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Brentuximab

Class: Antineoplastic Agents
Chemical Name: Complex with N-[[[4-[[N-[6-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-1-oxohexyl]-l-valyl-N5-(aminocarbonyl)-l-ornithyl]amino]phenyl]methoxy]carbonyl]-N-methyl-l-valyl-N-[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]amino]-1-methoxy-2-methyl-3-oxopropyl]-1-pyrrolidinyl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxobutyl]-N-methyl-l-valinamide, dimer, disulfide with human-mouse monoclonal cAC10 k-chain, anti-(human CD30 (antigen)) (human-mouse monoclonal cAC10 γ1-chain), immunoglobulin G1
Molecular Formula: C6476H9930N1690O2030S40 (C68H105N11O15)n
CAS Number: 914088-09-8
Brands: Adcetris

Medically reviewed by Drugs.com on Jun 1, 2020. Written by ASHP.

Warning

  • Progressive multifocal leukoencephalopathy (PML), sometimes fatal, can occur. (See Progressive Multifocal Leukoencephalopathy under Cautions.)

Introduction

Antineoplastic agent; an anti-CD30 antibody conjugated with a microtubule inhibitor (monomethyl auristatin E [MMAE]).

Uses for Brentuximab

Hodgkin Lymphoma

Used in combination with doxorubicin, vinblastine, and dacarbazine (AVD) for the treatment of previously untreated stage III or IV classical Hodgkin lymphoma (cHL). Efficacy determined based on substantially reduced risk of progression, death, or, in those who did not achieve a complete response, receipt of subsequent anticancer therapy compared with combination therapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).

Used as single agent consolidation therapy for cHL at high risk of relapse or progression following autologous stem cell transplantation. Efficacy determined based on substantially prolonged median progression-free survival compared with placebo.

Used as a single agent for the treatment of cHL following failure of autologous stem cell transplantation or following failure of ≥2 multiple-agent chemotherapy regimens in patients who are not candidates for autologous stem cell transplantation. Efficacy determined based on objective response rate in a noncomparative, open-label study in patients with relapsed Hodgkin lymphoma.

Designated an orphan drug by FDA for treatment of Hodgkin lymphoma.

Peripheral T-cell Lymphoma (PTCL)

Used in combination with cyclophosphamide, doxorubicin, and prednisone (CHP) for the treatment of previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-positive PTCL, including angioimmunoblastic T-cell lymphoma (AITL) and PTCL not otherwise specified (PTCL-NOS) (designated an orphan drug by FDA for treatment of these cancers ). Efficacy determined based on prolonged progression-free survival and overall survival compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).

Used as a single agent for the treatment of sALCL following failure of ≥1 multiple-agent chemotherapy regimen (designated an orphan drug by FDA for treatment of this cancer ). Efficacy determined based on objective response rate in a noncomparative, open-label study in patients with relapsed sALCL.

Used as a single agent for the treatment of primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-positive mycosis fungoides previously treated with systemic therapy (designated an orphan drug by FDA for treatment of these conditions ). Efficacy determined based on higher durable response rates compared with standard chemotherapy.

Brentuximab Dosage and Administration

General

  • Monitor CBC prior to each dose; consider more frequent monitoring in patients with grade 3 or 4 neutropenia.

  • When used in combination with AVD or CHP regimen, administer primary prophylaxis with a granulocyte colony-stimulating factor (G-CSF) beginning with cycle 1.

  • If the patient has experienced an infusion-related reaction to the drug, administer a premedication regimen (e.g., corticosteroid, antihistamine, and acetaminophen) prior to each subsequent dose. (See Sensitivity Reactions under Cautions.)

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.

Brentuximab vedotin powder for injection must be reconstituted and diluted prior to administration. Use within 24 hours following reconstitution. (See Storage under Stability.)

Do not mix with any other drug or administer any other drug simultaneously in the same IV line.

Reconstitution

Reconstitute vial containing 50 mg of brentuximab vedotin with 10.5 mL of sterile water for injection to provide a solution containing 5 mg/mL; direct diluent toward the wall of the vial. Gently swirl vial to ensure dissolution. Do not shake reconstituted solution.

Reconstituted solution should be clear to slightly opalescent, colorless, and free of visible particulates.

Dilution

Dilute appropriate dose in a minimum volume of 100 mL of 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer’s injection to yield a final concentration of 0.4–1.8 mg/mL. Mix the diluted solution by gentle inversion. Discard any partially used vial.

Rate of Administration

Administer by IV infusion over 30 minutes.

Dosage

Consult respective manufacturers' labelings or published protocols for information on the dosage, method of administration, and administration sequence of other antineoplastic agents used in combination regimens.

Adults

Body weight ≤100 kg: Calculate dosage based on actual body weight.

Body weight >100 kg: Calculate dosage based on 100 kg.

Hodgkin Lymphoma
Combination Therapy for Previously Untreated cHL
IV

1.2 mg/kg (up to a maximum of 120 mg) on days 1 and 15 of each 28-day cycle (use in combination with AVD). Continue therapy for up to 6 cycles or until disease progression or unacceptable toxicity occurs. In the ECHELON-1 study, brentuximab vedotin was administered approximately 1 hour after administration of AVD regimen.

Consolidation Therapy for High-risk cHL
IV

1.8 mg/kg (up to a maximum of 180 mg) every 3 weeks. Continue therapy for up to 16 cycles or until disease progression or unacceptable toxicity occurs. Initiate upon recovery from or within 4–6 weeks following autologous stem cell transplantation.

Monotherapy for Relapsed cHL
IV

1.8 mg/kg (up to a maximum of 180 mg) every 3 weeks. Continue therapy until disease progression or unacceptable toxicity occurs.

PTCL
Combination Therapy for Previously Untreated PTCL
IV

1.8 mg/kg (up to a maximum of 180 mg) on day 1 of each 21-day cycle (use in combination with CHP). Continue therapy for 6–8 cycles. In the ECHELON-2 study, 70 or 18% of patients received 6 or 8 cycles, respectively.

Monotherapy for Relapsed sALCL
IV

1.8 mg/kg (up to a maximum of 180 mg) every 3 weeks. Continue therapy until disease progression or unacceptable toxicity occurs.

Monotherapy for Relapsed pcALCL or Mycosis Fungoides
IV

1.8 mg/kg (up to a maximum of 180 mg) every 3 weeks. Continue therapy for up to 16 cycles or until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Adjust brentuximab vedotin dosage according to the severity of the toxicity. (See Tables 1, 2, and 3.)

Table 1: Dosage Modifications for Toxicity of Single-agent Brentuximab Vedotin

Toxicity

Relapsed cHL, Consolidation Therapy for cHL, Relapsed sALCL, or Relapsed pcALCL or Mycosis Fungoides. (Initial Dosage = 1.8 mg/kg every 3 weeks)

Peripheral neuropathy

New or worsening grade 2 or 3: Interrupt brentuximab vedotin; when toxicity resolves to grade 1 or baseline, resume at reduced dosage of 1.2 mg/kg (maximum 120 mg) every 3 weeks

Peripheral neuropathy

Grade 4: Discontinue brentuximab vedotin

Neutropenia

Grade 3 or 4: Interrupt brentuximab vedotin; when toxicity improves to grade 2 or less or to baseline, resume at same dosage; consider G-CSF use during subsequent cycles

Neutropenia

Recurrent grade 4 (despite G-CSF use): Consider drug discontinuance or dosage reduction (i.e., reduced brentuximab vedotin dosage of 1.2 mg/kg [maximum 120 mg] every 3 weeks)

Table 2: Dosage Modifications for Brentuximab Vedotin During Combination Therapy with Doxorubicin, Vinblastine, and Dacarbazine (AVD)

Toxicity

Previously Untreated cHL. (Initial Dosage = 1.2 mg/kg every 2 weeks)

Peripheral neuropathy

Grade 2: Reduce brentuximab vedotin dosage to 0.9 mg/kg (maximum 90 mg) every 2 weeks

Peripheral neuropathy

Grade 3: Consider dosage modification of concomitant neurotoxic drugs and interrupt brentuximab vedotin; when toxicity improves to grade 2 or less, resume brentuximab vedotin at reduced dosage of 0.9 mg/kg (maximum 90 mg) every 2 weeks

Peripheral neuropathy

Grade 4: Discontinue brentuximab vedotin

Neutropenia

Grade 3 or 4 (patient not receiving primary G-CSF prophylaxis): Administer G-CSF during subsequent cycles

Table 3: Dosage Modifications for Brentuximab Vedotin During Combination Therapy with Cyclophosphamide, Doxorubicin, and Prednisone (CHP)

Toxicity

Previously Untreated sALCL or Other PTCL. (Initial Dosage = 1.8 mg/kg every 3 weeks)

Peripheral sensory neuropathy

Grade 2: Continue same dosage

Peripheral sensory neuropathy

Grade 3: Reduce brentuximab vedotin dosage to 1.2 mg/kg (maximum 120 mg) every 3 weeks

Peripheral sensory neuropathy

Grade 4: Discontinue brentuximab vedotin

Peripheral motor neuropathy

Grade 2: Reduce brentuximab vedotin dosage to 1.2 mg/kg (maximum 120 mg) every 3 weeks

Peripheral motor neuropathy

Grade 3 or 4: Discontinue brentuximab vedotin

Neutropenia

Grade 3 or 4 (patient not receiving primary G-CSF prophylaxis): Administer G-CSF during subsequent cycles

Prescribing Limits

Adults

Hodgkin Lymphoma
Previously Untreated cHL
IV

Maximum 120 mg per dose.

Maximum 12 doses (6 cycles).

Consolidation Therapy for cHL
IV

Maximum 180 mg per dose.

Maximum 16 cycles of therapy.

Relapsed cHL
IV

Maximum 180 mg per dose.

PTCL
Previously Untreated PTCL
IV

Maximum 180 mg per dose.

Maximum 6–8 cycles of therapy.

Relapsed sALCL
IV

Maximum 180 mg per dose.

Relapsed pcALCL or Mycosis Fungoides
IV

Maximum 180 mg per dose.

Maximum 16 cycles of therapy.

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): When usual recommended dosage is 1.2 mg/kg every 2 weeks, reduce dosage to 0.9 mg/kg (up to a maximum of 90 mg) every 2 weeks. When usual recommended dosage is 1.8 mg/kg every 3 weeks, reduce dosage to 1.2 mg/kg (up to a maximum of 120 mg) every 3 weeks. (See Hepatic Impairment under Cautions.)

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

Renal Impairment

Mild to moderate renal impairment (Clcr 30–80 mL/minute): No dosage adjustment required.

Severe renal impairment (Clcr <30 mL/minute): Avoid use. (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations. (See Geriatric Use under Cautions.)

Cautions for Brentuximab

Contraindications

  • Concomitant use with bleomycin. (See Respiratory Effects under Cautions.)

Warnings/Precautions

Warnings

Progressive Multifocal Leukoencephalopathy

JC virus infection causing PML (sometimes fatal) reported; signs and symptoms may develop over several weeks or months. Other risk factors for PML include prior therapies and underlying disease that may cause immunosuppression.

Consider PML in any patient with new signs or symptoms suggestive of PML. (See Advice to Patients.) If PML is suspected, withhold the drug. If PML is confirmed, permanently discontinue brentuximab vedotin.

Other Warnings and Precautions

Peripheral Neuropathy

Peripheral neuropathy (mainly sensory neuropathy) occurs commonly; median time to onset is 2–3 months.

Monitor patients for manifestations of neuropathy (e.g., hypoesthesia, hyperesthesia, paresthesia, discomfort, burning sensation, neuropathic pain, weakness). Dosage reduction, treatment delay, or drug discontinuance may be required in patients with new or worsening symptoms. (See Dosage Modification for Toxicity under Dosage and Administration.)

Sensitivity Reactions

Infusion-related reactions (e.g., chills, nausea, dyspnea, pruritus, pyrexia, cough), including anaphylaxis, reported.

Monitor for manifestations of infusion reactions during the infusion.

If infusion-related effects occur, interrupt the infusion and initiate appropriate treatment. If anaphylaxis occurs, immediately and permanently discontinue brentuximab vedotin.

If an infusion-related reaction occurs, administer premedication regimen (e.g., corticosteroid, antihistamine, and acetaminophen) before each subsequent dose.

Hematologic Effects

Risk of severe and prolonged neutropenia and grade 3 or 4 anemia or thrombocytopenia. Febrile neutropenia, sometimes fatal, reported.

Monitor CBCs prior to each dose; consider more frequent monitoring in patients with grade 3 or 4 neutropenia. Monitor for fever.

Primary prophylaxis with G-CSF recommended in patients receiving brentuximab vedotin in combination with chemotherapy for cHL or PTCL.

If grade 3 or 4 neutropenia occurs, temporary interruption of therapy, dosage reduction, drug discontinuance, or, in those who did not receive primary G-CSF prophylaxis, use of G-CSF may be required. (See Dosage Modification for Toxicity under Dosage and Administration.)

Infectious Complications

Serious infections and opportunistic infections (i.e., pneumonia, bacteremia, sepsis/septic shock), sometimes fatal, reported.

Monitor closely for signs and symptoms of bacterial, fungal, or viral infections.

Tumor Lysis Syndrome

Possible tumor lysis syndrome following rapid lysis of malignant cells. Increased risk in patients with large tumor burden; closely monitor such patients and take appropriate precautions.

Hepatic Toxicity

Elevations in ALT, AST, or bilirubin serum concentrations, sometimes serious or fatal, reported following initiation of or rechallenge with brentuximab vedotin. Increased risk in patients with preexisting hepatic disease or elevated liver enzymes at baseline and those receiving other potentially hepatotoxic drugs. (See Hepatic Impairment under Cautions.)

Monitor liver function tests during therapy. Temporary interruption of therapy, dosage reduction, or drug discontinuance may be required in patients with new, worsening, or recurrent hepatotoxicity.

Respiratory Effects

Concomitant use with bleomycin in contraindicated; increased risk of pulmonary toxicity. Incidence of noninfectious pulmonary reactions (e.g., cough, dyspnea, interstitial infiltration, inflammation) in patients receiving brentuximab vedotin with bleomycin-containing chemotherapy was higher than historical incidence of pulmonary reactions in patients receiving bleomycin-based regimens (e.g., doxorubicin, bleomycin, vinblastine, and dacarbazine [ABVD]). Most patients responded to corticosteroid therapy. Pulmonary toxicity also reported in patients receiving single-agent brentuximab vedotin.

Monitor for signs or symptoms of pulmonary toxicity (e.g., cough, dyspnea). Temporarily interrupt therapy pending results of clinical investigation and until symptoms resolve in patients with new or progressive pulmonary symptoms.

Dermatologic Effects

Stevens-Johnson syndrome and toxic epidermal necrolysis, sometimes serious or fatal, reported. Discontinue therapy and administer appropriate treatment if Stevens-Johnson syndrome or toxic epidermal necrolysis occurs.

GI Complications

GI complications (i.e., acute pancreatitis; GI perforation, hemorrhage, erosion, or ulcer; intestinal obstruction; enterocolitis; neutropenic colitis; ileus), sometimes fatal or serious, reported. Increased risk of GI perforation in patients with preexisting lymphoma-related GI involvement.

If new or progressive GI symptoms (e.g., severe abdominal pain) occur, perform prompt diagnostic evaluation and initiate appropriate therapy.

Hyperglycemia

Serious, sometimes fatal, hyperglycemia (e.g., new-onset hyperglycemia, exacerbation of preexisting diabetes mellitus, ketoacidosis) reported; median time to onset is 1 month. Patients with high body mass index or preexisting diabetes mellitus may be at increased risk.

Monitor serum glucose concentrations during therapy; if hyperglycemia occurs, administer antidiabetic agents as clinically indicated.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Teratogenicity, embryotoxicity, and fetotoxicity demonstrated in animals.

Avoid pregnancy during therapy. Verify pregnancy status prior to initiation of therapy. Women of reproductive potential and men who are partners of such women should use an effective method of contraception while receiving brentuximab vedotin and for ≥6 months after discontinuance of therapy. If used during pregnancy or if patient or patient's partner becomes pregnant, apprise of potential fetal hazard.

Immunogenicity

Antibodies to brentuximab vedotin, including neutralizing antibodies to the drug, reported. Clinical relevance is not known. Higher incidence of infusion-related reactions observed in patients persistently positive for anti-brentuximab vedotin antibodies.

Impairment of Fertility

May impair male fertility based on animal findings.

Specific Populations

Pregnancy

May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether distributed into milk. Effects on nursing infants and on milk production also unknown. Discontinue nursing.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

In patients receiving brentuximab vedotin in combination with AVD for previously untreated stage III or IV cHL, insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults, but febrile neutropenia occurred more frequently in geriatric patients.

In patients receiving brentuximab vedotin in combination with CHP for previously untreated CD30-positive PTCL, grade 3 or greater adverse effects and serious adverse effects occurred more frequently in geriatric patients compared with younger adults. Increased risk for febrile neutropenia in geriatric patients.

In patients receiving single-agent brentuximab vedotin for relapsed cHL, cHL following autologous stem cell transplantation, or relapsed sALCL, insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.

In patients receiving single-agent brentuximab vedotin for relapsed pcALCL or CD30-positive mycosis fungoides, no overall differences in safety and efficacy relative to younger adults.

Hepatic Impairment

Systemic exposure may be increased. (See Absorption: Special Populations, under Pharmacokinetics.) Grade 3 or greater adverse effects, sometimes fatal, reported in patients with moderate or severe hepatic impairment; avoid use in such patients. (See Hepatic Toxicity under Cautions.)

Dosage adjustment required in patients with mild hepatic impairment (Child-Pugh class A). (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Systemic exposure may be increased. (See Absorption: Special Populations, under Pharmacokinetics.) Grade 3 or greater adverse effects, sometimes fatal, reported in patients with severe renal impairment (Clcr <30 mL/minute); avoid use in such patients.

No dosage adjustment required in patients with mild to moderate renal impairment (Clcr 30–80 mL/minute).

Common Adverse Effects

Combination therapy with AVD in patients with previously untreated stage III or IV cHL: Anemia, neutropenia, peripheral sensory neuropathy, constipation, vomiting, fatigue, diarrhea, pyrexia, abdominal pain, decreased weight, stomatitis, febrile neutropenia, bone pain, insomnia, decreased appetite, back pain, rash, dyspnea, peripheral motor neuropathy, elevated ALT concentrations.

Consolidation therapy as a single agent in patients with cHL at high risk for relapse or progression following autologous stem cell transplantation: Neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory tract infection, fatigue, peripheral motor neuropathy, nausea, cough, diarrhea, decreased weight, pyrexia, arthralgia, vomiting, abdominal pain, constipation, dyspnea, decreased appetite, pruritus, headache, muscle spasms, myalgia, chills.

Monotherapy in patients with relapsed cHL: Neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, vomiting, arthralgia/myalgia, headache, pruritus, constipation, cough, peripheral motor neuropathy, back pain, insomnia, alopecia, chills, dyspnea, night sweats, anxiety, decreased appetite, dizziness, lymphadenopathy, oropharyngeal pain, extremity pain.

Combination therapy with CHP in patients with previously untreated CD30-positive PTCL: Anemia, neutropenia, peripheral neuropathy, lymphopenia, nausea, diarrhea, fatigue/asthenia, mucositis, constipation, alopecia, pyrexia, vomiting, febrile neutropenia, abdominal pain, decreased appetite, thrombocytopenia, rash, edema, dyspnea, headache, upper respiratory tract infection, cough, dizziness, hypokalemia, decreased weight, insomnia, myalgia.

Monotherapy in patients with relapsed sALCL: Neutropenia, peripheral sensory neuropathy, anemia, fatigue, nausea, pyrexia, rash, diarrhea, pain, constipation, dyspnea, pruritus, cough, vomiting, decreased appetite, dizziness, headache, insomnia, myalgia, peripheral edema, thrombocytopenia, alopecia, decreased weight, chills, upper respiratory tract infection, back pain, dry skin, extremity pain, lymphadenopathy, muscle spasms.

Monotherapy in patients with relapsed pcALCL or CD30-positive mycosis fungoides: Anemia, peripheral sensory neuropathy, nausea, diarrhea, fatigue/asthenia, neutropenia, pruritus, pyrexia, vomiting, alopecia, decreased appetite, thrombocytopenia, arthralgia, myalgia, dyspnea, peripheral edema, rash.

Interactions for Brentuximab

MMAE (the microtubule-inhibiting component of brentuximab vedotin) is a substrate and inhibitor of CYP3A4/5. Does not inhibit other CYP enzymes and does not induce CYP enzymes.

MMAE is a substrate but not an inhibitor of P-glycoprotein (P-gp).

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Possible pharmacokinetic interaction (increased serum concentrations of MMAE). Monitor closely for adverse effects.

Potent CYP3A4 inducers: Possible pharmacokinetic interaction (decreased serum concentrations of MMAE); however, clinically important effects on MMAE concentrations are not expected.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4: Pharmacokinetic interaction not observed to date.

Protein-bound Drugs

MMAE is not likely to displace or be displaced by other highly protein-bound drugs.

Specific Drugs

Drug

Interaction

Comments

Bleomycin

Increased risk of noninfectious pulmonary reactions (e.g., cough, dyspnea, interstitial infiltration, inflammation) with concomitant use in chemotherapy regimens containing bleomycin.

Concomitant use contraindicated.

Carbamazepine

Clinically important pharmacokinetic interaction not expected

Dexamethasone

Clinically important pharmacokinetic interaction not expected

Ketoconazole

Increased systemic exposure of MMAE

Monitor closely for adverse effects

Midazolam

No change in systemic exposure of midazolam

Phenobarbital

Clinically important pharmacokinetic interaction not expected

Phenytoin

Clinically important pharmacokinetic interaction not expected

Rifampin

Decreased systemic exposure of MMAE

Dosage adjustment not required

Brentuximab Pharmacokinetics

Absorption

Bioavailability

Brentuximab vedotin is an anti-CD30 antibody conjugated with the tubulin inhibitor MMAE; MMAE is released via proteolytic cleavage of the dipeptide bond. Peak plasma concentrations of MMAE are attained approximately 1–3 days after IV administration of brentuximab vedotin.

AUCs of the antibody-drug conjugate and free MMAE are approximately dose proportional over the brentuximab vedotin dose range of 1.2–2.7 mg/kg.

Following administration of brentuximab vedotin 1.8 mg/kg every 3 weeks, steady-state concentrations of antibody-drug conjugate and MMAE achieved within 21 days; minimal systemic accumulation of antibody-drug conjugate occurs.

Following administration of brentuximab vedotin 1.2 mg/kg every 2 weeks, steady-state concentrations of antibody-drug conjugate and MMAE achieved within 56 days; accumulation ratio of antibody-drug conjugate is 1.27-fold.

Following multiple doses of brentuximab vedotin, MMAE exposure is approximately 50–80% of that achieved following the initial dose.

Pharmacokinetic profile of brentuximab vedotin in combination with chemotherapy is similar to that of single-agent brentuximab vedotin.

Special Populations

In patients with hepatic impairment (Child-Pugh class A, B, or C), systemic exposure of MMAE is increased 2.3-fold compared with individuals with normal hepatic function.

In patients with severe renal impairment (Clcr <30 mL/minute), systemic exposure of MMAE is increased approximately twofold compared with individuals with normal renal function. Mild to moderate renal impairment (Clcr 30–80 mL/minute) does not substantially alter MMAE exposure.

Distribution

Extent

Not known whether brentuximab vedotin is distributed into milk.

Plasma Protein Binding

MMAE: 68–82%.

Elimination

Metabolism

Small fraction of free MMAE is metabolized in the liver, primarily via oxidation by CYP3A4/5.

Elimination Route

Following brentuximab vedotin administration, approximately 24% of the total administered dose of MMAE is excreted over 1 week in feces (72%) and to a lesser extent in urine, mainly as unchanged drug.

Half-life

Antibody-drug conjugate: 4–6 days.

MMAE: 3–4 days. Elimination of MMAE apparently is limited by rate of release from the antibody-drug conjugate.

Special Populations

Sex, race, and age do not have meaningful effects on pharmacokinetics of brentuximab vedotin.

Stability

Storage

Parenteral

Powder for Injection

2–8°C in original package to protect from light.

May store reconstituted drug in vial at 2–8°C; use within 24 hours. Protect from direct sunlight until time of use. Do not freeze.

May store infusion solution at 2–8°C; use within 24 hours of reconstitution. Protect from direct sunlight until time of use. Do not freeze.

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Dextrose 5% in water

Ringer’s injection, lactated

Sodium chloride 0.9%

Actions

  • Brentuximab vedotin is an anti-CD30 antibody (a chimeric human-murine IgG1) conjugated via dipeptide bond with the microtubule inhibitor monomethyl auristatin E (MMAE). Average of 4 MMAE molecules attached to each antibody molecule.

  • The antibody-drug conjugate binds to antigen CD30 on the surface of CD30-expressing cells, the resultant complex is taken up by the cell, and MMAE is released via proteolytic cleavage. MMAE then binds to tubulin, disrupting microtubule activity and resulting in cell cycle arrest, apoptosis, and antibody-dependent cellular phagocytosis (ADCP).

Advice to Patients

  • Risk of PML. Importance of patients, family, and caregivers being alert to and immediately reporting emergence of neurologic manifestations (e.g., changes in mood or behavior, confusion, changes in thinking, memory loss, vision changes, changes in speech or walking, decreased strength or weakness on one side of the body).

  • Risk of infusion-related reactions. Importance of reporting signs and symptoms of such reactions (e.g., fever, chills, rash, breathing difficulty) that occur within 24 hours of an infusion of the drug.

  • Risk of peripheral neuropathy. Importance of informing clinician of new or worsening symptoms of peripheral neuropathy (e.g., tingling or numbness of the hands or feet, any muscle weakness).

  • Risk of neutropenia. Importance of informing clinician of fever or other signs and symptoms of infection (e.g., chills, cough, painful urination).

  • Risk of hepatotoxicity. Importance of informing clinician if signs and symptoms of liver damage (e.g., jaundice, fatigue, dark urine, abdominal pain [particularly in the right upper quadrant], lack of appetite) occur.

  • Risk of pulmonary reactions. Importance of informing clinician if signs and symptoms of pulmonary reactions (e.g., cough, dyspnea) occur.

  • Risk of acute pancreatitis. Importance of informing clinician of severe abdominal pain.

  • Risk of adverse GI effects. Importance of informing clinician if severe abdominal pain, chills, fever, nausea, vomiting, or diarrhea occurs.

  • Risk of hyperglycemia. Importance of learning how to recognize symptoms of hyperglycemia.

  • Risk of fetal harm. Necessity of advising women of reproductive potential and men who are partners of such women that they should use an effective method of contraception while receiving the antibody-drug conjugate and for ≥6 months after the last dose. Importance of women informing clinicians if they are or plan to become pregnant. Advise pregnant women of risk to the fetus.

  • Importance of advising women to avoid breast-feeding while receiving brentuximab vedotin therapy.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Brentuximab Vedotin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion only

50 mg

Adcetris

Seattle Genetics

AHFS DI Essentials™. © Copyright 2021, Selected Revisions June 1, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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