brentuximab vedotin (Rx)

Brand and Other Names:Adcetris
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injection, lyophilized powder

  • 50mg/vial
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Hodgkin Lymphoma

Classical HL post-auto-HSCT consolidation

  • Indicated for classical HL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation
  • 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  
  • If patient weighs >100 kg, calculate dose based on a weight of 100 kg
  • Continue treatment until a maximum of 16 cycles, disease progression, or unacceptable toxicity

Relapsed classical HL

  • Indicated for classical HL after failure of auto-HSCT or after failure of at least 2 prior multi-agent chemotherapy regimens in patients who are not auto-HSCT 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

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; not to exceed 180 mg/dose  

Continue treatment until disease progression or unacceptable toxicity

Primary Cutaneous Anaplastic Large Cell Lymphoma

Indicated for primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30 expressing mycosis fungoides (MF) who have received prior systemic therapy

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

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; not to exceed 120 mg/dose
  • 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
  • Recurrent grade 4 neutropenia despite use of growth factors: Discontinue brentuximab vedotin or reduce dose to 1.2 mg/kg; not to exceed 120 mg/dose

Dosing Considerations

The dose for patients weighing >100 kg should be calculated based on a weight of 100 kg

Accelerated approval was granted for the sALCL indication based on overall response rate; continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials

Orphan Designations

Peripheral T-cell lymphoma, not otherwise specified

Angioimmunoblastic T-cell lymphoma

Cutaneous 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

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

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Interactions

Interaction Checker

and brentuximab vedotin

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10% (Any Grade)

            Anemia (62%)

            Peripheral sensory neuropathy (45%)

            Nausea (36%)

            Diarrhea (29%)

            Fatigue (29%)

            Neutropenia (21%)

            Vomiting (17%)

            Pruritus (17%)

            Pyrexia (17%)

            Alopecia (15%)

            Thrombocytopenia (15%)

            Decreased appetite (15%)

            Arthralgia (12%)

            Myalgia (12%)

            Peripheral edema (11%)

            Maculopapular rash (11%)

            Generalized pruritus (11%)

            Asthenia (11%)

            Dyspnea (11%)

            1-10%

            Extremity pain (10%)

            Muscle spasms (9-10%)

            Dry skin (4-10%)

            Chills (4%)

            Nausea (3–4%)

            Dyspnea (2–3%)

            Pruritus (2–5%)

            Pyrexia (2%)

            Cough (2%)

            Grade 3 or 4

            • Peripheral sensory neuropathy (5%)
            • Fatigue (5%)
            • Diarrhea (3%)
            • Neutropenia (2-3%)
            • Asthenia (2%)
            • Maculopapular rash (2%)
            • Generalized pruritus (2%)
            • Nausea (2%)
            • Vomiting (2%)
            • Thrombocytopenia (2%)

            Postmarketing reports

            Blood and lymphatic system disorders: Febrile neutropenia

            Gastrointestinal disorders: Acute pancreatitis and gastrointestinal complications (including fatal outcomes)

            Hepatobiliary disorders: Hepatotoxicity

            Infections: PML, serious infections and opportunistic infections

            Metabolism and nutrition disorders: Hyperglycemia

            Respiratory, thoracic and mediastinal disorders: Noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and ARDS (some with fatal outcomes)

            Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, including fatal outcomes

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            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 symptoms of neuropathy, including hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness; patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of therapy (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 (see Pregnancy)

            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 (see Dosage Modifications)

            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

            Acute pancreatitis, including fatal outcomes, has been reported; in the event of new or worsening GI symptoms, including severe abdominal pain, perform a prompt diagnostic evaluation and treat appropriately

            Fatal and serious gastrointestinal (GI) complications (eg, 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

            Drug interactions overview

            • Coadministration of brentuximab with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE which may increase the risk of adverse reaction
            • Closely monitor adverse reactions when brentuximab is given concomitantly with strong CYP3A4 inhibitors
            • Coadministration of brentuximab with P-gp inhibitors may increase exposure to MMAE; monitor adverse reactions when brentuximab is given concomitantly with P-gp inhibitors
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            Pregnancy & Lactation

            Pregnancy

            Based on the findings from animal studies and mechanism of action, brentuximab may cause fetal harm

            In animal reproduction studies, administration of brentuximab vedotin to pregnant rats during organogenesis at doses similar to the clinical dose of 1.8 mg/kg q3weeks caused embryo-fetal toxicities, including congenital malformations

            If brentuximab is used during pregnancy or if the patient becomes pregnant during treatment, patients should be apprised of the potential risk to the fetus

            Verify the pregnancy status of females of reproductive potential prior to initiating brentuximab

            Advise females of reproductive potential and males with female sexual partners of reproductive potential to avoid pregnancy during treatment and for at least 6 months after the final brentuximab dose

            Based on findings in rats, male fertility may be compromised by brentuximab

            Lactation

            There is no information related to the presence of brentuximab vedotin in human milk, the effects on the breastfed child, or the effects on milk production

            Owing to the potential for serious adverse reactions in a breastfed child from brentuximab, including cytopenias and neurologic or gastrointestinal toxicities, advise patients that breastfeeding is not recommended during treatment

            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.

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            Pharmacology

            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

            Absorption

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

            Steady-state: 21 days (ADC); 21 days (MMAE)

            Distribution

            Protein Bound: 68-82% (MMAE)

            Vd: 6-10 L (ADC)

            Metabolism

            MMAE was a P-gp substrate

            Data indicated MMAE metabolism occurs primarily via oxidation by CYP3A4/5

            Excretion

            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)

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            Administration

            IV Incompatibilities

            Do not mix or administer with other medicinal products

            IV Compatibilities

            0.9% NaCl

            D5W

            Lactated Ringer’s (LR)

            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 at 2-8°C (36-46°F) and use within 24 hr of reconstitution; do not freeze
            • Discard any unused portion left in the vial

            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 (0.9% NaCl, 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 hr

            IV Administration

            Infuse over 30 minutes

            Do not administer as an IV push or bolus

            Storage

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

            Diluted solutions or reconstituted vials: Store in refrigerator at 2-8°C (36-46°F) for up to 24 hr

            Do not freeze

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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
            • Manage and view all your plans together – even plans in different states.
            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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