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Adcetris

Generic Name: Brentuximab Vedotin
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

Warning(s)

  • Progressive multifocal leukoencephalopathy (PML), sometimes fatal, can occur.1 (See Progressive Multifocal Leukoencephalopathy under Cautions.)

Introduction

Antineoplastic agent; an anti-CD30 antibody conjugated with a microtubule inhibitor (monomethyl auristatin E [MMAE]).1 3 4 5 10

Uses for Adcetris

Hodgkin Lymphoma

Treatment of Hodgkin lymphoma following failure of autologous stem cell transplantation (ASCT) or following failure of ≥2 multiple-agent chemotherapy regimens in patients who are not ASCT candidates1 (designated an orphan drug by FDA for treatment of this cancer13 ). Efficacy determined based on overall response rate in a noncomparative, open-label study in patients with relapsed Hodgkin lymphoma.1 6 20

Slideshow: View Frightful (But Dead Serious) Drug Side Effects

Anaplastic Large Cell Lymphoma

Treatment of systemic anaplastic large cell lymphoma (sALCL) following failure of ≥1 multiple-agent chemotherapy regimens1 (designated an orphan drug by FDA for treatment of this cancer14 ). Efficacy determined based on overall response rate in a noncomparative, open-label study in patients with relapsed sALCL.1 7 21

Adcetris Dosage and Administration

General

  • Monitor CBC prior to each dose; consider more frequent monitoring in patients with grade 3 or 4 neutropenia.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.1 (See Sensitivity Reactions under Cautions.)

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.1

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.1 Do not administer by rapid IV injection (e.g., IV push or bolus).1

Brentuximab vedotin powder for injection must be reconstituted and diluted prior to administration.1 Use within 24 hours following reconstitution.1 (See Storage under Stability.)

Do not mix with any other drug or administer any other drug simultaneously in the same IV line.1

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.1 Gently swirl vial to ensure dissolution.1 Do not shake reconstituted solution.1

Reconstituted solution should be clear to slightly opalescent, colorless, and free of visible particulates.1

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.1 Mix the diluted solution by gentle inversion.1 Discard any partially used vial.1

Rate of Administration

Administer by IV infusion over 30 minutes.1

Dosage

Adults

Hodgkin Lymphoma
IV

1.8 mg/kg every 3 weeks.1 Continue therapy for a maximum of 16 cycles or until disease progression or unacceptable toxicity occurs.1

Body weight ≤100 kg: Calculate dosage based on actual body weight.19

Body weight >100 kg: Calculate dosage based on 100 kg.1

Anaplastic Large Cell Lymphoma
IV

1.8 mg/kg every 3 weeks.1 Continue therapy for a maximum of 16 cycles or until disease progression or unacceptable toxicity occurs.1

Body weight ≤100 kg: Calculate dosage based on actual body weight.19

Body weight >100 kg: Calculate dosage based on 100 kg.1

Dosage Modification for Toxicity
Peripheral Neuropathy

If grade 2 or 3 peripheral neuropathy occurs, interrupt therapy until toxicity resolves to grade 1 or to baseline; resume therapy at reduced dosage of 1.2 mg/kg every 3 weeks.1 (See Peripheral Neuropathy under Cautions.)

If grade 4 peripheral neuropathy occurs, discontinue drug.1

Neutropenia

If grade 3 or 4 neutropenia occurs, interrupt therapy until neutropenia resolves to grade 2 or less or to baseline; upon resumption of therapy, consider use of a granulocyte colony-stimulating factor (G-CSF) for subsequent cycles.1 20

If grade 4 neutropenia recurs despite use of a G-CSF, consider drug discontinuance or dosage reduction (i.e., reduced dosage of 1.2 mg/kg every 3 weeks).1 (See Neutropenia under Cautions.)

Special Populations

No special population dosage recommendations at this time.1 (See Specific Populations under Cautions.)

Cautions for Adcetris

Contraindications

  • Concomitant use with bleomycin.1 (See Respiratory Effects under Cautions.)

Warnings/Precautions

Warnings

Progressive Multifocal Leukoencephalopathy

JC virus infection causing PML (sometimes fatal) reported;1 15 signs and symptoms may develop over several weeks or months.15 Other risk factors for PML include prior therapies and underlying disease that may cause immunosuppression.1

Consider PML in any patient with new signs or symptoms suggestive of PML.1 (See Advice to Patients.) If PML is suspected, withhold the drug and initiate diagnostic evaluation (e.g., consultation with a neurologist, brain magnetic resonance imaging [MRI] scan, lumbar puncture, brain biopsy) as clinically indicated.1 If PML is confirmed, permanently discontinue brentuximab vedotin.1

Other Warnings and Precautions

Respiratory Effects

Concomitant use with bleomycin in contraindicated; increased risk of pulmonary toxicity.1 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]).1 15 Most patients responded to corticosteroid therapy.1

Peripheral Neuropathy

Peripheral neuropathy (mainly sensory neuropathy) occurs commonly;1 median time to onset is 12.4 weeks.19

Monitor patients for manifestations of neuropathy (e.g., hypoesthesia, hyperesthesia, paresthesia, discomfort, burning sensation, neuropathic pain, weakness).1 Dosage reduction, treatment delay, or drug discontinuance may be required in patients with new or worsening symptoms.1 (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.1

Monitor for manifestations of infusion reactions during the infusion.1

If infusion-related effects occur, interrupt the infusion and initiate appropriate treatment.1 If anaphylaxis occurs, immediately and permanently discontinue brentuximab vedotin.1

If an infusion-related reaction occurs, administer premedication regimen (e.g., corticosteroid, antihistamine, and acetaminophen) before each subsequent dose.1

Neutropenia

Risk of severe, prolonged neutropenia.1

Monitor CBCs prior to each dose; consider more frequent monitoring in patients with grade 3 or 4 neutropenia.1 If grade 3 or 4 neutropenia occurs, temporary interruption of therapy, dosage reduction, or drug discontinuance may be required.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Tumor Lysis Syndrome

Possible tumor lysis syndrome following rapid lysis of malignant cells.1 Increased risk in patients with large tumor burden; closely monitor such patients and take appropriate precautions.1

Dermatologic Effects

Stevens-Johnson syndrome reported.1 Discontinue therapy and administer appropriate treatment if Stevens-Johnson syndrome occurs.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Teratogenicity, embryotoxicity, and fetotoxicity demonstrated in animals.1 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.1

Immunogenicity

Antibodies to brentuximab vedotin, including neutralizing antibodies to the drug, reported.1 Clinical relevance is not known.1 Higher incidence of infusion-related reactions observed in patients persistently positive for anti-brentuximab vedotin antibodies.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1 Insufficient experience in pediatric patients to determine whether they respond differently than adults.1

Geriatric Use

Safety and efficacy not established.1 Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1

Hepatic Impairment

Not studied in patients with hepatic impairment.1 (See Elimination under Pharmacokinetics.)

Renal Impairment

Not studied in patients with renal impairment.1 (See Elimination under Pharmacokinetics.)

Common Adverse Effects

Neutropenia,1 5 7 peripheral neuropathy,1 5 6 7 fatigue,1 5 6 7 nausea,1 5 6 7 anemia,1 upper respiratory tract infection,1 diarrhea,1 5 7 pyrexia,1 5 7 rash,1 thrombocytopenia,1 cough,1 vomiting.1

Interactions for Adcetris

MMAE (the microtubule-inhibiting component of brentuximab vedotin) is a substrate and inhibitor of CYP3A4/5.1 Does not inhibit other CYP enzymes at clinically relevant concentrations and does not induce CYP enzymes.1

MMAE is a substrate of P-glycoprotein (P-gp) and is not a potent inhibitor of P-gp.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Possible pharmacokinetic interaction (increased serum concentrations of MMAE).1 Monitor closely for adverse effects.1

Potent CYP3A4 inducers: Possible pharmacokinetic interaction (decreased serum concentrations of MMAE);1 however, clinically important effects on MMAE concentrations are not expected.19 22

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4: Pharmacokinetic interaction not observed to date.1

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.1 15

Concomitant use contraindicated.1 15

Carbamazepine

Clinically important pharmacokinetic interaction not expected19 22

Dexamethasone

Clinically important pharmacokinetic interaction not expected19 22

Ketoconazole

Increased systemic exposure of MMAE1

Monitor closely for adverse effects1

Midazolam

No change in systemic exposure of midazolam1

Phenobarbital

Clinically important pharmacokinetic interaction not expected19 22

Phenytoin

Clinically important pharmacokinetic interaction not expected19 22

Rifampin

Decreased systemic exposure of MMAE1 22

Dosage adjustment not required22

Adcetris 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.1 3 4 5 10 Peak plasma concentrations of MMAE are attained approximately 1–3 days after IV administration of brentuximab vedotin.1 5 10

AUCs of the antibody-drug conjugate and free MMAE are dose proportional over the brentuximab vedotin single-dose range of 1.2–2.7 mg/kg; minimal systemic accumulation when administered every 3 weeks.1 5 10 11 12 22

Distribution

Extent

Not known whether brentuximab vedotin is distributed into milk.1

Plasma Protein Binding

68–82%.1

Elimination

Metabolism

Small fraction of free MMAE is metabolized in the liver, primarily via oxidation by CYP3A4/5.1

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.1

Half-life

Antibody-drug conjugate: 4–6 days.1 5 10

MMAE: 3–4 days.5 10 Elimination of MMAE apparently is limited by rate of release from the antibody-drug conjugate.1

Special Populations

Gender, race, and age do not have meaningful effects on pharmacokinetics of brentuximab vedotin.1

Effect of hepatic or renal impairment on pharmacokinetics of brentuximab vedotin not elucidated.1

Stability

Storage

Parenteral

Powder for Injection

2–8°C in original package to protect from light.1

May store reconstituted drug in vial at 2–8°C; use within 24 hours.1 Protect from direct sunlight until time of use.19 Do not freeze.1

May store infusion solution at 2–8°C; use within 24 hours of reconstitution.1 Protect from direct sunlight until time of use.19 Do not freeze.1

Compatibility

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

Parenteral

Solution Compatibility

Compatible1

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).1 3 4 5 10 Average of 4 MMAE molecules attached to each antibody molecule.1 4 10

  • 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.1 4 5 10 MMAE then binds to tubulin, disrupting microtubule activity and resulting in cell cycle arrest and apoptosis.1 3 4 5 10

Advice to Patients

  • Risk of PML.1 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).1 15

  • Risk of infusion-related reactions.1 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.1

  • Risk of peripheral neuropathy.1 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).1

  • Risk of neutropenia.1 Importance of informing clinician of fever or other signs and symptoms of infection (e.g., chills, cough, painful urination).1

  • Necessity of advising women to avoid pregnancy and breast-feeding while receiving therapy.1 Importance of women informing clinicians immediately if they are pregnant.1 Advise pregnant women of risk to the fetus.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

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

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, 2004-2014, Selected Revisions September 1, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Seattle Genetics, Inc. Adcetris (brentuximab vedotin) for injection prescribing information. Bothell, WA; 2012 Jan.

3. Deutsch YE, Tadmor T, Podack ER et al. CD30: an important new target in hematologic malignancies. Leuk Lymphoma. 2011; 52:1641-54. [PubMed 21619423]

4. Katz J, Janik JE, Younes A. Brentuximab Vedotin (SGN-35). Clin Cancer Res. 2011; 17:6428-36. [PubMed 22003070]

5. Younes A, Bartlett NL, Leonard JP et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010; 363:1812-21. [PubMed 21047225]

6. Chen R, Gopal AK, Smith SE et al. Results of a pivotal phase 2 study of brentuximab vedotin (SGN-35) in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2010; 116 (American Society of Hematology Annual Meeting Abstracts):Abstract No. 283.

7. Shustov AR, Advani R, Brice P et al. Complete remissions with brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large cell lymphoma. Blood. 2010; 116 (American Society of Hematology Annual Meeting Abstracts):Abstract No. 961.

8. Matsumoto K, Terakawa M, Miura K et al. Extremely rapid and intense induction of apoptosis in human eosinophils by anti-CD30 antibody treatment in vitro. J Immunol. 2004; 172:2186-93. [PubMed 14764685]

9. Falini B, Pileri S, Pizzolo G et al. CD30 (Ki-1) molecule: a new cytokine receptor of the tumor necrosis factor receptor superfamily as a tool for diagnosis and immunotherapy. Blood. 1995; 85:1-14. [PubMed 7803786]

10. Furtado M, Rule S. Emerging pharmacotherapy for relapsed or refractory Hodgkin’s lymphoma: Focus on brentuximab vedotin. Clin Med Insights Oncol.2012; 6:31–9.

11. Anon. Brentuximab vedotin. Drugs R & D. 2011; 11:85-95.

12. Fanale M, Bartlett NL, Forero-Torres A et al. The antibody-drug conjugate brentuximab vedotin (SGN-35) induced multiple objective responses in patients with relapsed or refractory CD30-positive lymphomas in a phase 1 weekly dosing study. Blood. 2009; 114 (American Society of Hematology Annual Meeting Abstracts):Abstract No. 2731.

13. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2012 Feb 2.

14. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2012 Feb 2.

15. US Food and Drug Administration. FDA drug safety communication: New boxed warning and contraindication for Adcetris (brentuximab vedotin). Rockville, MD; 2012 Jan 13. From FDA website.

16. US Food and Drug Administration. Oncologic Drugs Advisory Committee Meeting. Bethesda, MD; 2011 Jul 14. From FDA website.

17. US Food and Drug Administration. Oncologic Drugs Advisory Committee Meeting. Bethesda, MD; 2011 Jul 14. From FDA website.

19. Seattle Genetics, Inc., Bothell, WA: Personal communication.

20. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125388Orig1s000: Medical review(s). From FDA website.

21. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125399Orig1s000: Medical review(s). From FDA website.

22. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125388Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website.

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