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Drug Monographs
Treatment Regimens

Scientific Name:
BRENTUXIMAB VEDOTIN
Brand Name(s):
Adcetris

Drug Monograph

Pharmacology

Mechanism of Action

Brentuximab is an antibody-drug conjugate (ADC) comprised by 3 components:  10 a chimeric IgGI antibody directed against human CD30; 2) the potent microtubule-disrupting agent monomethyl auristatin E (MMAE), and 3) a protease-cleavable linker that covalently attaches MMAE to cAC10. The biological activity of brentuximab vedotin results from a multi-step process. Binding of the ADC to CD30 on the cell surface initiates internalization of the ADC-CD30 complex, which then traffics to the lysosomal compartment. Within the cell, MMAE is released via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, induces cell cycle arrest, and results in apoptotic death of the CD30-expressing tumor cell.

Pharmacokinetics

ADC
Distribution
PPB: 68-82%
Vd: 6-10 L for ADC
• Minimal to no accumulation of ADC with multiple doses
Metabolism
Elimination
• Terminal half-life: 4 to 6 days.

MMAE
Distribution
PPB: MMAE is not likely to displace or to be displaced by highly protein-bound drugs.
Steady-state: within 21 days (3-week dosing)
MMAE exposures decreased with continued administration- 50% to 80% of  first doseexposure in subsequent doses.
TMax-  1 to 3 days.
Substrate of P-gp; not a potent inhibitor of P-gp.
Metabolism
Only a small fraction of MMAE released from brentuximab vedotin is metabolized.
MMAE metabolism that occurs is primarily via oxidation by CYP3A4/5
MMAE inhibits CYP3A4/5 but not other CYP isoforms
Elimination
24% of total MMAE recovered in urine and feces over a 1-week period
• 72% was recovered in the feces
• Majority of the excreted MMAE was unchanged.

Side Effects

IMMEDIATE ONSET (hours to days)
   infusion reactions (12%).  Symptoms may include: chills (4%), nausea (3%), dyspnea (3%), pruritus (3%), pyrexia (2%), and cough (2%)
* tumor lysis syndrome
* septic shock (3%)
EARLY ONSET (days to weeks)
* neutropenia (55%; 12-15% Grade 3), anemia (33-52%; 2-8% Grade 3), thromcytopenia (16-28%; 5-7% Grade 3), lymphadenopathy (10%)
   peripheral sensory neuropathy (52%; 8-10% Grade 3), peripheral motor neuropathy (7-16%)
   headache (16-19%), dizziness (11-16%), fatigue(41-49%), decreased appetite (11-16%)
   pyrexia (29-38%), chills (12-13%), general pain (7-28%), peripheral edema (4-16%)
   nausea(38-42%), vomiting (17-22%), diarrhea (29-36%), constipation (16-19%)
   rash (30%), pruritus (18%), alopecia (13%), dry skin (4-10%)
   upper respiratory tract infection (12-47%), cough (17-25%), dyspnea (13-19%), oropharyngeal pain (10%)
   arthralgia (9-19%), myalgia (17%), back pain (10-14%), muscle spasms (10%)
   insomnia (15%), anxiety (7-11%)
* pulmonary embolism (2%)
* pneumonitis (2%)
* pneumothorax (2%)
* pyelonephritis (2%)
* Stevens-Johnson syndrome

Therapeutics

Approved Indications

ADCETRIS is a CD30-directed antibody-drug conjugate indicated for:
• The treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates
• The treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen

Routes

Intravenous infusion over 30 minutes
Do not administer as an intravenous push or bolus

Administration

Intravenous infusion over 30 minutes.
Do not administer as an intravenous push or bolus.

Reconstitution
• Reconstitute each 50 mg vial with 10.5 mL of Sterile Water for Injection, USP, to yield a single-use solution containing 5 mg/mL brentuximab vedotin.
• Direct the stream toward wall of vial and not directly at the cake or powder. Gently swirl the vial to aid dissolution. DO NOT SHAKE.
• Following reconstitution, dilute immediately into an infusion bag, or store the solution at 2-8°C (36-46°F) and use within 24 hours of reconstitution.
• DO NOT FREEZE. Discard any unused portion left in the vial.
Dilution
• Calculate the required volume of 5 mg/mL reconstituted solution needed and withdraw this amount from the vials.
• Immediately add the reconstituted solution to an infusion bag containing a minimum volume of 100 mL to achieve a final concentration of 0.4 mg/mL to 1.8 mg/mL brentuximab vedotin.
• Brentuximab Vedotin can be diluted into 0.9% Sodium Chloride Injection, 5% Dextrose Injection or Lactated Ringer's Injection.
• Gently invert the bag to mix the solution. ADCETRIS contains no bacteriostatic preservatives.
• Following dilution, infuse the Brentuximab Vedotin solution immediately, or store the solution at 2-8°C (36-46°F) and use within 24 hours of reconstitution.
• DO NOT FREEZE.

IV Compatibility

Do not mix Brentuximab Vedotin with, or administer as an infusion with, other medicinal products.

Dosing

The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks.
The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg.
Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity.

Dose Adjustment Criteria

Peripheral Neuropathy: 
• For new or worsening Grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg.
• For Grade 4 peripheral neuropathy, Brentuximab Vedotin should be discontinued.
Neutropenia: 
• The dose should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower.
• Growth factor support should be considered for subsequent cycles in patients who experience Grade 3 or 4 neutropenia.
• In patients with recurrent Grade 4 neutropenia despite the use of growth factors, discontinuation or dose reduction to 1.2 mg/kg may be considered.
Thrombocytopenia:
• If Grade 3 or 4 thrombocytopenia develops, monitor closely and consider platelet transfusions or dose delays.
Severe renal insufficiency:
• The starting dose should be 1.2 mg/kg.
• Patients with severe renal impairment should be closely monitored for adverse reactions.
Hepatic insufficiency:
• The starting dose should be 1.2 mg/kg.
• Patients with hepatic impairment should be closely monitored for adverse reactions.

Contraindications

Concomitant use of Brentuximab Vedotin and Bleomycin is contraindicated due to pulmonary toxicity. Brentuximab is contraindicated for patients who have or have had progressive multifocal leukoencephalopathy (PML)

Monitoring

Significant Interactions

Bleomycin: Co-administration of Brentuximab Vedotin with Bleomycin is associated with pulmonary toxicity. Monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5. CYP3A4 Inhibitors/Inducers- MMAE is primarily metabolized by CYP3A • Co-administration of Brentuximab Vedotin with ketoconazole, a potent CYP3A4 inhibitor and P-gp inhibitor, increased exposure to MMAE by approximately 34%. Patients who are receiving strong CYP3A4 inhibitors and and P-gp inhibitors concomitantly with Brentuximab Vedotin should be closely monitored for adverse reactions. • Ingestion of grapefruit while on Brentuximab Vedotin therapy may increase MMAE plasma concentrations • Co-administration of Brentuximab Vedotin with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%. • Co-administration of Brentuximab Vedotin did not affect exposure to midazolam, a CYP3A4 substrate. MMAE does not inhibit other CYP enzymes at relevant clinical concentrations

Product Information

Commercial Product Description

Brand Name: ADCETRIS (brentuximab vedotin) for Injection single-use vial containing 50 mg of brentuximab vedotin as a sterile, white to off-white lyophilized, preservative-free cake or powder.

Pharmaceutical Considerations

ADCETRIS (brentuximab vedotin) for Injection is supplied as a single-use vial containing 50 mg of brentuximab vedotin as a sterile, white to off-white, preservative-free lyophilized cake or powder. Following reconstitution with 10.5 mL Sterile Water for Injection, USP, a solution containing 5 mg/mL brentuximab vedotin is produced. The reconstituted product contains 70 mg/mL trehalose dihydrate, 5.6 mg/mL sodium citrate dihydrate, 0.21 mg/mL citric acid monohydrate, and 0.20 mg/mL polysorbate 80 and water for injection. The pH is approximately 6.6.

Note

HANDLING RISK LEVEL:
HAZARD RISK LEVEL 2
FDA Pregnancy Risk Factor D
• This drug must be handled using precautions outlined in CCNS Policies for Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy
• Go to "Additional Information" tab (above) for links to CCNS Policies

GUIDELINES:
Hodgkin Lymphoma
pCODR Recommendation:  In patients with relapsed Hodgkin lymphoma following autologous stem cell transplant (ASCT) and who have an ECOG performance status of 0 or 1.  Not recommended for patients with Hodgkin lymphoma who are not candidtes for ASCT and who have relapsed disease following at least two prior multiagent chemotherapies.  August 29, 2013

Hodgkin Lymphoma Post ASC Transplant
pCODR Recommendation:  For post-ASCT consolidation treatment of patients with Hodgkin Lymphoma at high risk of relapse or progression.- Under review as at 6 April 2016

Anaplastic Large Cell Lymphoma (Systemic)
pCODR Recommendations: in patients with systemic anaplastic large cell lymphoma (sALCL)who have failed at least one prior multi-agent chemotherapy regimen and who have an ECOG performance status of 0 or 1.  December 5, 2013

pCODR Recommendation: Under review as at 31 Mar 2016

Visit the Pan-Canadian Oncology Drug Review website (www.pcodr.ca) for the guidelines on brentuximab for anaplastic large cell lymphoma and Hodgkin lymphoma.
• Go to "Additional Information" tab (above) for links to pCODR Reviews

SERIOUS WARNINGS:
Progressive multifocal leukoencephalopathy: JC virus infection resulting in progressive multifocal leukoencephalopathy (PML) and death can occur in Brentuximab-treated patients. Contributing factors may include prior therapies and underlying disease that may cause immunosuppression. Healthcare professionals should monitor patients on Brentuximab for any new sign or symptom that may be suggestive of PML. Further treatment with Brentuximab should be withheld immediately at the first sign or symptom suggestive of PML

Availability & Funding

Administrative Information (Nova Scotia)

CCNS Provincial Formulary Status- Intermediate Level; Indication restriction- Provincial Cancer Drug Formulary • Go to "Additional Information" tab (above) for links to Provincial Formulary of Cancer Drugs Pharmacare Formulary Status- Non-Formulary

New Cancer Drug Fund Status (Nova Scotia)

New Cancer Drug Fund (NCDF) funding approved for: Treatment of Hodgkin’s Lymphoma - As a single agent in patients with Hodgkin’s Lymphoma who have relapsed disease following autologous stem cell transplant (ASCT) and who have an ECOG performance status (PS) of 0 or 1. Treatment of Systemic Anaplastic Large Cell Lymphoma - As a single agent in patients with Systemic Anaplastic Large Cell Lymphoma who have failed at least one prior multi-agent chemotherapy regimen and who have an ECOG performance status (PS) of 0 or 1.



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