ADCETRIS

Antineoplastic Monoclonal Antibodies Targeting CD30
Antineoplastic Monoclonal Antibody-Drug Conjugates (ADCs)

Hazardous Drugs Classification
NIOSH 2016 List: Group 1
NIOSH (Draft) 2020 List: Table 1
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Emetic Risk
Low
Administer routine antiemetic prophylaxis prior to treatment.

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

Administer as an intravenous (IV) infusion only; do not administer as an IV push or bolus.
Do not mix with, or administer as an infusion with, other IV products.
Reconstitution:
Calculate the dose (mg) and the number of vials required. For patients weighing more than 100 kg, use 100 kg to calculate the dose.
Reconstitute each 50-mg vial with 10.5 mL of sterile water for injection to yield a single-use solution of 5 mg/mL.
Direct the stream of sterile water toward the wall of the vial and not directly at the cake or powder.
Gently swirl the vial to aid in dissolution; do not shake.
Discard any unused portion left in the vial.
After reconstitution, dilute immediately with 0.9% sodium chloride, 5% dextrose, or lactated ringers solution to achieve a final concentration of 0.4 mg/mL to 1.8 mg/mL.
Storage: Use the diluted solution immediately or store at 2 to 8 degrees C (36 to 46 degree F) for up to 24 hours after reconstitution. Do not freeze.
Intravenous infusion:
Infuse the IV solution over 30 minutes.

neutropenia / Delayed / 5.0-82.0
lymphopenia / Delayed / 0-44.0
anemia / Delayed / 0-36.7
thrombocytopenia / Delayed / 0-32.0
infection / Delayed / 0-11.7
peripheral neuropathy / Delayed / 0-10.0
stomatitis / Delayed / 0-10.0
diarrhea / Early / 1.0-6.0
hyperglycemia / Delayed / 6.0-6.0
hypokalemia / Delayed / 0-5.7
fatigue / Early / 0-5.0
elevated hepatic enzymes / Delayed / 0-4.0
vomiting / Early / 0-3.7
nausea / Early / 0-3.7
hyponatremia / Delayed / 0-3.4
abdominal pain / Early / 0-3.0
fever / Early / 0-3.0
weight loss / Delayed / 0-3.0
anorexia / Delayed / 0-2.7
dehydration / Delayed / 0-2.7
colitis / Delayed / 0-2.3
rash / Early / 0-2.0
pruritus / Rapid / 0-2.0
maculopapular rash / Early / 0-2.0
oral ulceration / Delayed / 0-2.0
constipation / Delayed / 0-2.0
headache / Early / 0-2.0
pulmonary embolism / Delayed / 0-2.0
dyspnea / Early / 0-2.0
pneumothorax / Early / 0-2.0
muscle cramps / Delayed / 0-2.0
back pain / Delayed / 0-2.0
myalgia / Early / 0-2.0
anxiety / Delayed / 0-2.0
asthenia / Delayed / 0-2.0
vesicular rash / Delayed / 0-1.0
cough / Delayed / 0-1.0
bone pain / Delayed / 0-1.0
arthralgia / Delayed / 0-1.0
insomnia / Early / 0-1.0
edema / Delayed / 0-1.0
tumor lysis syndrome (TLS) / Delayed / Incidence not known
progressive multifocal leukoencephalopathy / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
ileus / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
GI obstruction / Delayed / Incidence not known
peptic ulcer / Delayed / Incidence not known
enterocolitis / Delayed / Incidence not known
GI bleeding / Delayed / Incidence not known
GI perforation / Delayed / Incidence not known
acute respiratory distress syndrome (ARDS) / Early / Incidence not known
diabetic ketoacidosis / Delayed / Incidence not known
bronchospasm / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known

antibody formation / Delayed / 0-30.0
peripheral edema / Delayed / 0-16.0
lymphadenopathy / Delayed / 0-11.0
supraventricular tachycardia (SVT) / Early / 0-3.0
pneumonitis / Delayed / 0-2.0
interstitial lung disease / Delayed / 0-0.2
hyperesthesia / Delayed / Incidence not known
neuropathic pain / Delayed / Incidence not known
memory impairment / Delayed / Incidence not known
confusion / Early / Incidence not known
hyperbilirubinemia / Delayed / Incidence not known

dizziness / Early / 0-16.0
alopecia / Delayed / 0-15.0
chills / Rapid / 0-13.0
night sweats / Early / 0-12.0
xerosis / Delayed / 0-10.0
hypoesthesia / Delayed / Incidence not known
paresthesias / Delayed / Incidence not known
weakness / Early / Incidence not known

Fatal cases of progressive multifocal leukoencephalopathy (PML), caused by the John Cunningham virus (JC virus), have been reported with brentuximab therapy; some cases occurred within the first 3 months of starting therapy. Patients with prior immunosuppressive therapies or immunosuppressive disease may be at increased risk of JC virus infection and PML. Evaluate patients who develop new neurological, cognitive, or behavioral signs and symptoms such as changes in mood or behavior; confusion; memory impairment; changes in vision, speech, or walking; and/or decreased strength or weakness on one side of the body. Hold therapy if PML is suspected; discontinue brentuximab in patients with confirmed PML.

ADCETRIS

Rx

CD30-directed antibody-drug conjugate
Used for classical Hodgkin lymphoma (cHL), anaplastic large-cell lymphoma, CD30-expressing mycosis fungoides in adult patients and cHL in pediatric patients aged 2 years and older
JC virus infection resulting in progressive multifocal leukoencephalopathy and death has occurred

1.8 mg/kg IV (not to exceed 180 mg/dose) over 30 minutes every 3 weeks until disease progression. Interrupt the infusion in patients who develop anaphylaxis or other infusion-related reactions. Premedicate (e.g., acetaminophen, an antihistamine, and a corticosteroid) prior to subsequent infusions in patients who have previously experienced an infusion-related reaction. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop toxicity.[45378] In a single-arm, multinational, phase 2 study (n = 102), treatment with up to 16 doses of brentuximab vedotin (median of 9 doses) led to an objective response rate assessed by independent central review (primary endpoint) of 75% in patients who had relapsed or refractory Hodgkin lymphoma after an autologous stem cell transplant (age range, 15 to 77 years; median of 3.5 prior systemic therapies). The complete remission (CR) rate was 34% in this study. The median time to objective response was 5.7 weeks (range, 5.1 to 56 weeks); the median response duration was 6.7 months. The median time to CR was 12 weeks (range, 5.1 to 56 weeks); the median duration of CR was 20.5 months. Additionally, the median progression-free survival (PFS) time was 5.6 months; the estimated 12-month overall survival (OS) rate was 89%.[55711] Eight patients in this study (6 patients in CR and 2 patients in partial remission) subsequently received an allogeneic stem cell transplant. At a median follow-up time of 33.3 months (range, 1.8 to 57.3 months), the investigator-reported median response duration was 11.2 months, the estimated median PFS time was 9.3 months, and the estimated median OS time was 40.5 months.[59367]

1.8 mg/kg IV (not to exceed 180 mg/dose) over 30 minutes repeated every 3 weeks until disease progression or a maximum of 16 cycles; start within 4 to 6 weeks after an autologous hematopoietic stem cell transplantation (auto-HSCT) or upon recovery after an auto-HSCT. Interrupt the infusion in patients who develop anaphylaxis or other infusion-related reactions. Premedicate (e.g., acetaminophen, an antihistamine, and a corticosteroid) prior to subsequent infusions in patients who have previously experienced an infusion-related reaction. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop toxicity.[45378]

1.2 mg/kg (not to exceed 120 mg/dose) IV over 30 minutes repeated every 2 weeks until maximum of 12 doses, disease progression, or unacceptable toxicity in combination with doxorubicin 25 mg/m2 IV, vinblastine 6 mg/m2 IV, and dacarbazine 375 mg/m2 IV each given on days 1 and 15 repeated every 28 days for up to 6 cycles was evaluated in a randomized, phase 3 trial.[62863] Administer primary prophylaxis with a granulocyte colony-stimulating factor starting in cycle 1 due to the high incidence of febrile neutropenia. Interrupt the infusion in patients who develop anaphylaxis or other infusion-related reactions. Premedicate (e.g., acetaminophen, an antihistamine, and a corticosteroid) prior to subsequent infusions in patients who have previously experienced an infusion-related reaction. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop toxicity.[45378]

1.8 mg/kg (not to exceed 180 mg/dose) IV over 30 minutes repeated every 3 weeks for up to 5 doses in combination with chemotherapy. Give brentuximab vedotin on day 1 with chemotherapy consisting of doxorubicin 25 mg/m2 IV on days 1 and 2; vincristine 1.4 mg/m2 IV on day 8; etoposide 125 mg/m2 IV on days 1, 2, and 3; prednisone 20 mg/m2 PO twice daily on days 1 to 7; and cyclophosphamide 600 mg/m2 IV on days 1 and 2 (AVEPC) for up to 5 cycles. Administer primary prophylaxis with a granulocyte colony-stimulating factor starting in cycle 1 due to the high incidence of febrile neutropenia. Interrupt the infusion in patients who develop anaphylaxis or other infusion-related reactions. Premedicate (e.g., acetaminophen, an antihistamine, and a corticosteroid) prior to subsequent infusions in patients who have previously experienced an infusion-related reaction. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop toxicity. At a median follow-up time of 42.1 (range, 0.1 to 80.9) months, the 3-year event-free survival rate was significantly improved in patients (median age, 15.6 years; range, 3.4 to 21.99 years) with newly diagnosed, stage IIB with bulk tumor or stage IIIB, IVA, or IVB classic Hodgkin lymphoma who received brentuximab vedotin plus AVEPC compared with doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) (92.1% vs. 82.5%; hazard ratio (HR) = 0.41; 95% CI, 0.25 to 0.67) in a multicenter, randomized, phase 3 trial (n = 587). The 3-year overall survival rates were 99.3% and 98.5% in the brentuximab vedotin plus AVEPC and ABVE-PC arms, respectively.

1.8 mg/kg (not to exceed 180 mg/dose) IV over 30 minutes repeated every 3 weeks until disease progression. Interrupt the infusion in patients who develop anaphylaxis or other infusion-related reactions. Premedicate (e.g., acetaminophen, an antihistamine, and a corticosteroid) prior to subsequent infusions in patients who have previously experienced an infusion-related reaction. Therapy interruption, a dose reduction, or discontinuation may be necessary in patients who develop toxicity.[45378] In a single-arm, multicenter, phase 2 study (n = 58), treatment with up to 16 doses of brentuximab vedotin (median of 7 doses) led to an overall objective response rate (primary endpoint) of 86% in patients with relapsed or refractory systemic anaplastic large cell lymphoma (age range, 14 to 76 years; median of 2 prior systemic therapies). The complete remission (CR) rate was 57% in this study. The median time to objective response was 5.9 weeks (range, 4.3 to 14 weeks); the median duration of objective response was 12.6 months. The median time to CR was 11.9 weeks (range, 5.1 to 50.3 weeks); the median duration of CR was 13.2 months. Additionally, the median progression-free survival time was 13.3 months and the estimated 12-month overall survival rate was 70%. Of the 33 patients in this study who achieved a CR, 6 patients received a subsequent allogeneic stem cell transplant and 5 patients received a subsequent autologous stem cell transplant.[55707]

1.8 mg/kg (not to exceed 180 mg/dose) IV over 30 minutes repeated every 3 weeks for 6 to 8 doses in combination with chemotherapy. Chemotherapy consisted of cyclophosphamide 750 mg/m2 IV on day 1, doxorubicin 50 mg/m2 IV on day 1, and prednisone 100 mg orally daily on days 1, 2, 3, 4, and 5 (CHP) given every 21 days for 6 to 8 cycles of therapy. Interrupt the infusion in patients who develop anaphylaxis or other infusion-related reactions. Premedicate (e.g., acetaminophen, an antihistamine, and a corticosteroid) prior to subsequent infusions in patients who have previously experienced an infusion-related reaction. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop toxicity. The progression-free survival (PFS) time (evaluated via an independent review facility) was significantly improved in patients with CD30-expressing sALCL or PTCL who received brentuximab vedotin plus CHP compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (48.2 months vs. 20.8 months; hazard ratio (HR) = 0.71; 95% CI, 0.54 to 0.93) in a multicenter, randomized, double-blind, phase 3 trial (the ECHELON-2 trial; n = 452). Overall survival was also significantly improved in the brentuximab vedotin-containing arm (HR = 0.66; 95% CI, 0.46 to 0.95). In patients with sALCL (n = 314; anaplastic lymphoma kinase (ALK)-negative sALCL, 48%; ALK-positive sALCL, 22%), the PFS times were 55.7 months and 54.2 months in patients who received brentuximab vedotin plus CHP and CHOP, respectively (HR = 0.59; 95% CI, 0.42 to 0.84).[45378]

1.8 mg/kg (not to exceed 180 mg/dose) IV over 30 minutes repeated every 3 weeks until disease progression or a maximum of 16 cycles. Interrupt the infusion in patients who develop anaphylaxis or other infusion-related reactions. Premedicate (e.g., acetaminophen, antihistamine, and/or corticosteroid) prior to subsequent infusions in patients who have previously experienced an infusion-related reaction. Therapy interruption, dose reduction, and/or discontinuation may be necessary in patients who develop toxicity.

1.8 mg/kg (not to exceed 180 mg/dose) IV over 30 minutes repeated every 3 weeks for 6 to 8 doses in combination with chemotherapy. Chemotherapy consisted of cyclophosphamide 750 mg/m2 IV on day 1, doxorubicin 50 mg/m2 IV on day 1, and prednisone 100 mg orally daily on days 1, 2, 3, 4, and 5 (CHP) given every 21 days for 6 to 8 cycles of therapy. Administer primary prophylaxis with a granulocyte colony-stimulating factor starting in cycle 1. Interrupt the infusion in patients who develop anaphylaxis or other infusion-related reactions. Premedicate (e.g., acetaminophen, an antihistamine, and a corticosteroid) prior to subsequent infusions in patients who have previously experienced an infusion-related reaction. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop toxicity. The progression-free survival time (evaluated via an independent review facility) was significantly improved in patients with CD30-expressing sALCL or PTCL who received brentuximab vedotin plus CHP compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (48.2 months vs. 20.8 months; hazard ratio (HR) = 0.71; 95% CI, 0.54 to 0.93) in a multicenter, randomized, double-blind, phase 3 trial (the ECHELON-2 trial; n = 452). Overall survival was also significantly improved in the brentuximab vedotin-containing arm (HR = 0.66; 95% CI, 0.46 to 0.95). In this trial, 70% of patients had systemic ALCL and 30% of patients had PTCL (e.g., including PTCL not otherwise specified (16%), angioimmunoblastic T-cell lymphoma (12%), adult T-cell leukemia/lymphoma (2%), and enteropathy-associated T-cell lymphoma (less than 1%)).[45378]

Mild hepatic impairment (Child-Pugh A): Reduce the brentuximab vedotin dosage as followsFor recommended starting dosage of 1.8 mg/kg IV every 3 weeks: Reduce the dosage to 1.2 mg/kg IV (maximum dose, 120 mg) every 3 weeks.For recommended starting dosage of 1.2 mg/kg IV every 2 weeks: Reduce the dosage to 0.9 mg/kg IV (maximum dose, 90 mg) every 2 weeks.
Moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment: Avoid use.

Mild (creatinine clearance (CrCl), greater than 50 to 80 mL/min) or moderate (CrCl, 30 to 50 mL/min) renal impairment: No dosage adjustment is necessary.
Severe renal impairment (CrCl less than 30 mL/min): Avoid use.[45378]

Adagrasib: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with adagrasib is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased MMAE exposure by approximately 34%.
Apalutamide: (Moderate) Monitor for decreased efficacy of brentuximab if coadministration with apalutamide is necessary. Monomethyl auristatin E (MMAE) is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased MMAE exposure by approximately 46%.
Aprepitant, Fosaprepitant: (Moderate) Although aprepitant, fosaprepitant is indicated for the prophylaxis of chemotherapy-induced nausea/vomiting, use caution if brentuximab vedotin and aprepitant are used concurrently and monitor for an increase in non-emetogenic brentuximab-related adverse effects for several days after administration of a multi-day aprepitant regimen. Brentuximab is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and could theoretically increase plasma concentrations of brentuximab. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Atazanavir: (Minor) Concomitant administration of brentuximab vedotin and atazanavir may increase the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. The manufacturer suggests that potent CYP3A4 inhibitors, such as atazanavir, may alter MMAE exposure as MMAE is a CYP3A4 substrate. Monitor patients for adverse reactions.
Atazanavir; Cobicistat: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with cobicistat is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased MMAE exposure by approximately 34%. (Minor) Concomitant administration of brentuximab vedotin and atazanavir may increase the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. The manufacturer suggests that potent CYP3A4 inhibitors, such as atazanavir, may alter MMAE exposure as MMAE is a CYP3A4 substrate. Monitor patients for adverse reactions.
Bleomycin: (Contraindicated) Concomitant administration of brentuximab vedotin and bleomycin is contraindicated due to an increased risk for non-infectious pulmonary toxicities. Pulmonary toxicies are a known adverse reaction associated with bleomycin therapy. In studies of chemotherapeutic regimens containing bleomycin (without brentuximab vedotin), some degree of pulmonary toxicity occurs in up to 10% of patients; however, in one study in which bleomycin was administered in combination with brentuximab vedotin, doxorubicin, vinbalstine, and darcarbazine (ABVD), approximately 40% of patients experienced pulmonary toxicities.
Carbamazepine: (Moderate) Concomitant administration of brentuximab vedotin and carbamazepine may decrease the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. MMAE is a CYP3A4 substrate and carbamazepine is a potent CYP3A4 inducer; therefore, the efficacy of brentuximab may be reduced.
Carbidopa: (Major) There was a 5% incidence of generalized polyneuropathy during clinical trial evaluation of carbidopa; levodopa enteral suspension (Duopa). The manufacturer recommends an initial evaluation for signs and symptoms of peripheral neuropathy, and periodic monitoring for peripheral neuropathy during treatment with Duopa, particularly in patients receiving other medications that are associated with neuropathy. Peripheral neuropathy has been reported with the use of brentuximab vedotin. Brentuximab vedotin-induced peripheral neuropathy is cumulative.
Carbidopa; Levodopa: (Major) There was a 5% incidence of generalized polyneuropathy during clinical trial evaluation of carbidopa; levodopa enteral suspension (Duopa). The manufacturer recommends an initial evaluation for signs and symptoms of peripheral neuropathy, and periodic monitoring for peripheral neuropathy during treatment with Duopa, particularly in patients receiving other medications that are associated with neuropathy. Peripheral neuropathy has been reported with the use of brentuximab vedotin. Brentuximab vedotin-induced peripheral neuropathy is cumulative.
Carbidopa; Levodopa; Entacapone: (Major) There was a 5% incidence of generalized polyneuropathy during clinical trial evaluation of carbidopa; levodopa enteral suspension (Duopa). The manufacturer recommends an initial evaluation for signs and symptoms of peripheral neuropathy, and periodic monitoring for peripheral neuropathy during treatment with Duopa, particularly in patients receiving other medications that are associated with neuropathy. Peripheral neuropathy has been reported with the use of brentuximab vedotin. Brentuximab vedotin-induced peripheral neuropathy is cumulative.
Ceritinib: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with ceritinib is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased MMAE exposure by approximately 34%.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Ciprofloxacin: (Moderate) Clinical monitoring for adverse effects, such as peripheral neuropathy or gastrointestinal side effects, is recommended during coadministration of brentuximab vedotin and ciprofloxacin. Plasma concentrations of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, may be elevated when administered concurrently with ciprofloxacin. Ciprofloxacin is a CYP3A4 inhibitor, while MMAE is a CYP3A4 substrate.
Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Cobicistat: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with cobicistat is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased MMAE exposure by approximately 34%.
Darunavir: (Minor) Concomitant administration of brentuximab vedotin and darunavir may increase exposure of monomethyl auristatin E (MMAE); if concurrent administration is necessary, monitor patients for adverse reactions. MMAE is one of the 3 components released from brentuximab vedotin. MMAE is a CYP3A4 substrate; darunavir is a CYP3A4 inhibitor.
Darunavir; Cobicistat: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with cobicistat is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased MMAE exposure by approximately 34%. (Minor) Concomitant administration of brentuximab vedotin and darunavir may increase exposure of monomethyl auristatin E (MMAE); if concurrent administration is necessary, monitor patients for adverse reactions. MMAE is one of the 3 components released from brentuximab vedotin. MMAE is a CYP3A4 substrate; darunavir is a CYP3A4 inhibitor.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with cobicistat is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased MMAE exposure by approximately 34%. (Minor) Concomitant administration of brentuximab vedotin and darunavir may increase exposure of monomethyl auristatin E (MMAE); if concurrent administration is necessary, monitor patients for adverse reactions. MMAE is one of the 3 components released from brentuximab vedotin. MMAE is a CYP3A4 substrate; darunavir is a CYP3A4 inhibitor.
Delavirdine: (Minor) Concomitant administration of brentuximab vedotin and delavirdine may increase the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. The manufacturer suggests that potent CYP3A4 inhibitors, such as delavirdine, may alter MMAE exposure as MMAE is a CYP3A4 substrate. Monitor patients for adverse reactions.
Efavirenz: (Moderate) Concomitant administration of brentuximab vedotin and efavirenz may decrease the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. MMAE is a CYP3A4 substrate and efavirenz is a potent CYP3A4 inducer; therefore, the efficacy of brentuximab may be reduced.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Concomitant administration of brentuximab vedotin and efavirenz may decrease the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. MMAE is a CYP3A4 substrate and efavirenz is a potent CYP3A4 inducer; therefore, the efficacy of brentuximab may be reduced.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Concomitant administration of brentuximab vedotin and efavirenz may decrease the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. MMAE is a CYP3A4 substrate and efavirenz is a potent CYP3A4 inducer; therefore, the efficacy of brentuximab may be reduced.
Elbasvir; Grazoprevir: (Moderate) Administering brentuximab vedotin with elbasvir; grazoprevir may result in elevated brentuximab vedotin plasma concentrations. Monomethyl auristatin E (MMAE) is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with cobicistat is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased MMAE exposure by approximately 34%.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with cobicistat is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased MMAE exposure by approximately 34%.
Enzalutamide: (Moderate) Monitor for decreased efficacy of brentuximab if coadministration with enzalutamide is necessary. Monomethyl auristatin E (MMAE) is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased MMAE exposure by approximately 46%.
Fosphenytoin: (Moderate) Concomitant administration of brentuximab vedotin with phenytoin or fosphenytoin may decrease the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. MMAE is a CYP3A4 substrate and phenytoin is a potent CYP3A4 inducer; therefore, the efficacy of brentuximab may be reduced.
Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with brentuximab vedotin, a CYP3A substrate, as brentuximab vedotin toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
Indinavir: (Minor) Concomitant administration of brentuximab vedotin and indinavir may increase the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. The manufacturer suggests that potent CYP3A4 inhibitors, such as indinavir, may alter MMAE exposure as MMAE is a CYP3A4 substrate. Monitor patients for adverse reactions.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with brentuximab vedotin may result in increased serum concentrations of brentuximab. Brentuximab is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Concomitant administration of brentuximab vedotin and rifampin decreased the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, by approximately 46%. MMAE is a CYP3A4 substrate and rifampin is a potent CYP3A4 inducer; therefore, the efficacy of brentuximab may be reduced.
Isoniazid, INH; Rifampin: (Moderate) Concomitant administration of brentuximab vedotin and rifampin decreased the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, by approximately 46%. MMAE is a CYP3A4 substrate and rifampin is a potent CYP3A4 inducer; therefore, the efficacy of brentuximab may be reduced.
Itraconazole: (Moderate) Closely monitor for adverse reactions if coadminsitration of itraconazole and brentuximab vedotin is necessary. Concurrent use may result in increased exposure to monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. MMAE is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Coadminsitration of another strong inhibitor increased exposure to MMAE by approximately 34%.
Ketoconazole: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with ketoconazole is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased MMAE exposure by approximately 34%.
Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of brentuximab vedotin; monitor for potential reduction in efficacy. Brentuximab vedotin is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of brentuximab vedotin; monitor for potential reduction in efficacy. Brentuximab vedotin is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Letermovir: (Moderate) A clinically relevant increase in the plasma concentration of brentuximab vedotin may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Brentuximab vedotin is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A4 inhibitor increased exposure to a component of brentuximab vedotin (monomethyl auristatin E), by approximately 34%.
Levoketoconazole: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with ketoconazole is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased MMAE exposure by approximately 34%.
Lonafarnib: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with lonafarnib is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased MMAE exposure by approximately 34%.
Lopinavir; Ritonavir: (Minor) Concomitant administration of brentuximab vedotin and ritonavir may increase the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. The manufacturer suggests that potent CYP3A4 inhibitors, such as ritonavir, may alter MMAE exposure as MMAE is a CYP3A4 substrate. Monitor patients for adverse reactions.
Mitotane: (Major) Concomitant use of mitotane with brentuximab vedotin should be undertaken with caution as it could result in decreased plasma concentrations of brentuximab, leading to reduced efficacy. Mitotane is a strong CYP3A4 inducer and monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of MMAE. Concomitant administration of brentuximab vedotin and rifampin, another strong CYP3A4 substrate, decreased the exposure of MMAE by approximately 46%.
Nirmatrelvir; Ritonavir: (Minor) Concomitant administration of brentuximab vedotin and ritonavir may increase the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. The manufacturer suggests that potent CYP3A4 inhibitors, such as ritonavir, may alter MMAE exposure as MMAE is a CYP3A4 substrate. Monitor patients for adverse reactions.
Phenobarbital: (Moderate) Concomitant administration of brentuximab vedotin and phenobarbital may decrease the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. MMAE is a CYP3A4 substrate and phenobarbital is a potent CYP3A4 inducer; therefore, the efficacy of brentuximab may be reduced.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Concomitant administration of brentuximab vedotin and phenobarbital may decrease the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. MMAE is a CYP3A4 substrate and phenobarbital is a potent CYP3A4 inducer; therefore, the efficacy of brentuximab may be reduced.
Phenytoin: (Moderate) Concomitant administration of brentuximab vedotin with phenytoin or fosphenytoin may decrease the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. MMAE is a CYP3A4 substrate and phenytoin is a potent CYP3A4 inducer; therefore, the efficacy of brentuximab may be reduced.
Primidone: (Moderate) Concomitant administration of brentuximab vedotin and primidone may decrease the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. MMAE is a CYP3A4 substrate and primidone is a potent CYP3A4 inducer; therefore, the efficacy of brentuximab may be reduced.
Ranolazine: (Minor) Concomitant administration of brentuximab vedotin and ranolazine, a P-glycoprotein inhibitor, may increase exposure of monomethyl auristatin E (MMAE), a P-glycoprotein substrate. MMAE is one of the 3 components released from brentuximab vedotin. If co-administration is necessary, monitor patients for adverse reactions.
Ribociclib: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with ribociclib is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate and ribociclib is a strong CYp3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased MMAE exposure by approximately 34%.
Ribociclib; Letrozole: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with ribociclib is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate and ribociclib is a strong CYp3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased MMAE exposure by approximately 34%.
Rifampin: (Moderate) Concomitant administration of brentuximab vedotin and rifampin decreased the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, by approximately 46%. MMAE is a CYP3A4 substrate and rifampin is a potent CYP3A4 inducer; therefore, the efficacy of brentuximab may be reduced.
Rifapentine: (Moderate) Monitor for decreased efficacy of brentuximab if coadministration with rifapentine is necessary. Monomethyl auristatin E (MMAE) is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased MMAE exposure by approximately 46%.
Ritonavir: (Minor) Concomitant administration of brentuximab vedotin and ritonavir may increase the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. The manufacturer suggests that potent CYP3A4 inhibitors, such as ritonavir, may alter MMAE exposure as MMAE is a CYP3A4 substrate. Monitor patients for adverse reactions.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
St. John's Wort, Hypericum perforatum: (Minor) Concomitant administration of brentuximab vedotin and potent CYP3A4 inducers, like St. John's wort, Hypericum perforatum may decrease the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. MMAE is a CYP3A4 substrate and St. John's wort, Hypericum perforatum is a potent CYP3A4 inducer. It may be advisable for patients to avoid St. John's wort when receiving brentuximab vedotin treatment.
Tipranavir: (Minor) Concomitant administration of brentuximab vedotin and tipranavir may increase the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. The manufacturer suggests that potent CYP3A4 inhibitors, such as tipranavir, may alter MMAE exposure as MMAE is a CYP3A4 substrate. Monitor patients for adverse reactions.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Tucatinib: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with tucatinib is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased MMAE exposure by approximately 34%.
Voriconazole: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with voriconazole is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased MMAE exposure by approximately 34%.

ADCETRIS Intravenous Inj Pwd F/Sol: 50mg

180 mg IV every 3 weeks or 120 mg IV every 2 weeks.

180 mg IV every 3 weeks or 120 mg IV every 2 weeks.

1.8 mg/kg (maximum of 180 mg) IV every 3 weeks.

2 years and older: 1.8 mg/kg (maximum of 180 mg) IV every 3 weeks.Less than 2 years: Safety and efficacy have not been established.

Safety and efficacy have not been established.

Brentuximab vedotin is a CD30-directed antibody-drug conjugate (ADC) consisting of 3 components including the chimeric IgG1 antibody cAC10, specific for human CD30; the microtubule disrupting agent monomethyl auristatin E (MMAE); and a protease-cleavable linker that covalently attaches MMAE to cAC10. CD30 is expressed on the surface of Hodgkin's Reed-Sternberg (HRS) cells and cells in anaplastic large-cell lymphomas (ALCLs), embryonal carcinomas, and select subtypes of B-cell derived, non-Hodgkin's lymphomas and mature T-cell lymphomas.
Nonclinical data suggest that the anticancer activity of brentuximab vedotin is due to the binding of the ADC to CD30-expressing cells, followed by the internalization and transportation of the ADC-CD30 complex to lysosomes, and the release of MMAE via selective proteolytic cleavage. MMAE binds to tubulin and disrupts the microtubule network within the cell, inducing cell cycle arrest and apoptotic death of the cells. In vitro, antibody-dependent cellular phagocytosis has been demonstrated.

Brentuximab vedotin is administered intravenously. It is a CD30-directed antibody-drug conjugate (ADC) consisting of 3 components including the chimeric IgG1 antibody cAC10, specific for human CD30; the microtubule disrupting agent monomethyl auristatin E (MMAE); and a protease-cleavable linker that covalently attaches MMAE to cAC10. In studies, the pharmacokinetics of the ADC, MMAE, and the total antibody were evaluated. Total antibody had the greatest exposure and had similar pharmacokinetic parameters as the ADC. The protein binding of MMAE ranges from 68% to 82% in vitro. MMAE is not likely to displace or be displaced by highly protein-bound drugs. In humans, the mean steady-state volume of distribution for the ADC is approximately 6 to 10 L. MMAE appears to follow metabolite kinetics with the elimination of MMAE appearing to be limited by its rate of release from the ADC. Following a single dose of 1.8 mg/kg IV, approximately 24% of the total MMAE administered as part of the ACD during the infusion was recovered in both the urine and feces over a 1-week period. Of the recovered MMAE, approximately 72% was recovered in the feces and the majority of the excreted MMAE was unchanged. The terminal half-life of the ADC is approximately 4 to 6 days and the terminal half-life of MMAE is approximately 3 to 4 days.[45378] [45385]
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4/5, P-gp
Only a small fraction of MMAE released from brentuximab vedotin is metabolized. In vitro data show that MMAE is a substrate and an inhibitor of CYP3A4/5 and a P-glycoprotein (P-gp) substrate. Potent inhibitors or inducers of CYP3A4 may alter MMAE exposure. In vivo, MMAE did not affect exposure to midazolam, a CYP3A4 substrate.[45378]

After IV administration, maximum concentrations of the brentuximab vedotin antibody-drug conjugate (ADC) are typically observed at the end of the infusion with a multi-exponential decline in ADC concentrations. Exposures were approximately dose proportional over a range of 1.2 to 2.7 mg/kg. The single-dose Cmax for the ADC was 31.09 mcg/mL (coefficient of variation (CV), 29%) after a 1.8 mg/kg dose and 45.01 mcg/mL (CV, 16%) after a 2.7 mg/kg dose in a dose-escalation study. The single-dose, 21-day AUC after a 1.8 mg/kg dose was 76.65 mcg X days/mL (CV, 31%) and was 116.94 mcg X days/mL (CV, 20%) after a 2.7 mg/kg dose. After IV administration, the time to maximum concentration for monomethyl auristatin E (MMAE) ranged from approximately 1 to 3 days. The single-dose Cmax for MMAE was 0.005 mcg/mL (CV, 43%) after a 1.8 mg/kg dose and 0.007 mcg/mL (CV, 44%) after a 2.7 mg/kg dose in a dose-escalation study. The single-dose, 21-day AUC after a 1.8 mg/kg dose was 0.036 mcg X days/mL (CV, 47%) and was 0.051 mcg X days/mL (CV, 39%) after a 2.7 mg/kg dose. The steady-state values of ADC and MMAE were achieved within 21 days following brentuximab vedotin 1.8 mg/kg IV given every 3 weeks (with minimal to no ADC accumulation) and within 56 days following brentuximab vedotin 1.2 mg/kg IV given every 2 weeks (with 1.27-fold ADC accumulation). MMAE exposures decreased with continued administration of brentuximab vedotin with approximately 50% to 80% of the exposure of the first dose being observed at subsequent doses.[45378] [45385]

Brentuximab vedotin may cause fetal harm if administered during pregnancy based on its mechanism of action and data from animal studies. Patients of reproductive potential should be advised to use effective contraception while receiving brentuximab vedotin. Apprise patients who are or become pregnant of the potential hazard to the fetus. In animal studies, embryo-fetal toxicities including congenital malformations were observed at brentuximab doses that resulted in maternal exposures that were similar to human exposures at the recommended dose.

Counsel patients about the reproductive risk and contraception requirements during brentuximab vedotin treatment. Pregnancy testing should be performed prior to starting brentuximab in patients of reproductive potential. These patients should use effective contraception during and for 2 months after brentuximab vedotin therapy. Women who become pregnant while receiving brentuximab vedotin should be apprised of the potential hazard to the fetus. Additionally, patients who have a partner of reproductive potential should use effective contraception during and for 4 months after therapy due to the risk of male-mediated teratogenicity. Based on animal studies, brentuximab vedotin may cause infertility in males or females; the effect on fertility appears to be reversible in females.