressive multifocal leukoencephalopathy (PML) reported
• PML is a rare, but serious brain infection that can result in death
• Signs and symptoms of PML may develop over several weeks or months and may include mood changes, unusual behavior, confusion, thinking problems, memory loss, changes in vision, speech, or walking, and a unilateral decrease in strength or weakness

 

Contraindications

Concomitant use of brentuximab with bleomycin because of pulmonary toxicity

 

Cautions

Monitor patients for peripheral neuropathy and institute dose modifications accordingly (see Dosage modifications)

If an infusion reaction occurs, the infusion should be interrupted and appropriate medical management instituted (higher incidence in patients who developed persistently positive antibodies)

If anaphylaxis occurs, the infusion should be discontinued immediately and appropriate medical management instituted

If Stevens-Johnson syndrome or toxic epidermal necrolysis occurs, discontinue and administer appropriate medical therapy

Monitor CBC prior to each dose; if Grade 3 or 4 neutropenia develops, manage by dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses (see Dosage modifications)

Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome; monitored closely and take appropriate measures

Fetal harm can occur; advise pregnant women of the potential hazard to the fetus

Coadministration of strong CYP3A4 inhibitors may increase risk for toxicity

Avoid use with severe renal impairment (CrCl <30 mL/min); frequency of Grade 3 adverse reactions and deaths reported to be greater in patients with severe renal impairment compared to patients with normal renal function, possibly due to higher MMAE exposure

Serious cases of hepatotoxicity, including fatal outcomes reported after first dose or after rechallenge; serious cases of hepatotoxicity, including fatal outcomes; preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase risk; monitor liver enzymes and bilirubin; patients experiencing new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of therapy

Decrease dose with mild hepatic impairment and avoid use with moderate or severe hepatic impairment (see Dosage modifications)

JC virus infection resulting in progressive multifocal leukoencephalopathy (PML) and death reported in brentuximab-treated patients; consider the diagnosis of PML in any patient presenting with new onset signs and symptoms of CNS abnormalities; hold dosing for any suspected case of PML and discontinue drug dosing if a diagnosis of PML is confirmed

Events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS), some with fatal outcomes, reported; monitor patients for new or worsening symptoms

Closely monitor patients for emergence of bacterial, fungal or viral infections

Fatal and serious gastrointestinal (GI) complications including perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus reported; lymphoma with preexisting GI involvement may increase risk of perforation; perform prompt diagnostic evaluation in the event of new or worsening GI symptoms, and treat appropriately

 

Pregnancy and lactation

Pregnancy category: D; caused embryo-fetal toxicities, including significantly decreased embryo viability and fetal malformations, in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL

Lactation: Unknown whether distributed in breast milk; breastfeeding not recommended

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Adcetris (brentuximab vedotin)

Mechanism of action

CD30-directed antibody-drug conjugate (ADC) consisting of chimeric IgG1 antibody cAC10, specific for human CD30 and the microtubule disrupting agent, monomethyl auristatin E (MMAE, or vedotin); the conjugate binds to cell expressing the CD30 antigen and forms a complex that is internalized within the cell and MMAE is released; MMAE induces cell cycle (G2/M phase) arrest by binding to the tubules and disrupting the cellular microtubule network

 

Pharmacokinetics

Peak Plasma Time: 20-30 min (ADC); 1-3 days (MMAE)

Protein Bound: 68-82% (MMAE)

Vd: 6-10 L (ADC)

P-gp substrate

Metabolism CYP3A4/5 (MMAE)

MMAE inhibits CYP3A4/5

Half-life: 4-6 days

Excretion: 24% of the total MMAE administered was recovered in both urine and feces over 1 week (72% of which was recovered in the feces)

 

Administration

IV Incompatibilities

Do not mix or administer with other medicinal products

 

IV Compatibilities

0.9% NaCL

Dextrose 5%

Lactated Ringer’s

 

IV Preparation

Adhere to procedures for proper handling, dispensing, and administration of anticancer drugs

Reconstitution

• Reconstitute each 50 mg vial of lyophilized powder with 10.5 mL sterile water for injection to yield 5 mg/mL
• Direct stream toward vial wall and not directly at cake or powder to prevent foaming
• Do not shake vial; gently swirl the vial to aid dissolution
• Reconstituted solution should be clear to slightly opalescent, colorless, and free of visible particulates
• Following reconstitution, dilute immediately into infusion bag, or store solution at 2-8 degrees C (36-46 degrees F) and use within 24 hours of reconstitution; do not freeze

Dilution

• Calculate dosage volume (mL) and withdraw dose from vial(s)
• The dose for patients weighing >100 kg should be calculated for 100 kg
• Dilute reconstituted solution in at least 100 mL (NS, D5W, LR) to final concentration range of 0.4-1.8 mg/mL
• Gently invert bag to mix solution
• Contains no bacteriostatic preservatives, use immediately or refrigerate solution and use within 24 hours

 

IV Administration

Administer diluted solution IV over 30 minutes

Do not administer as an IV push or bolus

 

Storage

Store unopened vials in refrigerator at 2-8 degrees C (36-46 degrees F) in the original carton to protect from light

May refrigerate reconstituted or diluted solution if administered within 24 hr

Do not freeze