Brentuximab vedotin is an antibody-drug conjugate that targets CD30, a protein expressed on the surface of certain cancer cells. It is indicated for the treatment of classical Hodgkin lymphoma (cHL), systemic anaplastic large-cell lymphoma or other CD30-expressing peripheral T-cell lymphomas, primary cutaneous anaplastic large-cell lymphoma, and CD30-expressing mycosis fungoides in adult patients. It is also indicated for the treatment of cHL in pediatric patients aged 2 years and older. JC virus infection resulting in progressive multifocal leukoencephalopathy and death has been reported in patients who received brentuximab vedotin therapy.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
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.
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-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.
Peripheral neuropathy has been reported in 20% to 67% of brentuximab vedotin-treated adult patients in clinical trials. Brentuximab vedotin-induced neuropathy is cumulative. Monitor patients for symptoms of neuropathy (e.g., hypoesthesia, hyperesthesia, paresthesias, discomfort, burning sensation, neuropathic pain, or weakness). Therapy interruption, dosage reduction, or discontinuation may be necessary in patients who develop new or worsening peripheral neuropathy. Sensory peripheral neuropathy (45% to 56%; grade 3, 5% to 10%) and motor peripheral neuropathy (23% or less; grade 3, 6% or less) have been reported in adult patients who received single-agent brentuximab vedotin in clinical trials. Peripheral sensory (65%; grade 3 or 4, 10%) and motor (11%; grade 3, 2%) neuropathy occurred in adult patients with previously untreated classical Hodgkin lymphoma (cHL) who received brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine (n = 662) in a randomized trial. Additionally, peripheral neuropathy occurred in 52% (grade 3 or 4, 3%) of adult patients with previously untreated, CD30-positive peripheral T-cell lymphoma who received brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (n = 223) in a randomized trial. In clinical trials, the time to neuropathy onset ranged from 0 to 12 months and the time to improvement or resolution of neuropathy ranged from 0 to 67 months. Peripheral neuropathy was reported in 20% (grade 3, 7%; grade 4, less than 1%) of pediatric patients with cHL who received brentuximab vedotin plus chemotherapy (n = 296) in a randomized trial; most patients (81%) experienced sensory neuropathy.
Hematologic toxicity has been reported in brentuximab vedotin-treated patients. Obtain complete blood counts prior to each brentuximab dose and more frequently if grade 3 or 4 neutropenia occurs; monitor all patients for signs of febrile illness. Therapy interruption, dosage reduction, or discontinuation may be necessary in patients who develop grade 3 or 4 neutropenia; consider the addition of prophylactic granulocyte-colony stimulating factor (G-CSF) with subsequent doses. Administer G-CSF starting with cycle 1 in patients receiving brentuximab vedotin in combination with chemotherapy. Anemia (single-agent, 27% to 52%; with chemotherapy, 87% or less), neutropenia (single-agent, 54% to 78%; with chemotherapy, 91% or less), thrombocytopenia (41% or less) has been reported in brentuximab vedotin-treated adult patients in clinical trials. Neutropenia may be prolonged (lasting 1 week or longer). Additionally, febrile neutropenia was reported with brentuximab therapy in 19% of patients who received brentuximab in combination with chemotherapy and in postmarketing surveillance. Anemia (27% to 62%; grade 3 or 4, 10% or less), neutropenia (21% to 78%; grade 3 or 4, 5% to 39%), thrombocytopenia (41% or less; grade 3 or 4, 10% or less), and lymphadenopathy (11% or less) were reported in adult patients who received single-agent brentuximab vedotin in clinical trials. Anemia (98%; grade 3 or 4, 11%) and neutropenia (91%; grade 3 or 4, 82%) occurred in adult patients with previously untreated classical Hodgkin lymphoma (cHL) who received brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine (n = 662) in a randomized trial. Additionally, anemia (66%; grade 3 or 4, 13%), neutropenia (59%; grade 3 or 4, 39%), thrombocytopenia (17%; grade 3 or 4, 6%), and lymphopenia (51%; grade 3 or 4, 19%) occurred in adult patients with previously untreated, CD30-positive peripheral T-cell lymphoma who received brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (n = 223) in a randomized trial. Severe anemia (grade 3, 35%; grade 4, 1.7%), febrile neutropenia (grade 3, 28%; grade 4, 3.4%), lymphopenia (grade 3, 13%; grade 4, 11%), thrombocytopenia (grade 3, 10%; grade 4, 22%), and neutropenia (grade 3, 8%; grade 4, 43%) were reported in pediatric patients with cHL who received brentuximab vedotin plus chemotherapy (n = 296) in a randomized trial.
Tumor lysis syndrome (TLS) was reported in postmarketing surveillance of brentuximab and in patients with Hodgkin lymphoma and systemic anaplastic large-cell lymphoma who received brentuximab vedotin in clinical trials. Monitor patients for signs of TLS (e.g., serum electrolytes, uric acid, serum creatinine) prior to and during therapy; institute appropriate prophylactic and treatment (e.g., hydration, uric acid lowering therapy) as necessary.
Fatal cases of progressive multifocal leukoencephalopathy (PML), caused by the John Cunningham virus (JC virus), have been reported in postmarketing surveillance of brentuximab; some cases occurred within the first 3 months of starting therapy. 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.
Serious dermatologic reactions including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) have been reported in clinical trials or postmarketing surveillance of brentuximab. If SJS or TEN occur, discontinue therapy and administer appropriate medical treatment. Rash (31% or less; grade 3 or 4, 2% or less), pruritus (19% or less), and alopecia (single-agent, 15% or less; with chemotherapy, 26% or less) were reported in brentuximab vedotin-treated patients in clinical trials. The term rash included maculopapular rash and/or vesicular rash in some trials. Night sweats were reported in 12% of patients with relapsed Hodgkin lymphoma who received brentuximab vedotin after an autologous hematopoietic stem-cell transplant in a single-arm trial (n = 102). Xerosis/dry skin occurred in 10% of patients with relapsed systemic anaplastic large cell lymphoma who received brentuximab vedotin in a single-arm trial (n = 58).
Gastrointestinal (GI) adverse events including constipation (42% or less; grade 3 or 4, 2% or less), vomiting (16% to 33%; grade 3 or 4, 3% or less), diarrhea (20% to 38%; grade 3 or 4, 1% to 6%), abdominal pain (25% or less; grade 3 or 4, 3% or less), anorexia (11% to 18%; grade 3 or 4, 2% or less), and nausea (46% or less; grade 3 or 4, 3% or less) have been reported in brentuximab vedotin-treated patients in clinical trials. In postmarketing surveillance of brentuximab vedotin, pancreatitis and serious GI complications including GI perforation, GI bleeding, GI erosion, peptic ulcer disease, GI obstruction, neutropenic colitis, enterocolitis, and ileus have been reported; some cases resulted in death. Promptly evaluate and treat GI complications in patients who develop new or worsening GI symptoms. Patients with severe abdominal pain should be evaluated for pancreatitis. Stomatitis occurred in 21% (grade 3, 2%) of patients with previously untreated classical Hodgkin lymphoma (cHL) who received brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (n = 662) in a randomized trial. Mucositis/oral ulceration occurred in 30% (grade 3 or 4, 2%) of patients with previously untreated, CD30-positive peripheral T-cell lymphoma who received brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (n = 223) in a randomized trial. Severe stomatitis (grade 3, 10%), nausea (grade 3, 3.7%), vomiting (grade 3, 3.7%), diarrhea (grade 3, 2.4%), colitis (grade 3, 2%; grade 4, 0.3%), and decreased appetite/anorexia (grade 3, 2.7%) were reported in pediatric patients with cHL who received brentuximab vedotin plus chemotherapy (n = 296) in a randomized trial.
Headache (19% or less; grade 3 or 4, 2% or less) and dizziness (16% or less) were reported in brentuximab vedotin-treated patients in clinical trials.
Fever (17% to 38%; grade 3 or 4, 3% or less) and chills (13% or less) were reported in brentuximab vedotin-treated patients in clinical trials.
Infection including upper respiratory tract infection (47% or less; grade 3, less than 1%) and pneumonia (5% or less) occurred in patients who received brentuximab vedotin in clinical trials. Closely monitor patients during treatment for signs and symptoms of bacterial, fungal, or viral infections. In postmarketing surveillance, opportunistic infection and other serious infections including pneumonia, bacteremia, and sepsis/septic shock (some cases fatal) were reported in patients who received brentuximab vedotin. Pyelonephritis occurred in 2% of adult patients with classical Hodgkin lymphoma (cHL) who relapsed after an autologous hematopoietic stem-cell transplant in a single-arm trial (n = 102). Septic shock (3%) and urinary tract infection (3%) occurred in adult patients with relapsed systemic anaplastic large cell lymphoma in a single-arm trial (n = 58). Cellulitis was reported in 3% of adult patients with relapsed primary cutaneous systemic anaplastic large cell lymphoma or CD30-expressing mycosis fungoides who received brentuximab vedotin (n = 66) in a randomized trial. Sepsis occurred in 3% of adult patients with previously untreated, CD30-positive peripheral T-cell lymphoma who received brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (n = 223) in a randomized trial. Severe infection (grade 3, 9%; grade 4, 2.7%) was reported in pediatric patients with cHL who received brentuximab vedotin plus chemotherapy (n = 296) in a randomized trial.
Pulmonary toxicity including cough (25% or less; grade 3, less than 1%) and dyspnea (11% to 19%; grade 3, 2% or less) has been reported in patients who received brentuximab vedotin in clinical trials. In postmarketing surveillance, noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS) (some cases fatal) was reported in patients who received brentuximab vedotin. Monitor patients for signs and symptoms of pulmonary toxicity. Evaluate patients who develop new or worsening pulmonary symptoms; hold brentuximab until symptoms improve. Oropharyngeal pain (11%), pulmonary embolism (2%), pneumonitis (2%), and pneumothorax (2%) were reported in patients with relapsed Hodgkin lymphoma (HL) who received brentuximab vedotin after an autologous hematopoietic stem-cell transplant in a single-arm trial (n = 102). Noninfectious pulmonary toxicity occurred in 2% of patients with previously untreated HL who received brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (n = 662) in a randomized trial. Noninfectious pulmonary toxicity events included lung infiltration (0.9%), pneumonitis (0.9%), and interstitial lung disease (0.15%) in this trial. Additionally, pneumonitis occurred in 2% of patients with previously untreated, CD30-positive peripheral T-cell lymphoma who received brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (n = 223) in a randomized trial.
Musculoskeletal adverse events including arthralgia (19% or less; grade 3, 1% or less), back pain (14% or less; grade 3, 2% or less) and myalgia (17% or less; grade 3, 2% or less) have been reported in patients who received brentuximab vedotin in clinical trials. Pain (28%; grade 4, 5%), muscle cramps/spasms (10%; grade 3, 2%), and extremity pain (10%; grade 3, 4%) occurred in patients with relapsed systemic anaplastic large cell lymphoma who received brentuximab vedotin in a single-arm trial (n = 58). Muscle cramps/spasm occurred in 11% of Hodgkin lymphoma (HL) patients who received consolidation therapy with brentuximab vedotin (n = 167) following an autologous hematopoietic stem-cell transplant (HSCT). Extremity pain was reported in 10% of patients with relapsed HL who received brentuximab vedotin after an autologous HSCT in a single-arm trial (n = 102). Bone pain (19%; grade 3, less than 1%) occurred in 19% of patients with previously untreated HL who received brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (n = 662) in a randomized trial; grade 3 bone pain was reported in less than 1% of patients.
Weight loss was reported in 22% or less of patients who received brentuximab vedotin in clinical trials; grade 3 weight loss occurred in 3% or less of patients.
Supraventricular arrhythmia/supraventricular tachycardia (SVT) was reported in 3% of patients with relapsed systemic anaplastic large-cell lymphoma who received brentuximab vedotin in a single-arm trial (n = 58).
Antibody formation has been reported in patients with Hodgkin lymphoma (n = 102) and systemic anaplastic large-cell lymphoma (n = 58) who received brentuximab vedotin in single-arm trials. Antibody testing (using an electrochemiluminescent immunoassay) demonstrated that about 7% of patients had persistently positive antibodies (defined as a positive test at more than 2 time points) and 30% of patients had transiently positive antibodies (defined as positive in 1 or 2 post-baseline time points). The antibodies were directed against the antibody component of brentuximab vedotin in all of these patients. Infusion-related reactions occurred more often in patients who developed persistently positive antibodies. Additionally, an infusion reaction that led to treatment discontinuation occurred in 2 patients who had persistently positive antibodies. Of the 58 patients with transiently or persistently positive antibodies, 62% of these patients tested positive at least once for the presence of neutralizing antibodies. No anti-brentuximab vedotin antibodies were present in 26 evaluable pediatric patients with cHL who received brentuximab vedotin plus chemotherapy in a randomized trial.
Serious events of hyperglycemia, such as new-onset hyperglycemia, exacerbation of pre-existing diabetes mellitus, and sometimes fatal diabetic ketoacidosis have been reported in brentuximab-treated patients. Administer antihyperglycemic medications as clinically indicated if hyperglycemia develops. In monotherapy studies, 8% of patients experienced any grade hyperglycemia, with 6% experiencing Grade 3 or 4 hyperglycemia. Median time to hyperglycemia was 1 month (range: 0 to 10 months).
Hepatotoxicity (e.g., hepatocellular injury, elevated hepatic enzymes, and hyperbilirubinemia) has been reported in patients who received brentuximab vedotin in combination with chemotherapy and in postmarketing surveillance of brentuximab. Some cases occurred after the first dose or upon a drug rechallenge; hepatotoxicity-related death has been reported. Monitor liver function tests (LFTs), including bilirubin, before and during therapy. Therapy interruption, dosage reduction, or discontinuation may be necessary in patients who develop new, worsening, or recurrent hepatotoxicity. Increased ALT level occurred in 10% (grade 3, 3%) of adult patients with previously untreated classical Hodgkin lymphoma (cHL) who received brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine (n = 662) in a randomized trial. Severe increased ALT level (grade 3, 3.7%; grade 4, 0.3%) was reported in pediatric patients with cHL who received brentuximab vedotin plus chemotherapy (n = 296) in a randomized trial.
Insomnia was reported in 19% or less of patients who received brentuximab vedotin in clinical trials; grade 3 insomnia occurred in less than 1% of patients. Anxiety occurred in 11% of patients with relapsed Hodgkin lymphoma who received brentuximab vedotin after an autologous hematopoietic stem-cell transplant in a single-arm trial (n = 102); grade 3 anxiety was reported in 2% of patients.
Fatigue occurred in 49% or less of patients who received brentuximab in clinical trials; grade 3 or 4 fatigue was reported in 5% or less of patients. Asthenia (11%; grade 3, 2%) was reported in 11% of patients with relapsed primary cutaneous anaplastic large-cell lymphoma or CD30-expressing mycosis fungoides who received brentuximab vedotin (n = 66) in a randomized trial; grade 3 asthenia occurred in 2% of patients. Fatigue/asthenia occurred in 35% of patients with previously untreated, CD30-positive peripheral T-cell lymphoma who received brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (n = 223) in a randomized trial; grade 3 fatigue/asthenia was reported in 2% of patients.
Edema occurred in 15% of patients with previously untreated, CD30-positive peripheral T-cell lymphoma who received brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (n = 223) in a randomized trial; grade 3 edema was reported in less than 1% of patients. Peripheral edema occurred in 16% of patients with relapsed systemic anaplastic large-cell lymphoma (ALCL) who received brentuximab vedotin in a single-arm trial (n = 58) and in 11% of patients with relapsed primary cutaneous ALCL or CD30-expressing mycosis fungoides who received brentuximab vedotin (n = 66) in a randomized trial.
Infusion-related reactions were reported in 4% to 13% (grade 3, 1% or less) of adult patients who received brentuximab vedotin in clinical trials. Anaphylactoid reactions have also been reported. Monitor patients close for symptoms of a reaction during the brentuximab infusion. Immediately and permanently discontinue therapy if anaphylaxis occurs. Stop the infusion and institute appropriate medical management in patients who develop an infusion-related reaction. Premedicate (e.g., acetaminophen, antihistamine, and/or corticosteroid) prior to subsequent infusions in patients who have previously experienced an infusion-related reaction. Severe infusion-related reactions (grade 3, 3%; grade 4, 1%) including anaphylactoid reactions, hypersensitivity, and bronchospasm occurred in pediatric patients with classical Hodgkin lymphoma (cHL) who received brentuximab vedotin plus chemotherapy (n = 296) in a randomized trial. In brentuximab vedotin monotherapy studies, infusion-related adverse reactions included chills (4%), nausea (3% to 4%), dyspnea (2% to 3%), pruritus (2% to 5%), fever (2%), and cough (2%). Nausea was the most common infusion reaction (2%) in patients with previously untreated cHL who received brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (n = 662) in a randomized trial.
Hypokalemia occurred in 12% (grade 3, 4%) of patients with previously untreated, CD30-positive peripheral T-cell lymphoma who received brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (n = 223) in a randomized trial. Severe hypokalemia (grade 3, 5%; grade 4, 0.7%) and hyponatremia (grade 3, 3.4%) were reported in pediatric patients with classical Hodgkin lymphoma who received brentuximab vedotin plus doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (n = 296) in a randomized trial.
Severe dehydration (grade 3, 2.7%) was reported in pediatric patients with classical Hodgkin lymphoma who received brentuximab vedotin plus doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (n = 296) in a randomized trial.
Severe noninfectious pulmonary toxicity (e.g., pneumonitis, interstitial pulmonary disease, acute respiratory distress syndrome) has been reported with brentuximab therapy; some cases were fatal. Monitor patients for signs and symptoms of pulmonary toxicity such as cough and dyspnea. Evaluate patients who develop new or worsening pulmonary symptoms; hold brentuximab until symptoms improve. The concomitant use of brentuximab with bleomycin-containing chemotherapy (off-label), such as ABVD (adriamycin, bleomycin, vinblastine, dacarbazine), is contraindicated due to an increased risk of noninfectious pulmonary toxicity. Interstitial infiltration and/or inflammation (found on chest X-ray or computed tomographic imaging) occurred more often in Hodgkin lymphoma patients who received brentuximab plus ABVD in a clinical trial compared with historical control patients who received ABVD alone. Most cases resolved following corticosteroid treatment.
Peripheral neuropathy, primarily sensory neuropathy, has been reported with brentuximab vedotin therapy; peripheral neuropathy is cumulative. Monitor patients for symptoms of neuropathy (e.g., hypoesthesia, hyperesthesia, paresthesia, discomfort, burning sensation, neuropathic pain, or weakness). Therapy interruption, dosage reduction, or discontinuation may be necessary in patients who develop new or worsening peripheral neuropathy.
Severe hematologic toxicities (e.g., anemia, thrombocytopenia, neutropenia) and fatal and serious cases of febrile neutropenia have been reported with brentuximab vedotin therapy; neutropenia may be prolonged (lasting 1 week or longer). Geriatric patients aged 65 years and older who received brentuximab vedotin in combination with chemotherapy experienced higher rates of febrile neutropenia compared with younger patients in clinical trials. Obtain complete blood counts prior to each brentuximab dose and more frequently if grade 3 or 4 neutropenia occurs; monitor all patients for fever. Therapy interruption, dosage reduction, or discontinuation may be necessary in patients who develop grade 3 or 4 neutropenia; consider the addition of prophylactic granulocyte-colony stimulating factor (G-CSF) with subsequent doses. Administer G-CSF starting with cycle 1 in patients receiving brentuximab vedotin in combination with chemotherapy for the treatment of previously untreated classical Hodgkin lymphoma (adult and pediatric patients) or peripheral T-cell lymphoma.
Tumor lysis syndrome (TLS) has been reported in patients who received brentuximab vedotin. Patients with rapidly proliferating tumors and/or a high tumor burden may have an increased risk of developing TLS. Monitor patients for signs of TLS (e.g., serum electrolytes, uric acid, serum creatinine) prior to and during therapy; institute appropriate prophylactic and treatment (e.g., hydration, uric acid lowering therapy) as necessary.
Opportunistic infections and other serious infections, including pneumonia, bacteremia, and sepsis (some cases fatal), have been reported with brentuximab vedotin therapy. Closely monitor patients during treatment for signs and symptoms of bacterial, fungal, or viral infection.
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.
Avoid the use of brentuximab vedotin in patients with severe renal impairment (creatinine clearance (CrCl) less than 30 mL/min). The incidence of grade 3 or higher adverse events and death was higher in patients with severe renal impairment compared with patients with normal renal function (CrCl greater than 80 mL/min) in a small, single-dose pharmacokinetic study.
Avoid the use of brentuximab vedotin in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic disease/impairment; a reduced starting dose is recommended in patients with mild hepatic impairment (Child-Pugh A). The incidence of grade 3 or higher adverse events and death was higher in patients with moderate or severe hepatic impairment compared with patients with normal hepatic function in a small, single-dose pharmacokinetic study. Hepatotoxicity (e.g., hepatocellular injury, elevated hepatic enzymes, and hyperbilirubinemia) has been reported with brentuximab vedotin therapy. Some cases occurred after the first dose or upon a drug rechallenge; hepatotoxicity-related death has been reported. Monitor liver function tests (LFTs), including bilirubin, before and during therapy. Therapy interruption, dosage reduction, or discontinuation may be necessary in patients who develop new, worsening, or recurrent hepatotoxicity. Patients with pre-existing hepatic disease or elevated LFTs at baseline and patients who are receiving concomitant medications may be at increased risk for developing hepatotoxicity.
Infusion-related reactions including anaphylaxis have been reported with brentuximab vedotin therapy; therefore, monitor patients close for symptoms of a reaction during the brentuximab infusion. Immediately and permanently discontinue therapy if anaphylaxis occurs. Stop the infusion and institute appropriate medical management in patients who develop an infusion-related reaction. Premedicate (e.g., acetaminophen, an antihistamine, and a corticosteroid) prior to subsequent infusions in patients who have previously experienced an infusion-related reaction.
Serious gastrointestinal (GI) complications including GI perforation, GI bleeding, GI erosion, peptic ulcer disease, GI obstruction, neutropenic colitis, enterocolitis, and ileus have been reported with brentuximab vedotin therapy; some cases resulted in death. Promptly evaluate and treat GI complications in patients who develop new or worsening GI symptoms. Use brentuximab with caution in patients with a history of GI disease. Patients who have a history of lymphoma with GI involvement may be at increased risk of GI perforation.
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.
No information is available regarding the presence of brentuximab vedotin in human milk, the effects on the breastfed infant, or the effects on milk production. Due to the potential for serious adverse reactions in the nursing infant (e.g., cytopenias and neurologic or gastrointestinal toxicities), breast-feeding is not recommended during brentuximab therapy.
Serious events of hyperglycemia, such as new-onset hyperglycemia, exacerbation of pre-existing diabetes mellitus, and sometimes fatal ketoacidosis have been reported in brentuximab-treated patients. Monitor serum glucose; if hyperglycemia develops, administer antihyperglycemic medications as clinically indicated. In monotherapy studies, median time to hyperglycemia was 1 month (range: 0 to 10 months). Hyperglycemia occurred more often in patients with high body mass index (e.g., obesity) or diabetes.
For the treatment of classical Hodgkin lymphoma:
NOTE: Brentuximab has been designated an orphan drug by the FDA for this indication.
-after failure of autologous hematopoietic stem cell transplant (auto-HSCT) or after failure of at least 2 prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates:
Intravenous dosage:
Adults: 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. 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%. 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.
-as consolidation therapy following an autologous hematopoietic stem cell transplant in patients at high risk for relapse or progression:
Intravenous dosage:
Adults: 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.
-for the treatment of previously untreated stage III or IV classical Hodgkin lymphoma, in combination with doxorubicin, vinblastine, and dacarbazine:
Intravenous dosage:
Adults: 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. 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.
-for the treatment of previously untreated, high-risk classical Hodgkin lymphoma, in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide:
Intravenous dosage:
Children 2 years and older and Adolescents: 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.
For the treatment of systemic anaplastic large-cell lymphoma (sALCL):
Note: Brentuximab vedotin has been designated an orphan drug by the FDA for the treatment of anaplastic large-cell lymphoma.
-for the treatment of sALCL after failure of at least 1 prior multi-agent chemotherapy regimen:
Intravenous dosage:
Adults: 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. 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.
-for the treatment of previously untreated sALCL, in combination with cyclophosphamide, doxorubicin, and prednisone:
Intravenous dosage:
Adults: 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).
For the treatment of cutaneous T-cell lymphoma (CTCL), specifically mycosis fungoides or primary cutaneous anaplastic large-cell lymphoma, in patients who have received prior systemic therapy:
Note: Brentuximab vedotin has been designated an orphan drug by the FDA for the treatment of CTCL and mycosis fungoides.
Intravenous dosage:
Adults: 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.
For the treatment of peripheral T-cell lymphoma (PTCL):
NOTE: Brentuximab vedotin has been designated an orphan drug by the FDA for the treatment of peripheral T-cell lymphoma not otherwise specified, adult T-cell leukemia/lymphoma, enteropathy-associated T-cell lymphoma, and angioimmunoblastic T-cell lymphoma.
-for the treatment of previously untreated CD30-expressing PTCL, in combination with cyclophosphamide, doxorubicin, and prednisone:
Intravenous dosage:
Adults: 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%)).
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
Peripheral Neuropathy
-Adults
Starting dosage of 1.8 mg/kg IV every 3 weeks, monotherapy:
Grade 2 or 3 toxicity (new or worsening): Hold brentuximab vedotin until the toxicity resolves to grade 1 or baseline. Resume therapy at a reduced dose of 1.2 mg/kg IV every 3 weeks.
Grade 4 toxicity: Discontinue brentuximab therapy.
Starting dosage of 1.8 mg/kg IV every 3 weeks, combination therapy:
Grade 2 sensory neuropathy: No dosage adjustment is necessary.
Grade 2 motor neuropathy: Reduce brentuximab vedotin dose to 1.2 mg/kg IV (maximum dose, 120 mg) every 3 weeks.
Grade 3 sensory neuropathy: Reduce brentuximab vedotin dose to 1.2 mg/kg IV (maximum dose, 120 mg) every 3 weeks.
Grade 3 motor neuropathy or grade 4 toxicity: Discontinue brentuximab vedotin therapy.
Starting dosage of 1.2 mg/kg IV every 2 weeks, combination therapy:
Grade 2 toxicity: Reduce brentuximab vedotin dose to 0.9 mg/kg IV (maximum dose, 90 mg) every 2 weeks.
Grade 3 toxicity: Hold brentuximab vedotin until the toxicity resolves to baseline or grade 2 or less. Resume therapy at a reduced dose of 0.9 mg/kg IV (maximum dose, 90 mg) every 2 weeks. Consider modifying the dose of other neurotoxic chemotherapy agents.
Grade 4 toxicity: Discontinue brentuximab vedotin therapy.
-Pediatric Patients
Grade 2 toxicity: Reduce the vincristine dose per its manufacturer prescribing information; continue brentuximab vedotin. If the neuropathy improves to grade 1 or less by day 8 of the next cycle, resume vincristine at the full dose.
Grade 3 toxicity: Discontinue vincristine. For the first occurrence, hold brentuximab vedotin until the toxicity improves to grade 2 or less and then resume brentuximab vedotin at a reduced dosage of 1.2 mg/kg IV (up to a maximum dose of 120 mg) every 3 weeks. For the second occurrence: hold brentuximab vedotin until the toxicity improves to grade 2 or less and then resume brentuximab vedotin at a reduced dosage of 0.8 mg/kg IV (up to a maximum dose of 80 mg) every 3 weeks. For the third occurrence, discontinue brentuximab vedotin therapy.
Grade 4 toxicity: Discontinue brentuximab vedotin and vincristine.
Neutropenia
-Adults
Starting dosage of 1.8 mg/kg IV every 3 weeks, monotherapy:
Grade 3 or 4 toxicity: Hold brentuximab vedotin until the toxicity resolves to baseline or grade 2 or less. Consider the prophylactic use of granulocyte colony stimulating factors (G-CSF) for subsequent cycles of therapy.
Grade 4 toxicity despite G-CSF prophylaxis: Discontinue brentuximab vedotin therapy or reduce the dosage to 1.2 mg/kg IV (maximum dose, 120 mg) every 3 weeks if therapy is resumed.
Starting dosage of 1.8 mg/kg every 3 weeks or 1.2 mg/kg IV every 2 weeks, combination therapy:
Grade 3 or 4 toxicity: Administer G-CSF prophylaxis for subsequent cycles of therapy in patients not receiving primary G-CSF prophylaxis.
-Pediatric patients
Grade 3 or 4 toxicity: Reduce brentuximab vedotin dose to 1.2 mg/kg IV (maximum dose, 120 mg) every 3 weeks in patients who are unable to start a cycle at more than 5 weeks after the start of the previous cycle (i.e., more than a 2-week delay) due to neutropenia.
Maximum Dosage Limits:
-Adults
180 mg IV every 3 weeks or 120 mg IV every 2 weeks.
-Geriatric
180 mg IV every 3 weeks or 120 mg IV every 2 weeks.
-Adolescents
1.8 mg/kg (maximum of 180 mg) IV every 3 weeks.
-Children
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.
-Infants
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Mild hepatic impairment (Child-Pugh A): Reduce the brentuximab vedotin dosage as follows
For 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.
Patients with Renal Impairment Dosing
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.
*non-FDA-approved indication
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.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
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%.
Encorafenib: (Moderate) Monitor for decreased efficacy of brentuximab if coadministration with encorafenib is necessary. Monomethyl auristatin E (MMAE) is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased MMAE exposure by approximately 46%.
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%.
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.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (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%.
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.
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.
-Route-Specific Pharmacokinetics
Intravenous Route
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.
-Special Populations
Hepatic Impairment
Following a single-dose of brentuximab vedotin 1.2 mg/kg IV, the AUC value of the active metabolite, monomethyl auristatin E (MMAE), increased about 2.3-times in patients with hepatic impairment.
Renal Impairment
Following a single-dose of brentuximab vedotin 1.2 mg/kg IV, the AUC value of the microtubule disrupting agent monomethyl auristatin E (MMAE), increased by about 2-times in patients with severe renal impairment (creatinine clearance (CrCl less than 30 mL/min; n = 3) compared with patients who had normal renal function (CrCl greater than 80 mL/min; n = 8).
Pediatrics
Following the recommended dosage of brentuximab vedotin 1.8 mg/kg IV every 3 weeks in pediatric patients aged 2 to 16 years (n = 65), the dose-normalized steady-state average levels were consistent with average levels in adult patients who received brentuximab vedotin 1.2 mg/kg IV every 2 weeks. The median AUC value was decreased by 22% in patients aged 6 to 11 years (median weight, 28.8 kg) and by 37% in patients aged 3 to 5 years (median weight, 17 kg) compared with exposure in patients aged 12 to 16 years (median weight, 52.7 kg). AUC values of monomethyl auristatin E (MMAE) were decreased by 25% and 41% in patients aged 6 to 11 years and 3 to 5 years, respectively, compared with MMAE exposure in patients aged 12 to 16 years.
Gender Differences
Sex has no clinically significant effect on the pharmacokinetic parameters of brentuximab vedotin.
Ethnic Differences
Race has no clinically significant effect on the pharmacokinetic parameters of brentuximab vedotin.
Other
Hypoalbuminemia
Baseline albumin level has no clinically significant effect on the pharmacokinetic parameters of the antibody-drug conjugate (brentuximab vedotin) or the microtubule disrupting agent (monomethyl auristatin E) in pediatric patients aged 3 to 16 years.