Brentuximab vedotin

Brentuximab vedotin is injected into a vein through an IV. You will receive this injection in a clinic or hospital setting.

Before you receive brentuximab vedotin, you may be given other medications to prevent certain side effects that brentuximab vedotin can cause.

Brentuximab vedotin is usually given once every 3 weeks for up to 16 treatment cycles, or until your body no longer responds to the medication. Follow your doctor's dosing instructions very carefully.

Brentuximab vedotin can lower blood cells that help your body fight infections and help your blood to clot. Your blood will need to be tested often. Your cancer treatments may be delayed based on the results of these tests.

If you need surgery, tell the surgeon ahead of time that you are using brentuximab vedotin. You may need to stop using the medicine for a short time.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include severe forms of some of the side effects listed in this medication guide.

Call your doctor if you miss an appointment for your brentuximab vedotin injection.

ADCETRIS (brentuximab vedotin) is a CD30-directed antibody-drug conjugate (ADC) consisting of three components: 1) the chimeric IgG1 antibody cAC10, specific for human CD30, 2) the microtubule disrupting agent MMAE, and 3) a protease-cleavable linker that covalently attaches MMAE to cAC10.

Brentuximab vedotin has an approximate molecular weight of 153 kDa. Approximately 4 molecules of MMAE are attached to each antibody molecule. Brentuximab vedotin is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells, and the small molecule components are produced by chemical synthesis.

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

The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information:

• Peripheral Neuropathy [see WARNINGS AND PRECAUTIONS]
• Anaphylaxis and Infusion Reactions [see WARNINGS AND PRECAUTIONS]
• Hematologic Toxicities [see WARNINGS AND PRECAUTIONS]
• Serious Infections and Opportunistic Infections [see WARNINGS AND PRECAUTIONS]
• Tumor Lysis Syndrome [see WARNINGS AND PRECAUTIONS]
• Increased Toxicity in the Presence of Severe Renal Impairment [see WARNINGS AND PRECAUTIONS]
• Increased Toxicity in the Presence of Moderate or Severe Hepatic Impairment [see WARNINGS AND PRECAUTIONS]
• Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
• Progressive Multifocal Leukoencephalopathy [see WARNINGS AND PRECAUTIONS]
• Pulmonary Toxicity [see WARNINGS AND PRECAUTIONS]
• Serious Dermatologic Reactions [see WARNINGS AND PRECAUTIONS]
• Gastrointestinal Complications [see WARNINGS AND PRECAUTIONS]

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data below reflect exposure to ADCETRIS as monotherapy in 327 patients with classical Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL), including 160 patients in two uncontrolled single-arm trials (Studies 1 and 2) and 167 patients in one placebo-controlled randomized trial (Study 3).

In Studies 1 and 2, the most common adverse reactions ( ≥ 20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough, and vomiting. The most common adverse reactions occurring in at least 10% of patients in either Study 1 or 2, regardless of causality, using the NCI Common Toxicity Criteria (CTC) Version 3.0, are shown in Table 2.

In Study 3, the most common adverse reactions ( ≥ 20%) in the ADCETRIS-treatment arm, regardless of causality, were neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory tract infection, fatigue, peripheral motor neuropathy, nausea, cough, and diarrhea. The most common adverse reactions occurring in at least 10% of patients, using the NCI CTC Version 4, are shown in Table 3.

Experience In Classical Hodgkin Lymphoma

ADCETRIS was studied in 102 patients with classical HL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 9 cycles (range, 1–16) [see Clinical Studies].

The most common adverse reactions ( ≥ 20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting.

ADCETRIS was studied in 329 patients with classical HL at high risk of relapse or progression post-auto-HSCT in a randomized, double-blind, placebo-controlled clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg of ADCETRIS administered intravenously over 30 minutes every 3 weeks or placebo for up to 16 cycles. Of the 329 enrolled patients, 327 (167 brentuximab vedotin, 160 placebo) received at least one dose of study treatment. The median number of treatment cycles in each study arm was 15 (range, 1–16) and 80 patients (48%) in the ADCETRIS-treatment arm received 16 cycles [see Clinical Studies].

Standard international guidelines were followed for infection prophylaxis for herpes simplex virus (HSV), varicella-zoster virus (VZV), and Pneumocystis jiroveci pneumonia (PCP) post-auto-HSCT. Overall, 312 patients (95%) received HSV and VZV prophylaxis with a median duration of 11.1 months (range, 0–20) and 319 patients (98%) received PCP prophylaxis with a median duration of 6.5 months (range, 0–20).

Experience In Systemic Anaplastic Large Cell Lymphoma

ADCETRIS was studied in 58 patients with sALCL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 7 cycles (range, 1–16) [see Clinical Studies].

The most common adverse reactions ( ≥ 20%), regardless of causality, were neutropenia, anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, diarrhea, and pain.

Table 2: Most Commonly Reported ( ≥ 10%) Adverse Reactions in Studies 1 and 2

Table 3: Most Commonly Reported ( ≥ 10% in the ADCETRIS arm) Adverse Reactions in Study 3

Additional Important Adverse Reactions

In Studies 1 and 2, 54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy at the time of their last evaluation.

In Study 3, 67% of patients treated with ADCETRIS experienced any grade of neuropathy. The median time to first onset of any grade was 14 weeks (range, 0.1–47), of Grade 2 was 27 weeks (range, 0.4–52) and of Grade 3 was 34 weeks (range, 7–106). The median time from onset to resolution or improvement of any grade was 23 weeks (range, 0.1–138), of Grade 2 was 24 weeks (range, 1–108), and of Grade 3 was 25 weeks (range, 2–98). Of the patients who reported neuropathy, 59% had complete resolution and 41% had residual neuropathy (26% partial improvement, 15% no improvement) at the time of their last evaluation.

Two cases of anaphylaxis were reported in the dose-finding trials. There were no Grade 3 or 4 infusion-related reactions reported in Studies 1 and 2; however, Grade 1 or 2 infusion-related reactions were reported for 19 patients (12%). In Studies 1 and 2, the most common adverse reactions ( ≥ 2%) associated with infusion-related reactions were chills (4%), nausea (3%), dyspnea (3%), pruritus (3%), pyrexia (2%), and cough (2%).

In Study 3, infusion-related reactions were reported in 25 patients (15%) in the ADCETRIS-treated arm and 3 patients (2%) in the placebo arm. Grade 3 events were reported in 3 of the 25 patients treated with ADCETRIS who experienced infusion-related reactions. No Grade 4 infusion-related reactions were reported. The most common adverse reactions ( ≥ 2%) associated with infusion-related reactions were nausea (4%), chills (4%), dyspnea (2%), headache (2%), pruritus (2%), rash (2%), back pain (2%), and vomiting (2%).

In a trial in patients with classical HL that studied ADCETRIS with bleomycin as part of a combination regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients typically reported cough and dyspnea. Interstitial infiltration and/or inflammation were observed on radiographs and computed tomographic imaging of the chest. Most patients responded to corticosteroids. The concomitant use of ADCETRIS with bleomycin is contraindicated [see CONTRAINDICATIONS].

Cases of pulmonary toxicity have also been reported in patients receiving ADCETRIS. In Study 3, pulmonary toxicity was reported in 8 patients (5%) in the ADCETRIS-treated arm and 5 patients (3%) in the placebo arm. A causal association with single-agent ADCETRIS has not been established.

In Studies 1 and 2, serious adverse reactions, regardless of causality, were reported in 31% of patients receiving ADCETRIS. The most common serious adverse reactions experienced by patients with classical HL include peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%). The most common serious adverse reactions experienced by patients with sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%). Other important serious adverse reactions reported include PML, Stevens-Johnson syndrome, and tumor lysis syndrome.

In Study 3, serious adverse reactions, regardless of causality, were reported in 25% of ADCETRIS-treated patients. The most common serious adverse reactions were pneumonia (4%), pyrexia (4%), vomiting (3%), nausea (2%), hepatotoxicity (2%), and peripheral sensory neuropathy (2%).

Adverse reactions that led to dose delays in more than 5% of patients in Studies 1 and 2 were neutropenia (14%) and peripheral sensory neuropathy (11%) [see DOSAGE AND ADMINISTRATION].

Adverse reactions that led to dose delays in more than 5% of ADCETRIS-treated patients in Study 3 were neutropenia (22%), peripheral sensory neuropathy (16%), upper respiratory tract infection (6%), and peripheral motor neuropathy (6%) [see DOSAGE AND ADMINISTRATION].

Adverse reactions led to treatment discontinuation in 21% of patients in Studies 1 and 2. Adverse reactions that led to treatment discontinuation in 2 or more patients with classical HL or sALCL were peripheral sensory neuropathy (8%) and peripheral motor neuropathy (3%).

Adverse reactions led to treatment discontinuation in 32% of ADCETRIS-treated patients in Study 3. Adverse reactions that led to treatment discontinuation in 2 or more patients were peripheral sensory neuropathy (14%), peripheral motor neuropathy (7%), acute respiratory distress syndrome (1%), paraesthesia (1%), and vomiting (1%).

Post Marketing Experience

The following adverse reactions have been identified during post-approval use of ADCETRIS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: febrile neutropenia [see WARNINGS AND PRECAUTIONS].

Gastrointestinal disorders:

• Pancreatitis (including fatal outcomes). Consider the diagnosis of pancreatitis for patients presenting with severe abdominal pain.
• Gastrointestinal complications (including fatal outcomes) [see WARNINGS AND PRECAUTIONS].

Hepatobiliary disorders: hepatotoxicity [see WARNINGS AND PRECAUTIONS].

Infections: PML [see BOXED WARNING, WARNINGS AND PRECAUTIONS], serious infections and opportunistic infections [see WARNINGS AND PRECAUTIONS].

Metabolism and nutrition disorders: hyperglycemia.

Respiratory, thoracic and mediastinal disorders: noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and ARDS (some with fatal outcomes) [see WARNINGS AND PRECAUTIONS and Clinical Trial Experience above].

Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, including fatal outcomes [see WARNINGS AND PRECAUTIONS].

Immunogenicity

Patients with classical HL and sALCL in Studies 1 and 2 [see Clinical Studies] were tested for antibodies to brentuximab vedotin every 3 weeks using a sensitive electrochemiluminescent immunoassay. Approximately 7% of patients in these trials developed persistently positive antibodies (positive test at more than 2 timepoints) and 30% developed transiently positive antibodies (positive in 1 or 2 post-baseline timepoints). The anti-brentuximab antibodies were directed against the antibody component of brentuximab vedotin in all patients with transiently or persistently positive antibodies. Two of the patients (1%) with persistently positive antibodies experienced adverse reactions consistent with infusion reactions that led to discontinuation of treatment. Overall, a higher incidence of infusion related reactions was observed in patients who developed persistently positive antibodies.

A total of 58 patient samples that were either transiently or persistently positive for antibrentuximab vedotin antibodies were tested for the presence of neutralizing antibodies. Sixty-two percent of these patients had at least one sample that was positive for the presence of neutralizing antibodies. The effect of anti-brentuximab vedotin antibodies on safety and efficacy is not known.

Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ADCETRIS with the incidence of antibodies to other products may be misleading.

>10%

Neutropenia (54-55%)

Peripheral sensory neuropathy (52-53%)

Anemia (33-52%)

Fatigue (41-49%)

URIs (12-47%)

Nausea (38-42%)

Pyrexia (29-38%)

Diarrhea (29-36%)

Rash (27-31%

Thrombocytopenia (16-28%)

Pain (7-28%)

Cough (17-25%)

Abdominal pain (9-25%)

Vomiting (17-22%)

Pruritus (17-19%)

Constipation (16-19%)

Headache (16-19%)

Dyspnea (13-19%)

Arthralgia (9-19%)

Myalgia (16-17%)

Insomnia (14-16%)

Dizziness (11-16%)

Peripheral motor neuropathy (7-16%)

Peripheral edema (4-16%)

Alopecia (13-14%)

Back pain (10-14%)

Chills (12-13%)

Night sweats (9-12%)

Lymphadenopathy (10-11%)

Oropharyngeal pain (9-11%)

Anxiety (7-11%)

1-10%

Extremity pain (10%)

Muscle spasms (9-10%)

Dry skin (4-10%)

Postmarketing reports

Noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and ARDS (some with fatal outcomes)

Brentuximab vedotin is a cancer medication that interferes with the growth and spread of cancer cells in the body.

Brentuximab vedotin is used to treat Hodgkin's lymphoma or anaplastic large cell lymphoma.

Brentuximab vedotin is given after a stem cell transplant or other cancer medications have been tried without successful treatment.

Brentuximab vedotin may also be used for purposes not listed in this medication guide.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include severe forms of some of the side effects listed in this medication guide.

• Risk of PML.1 Importance of patients, family, and caregivers being alert to and immediately reporting emergence of neurologic manifestations (e.g., changes in mood or behavior, confusion, changes in thinking, memory loss, vision changes, changes in speech or walking, decreased strength or weakness on one side of the body).1 15

• Risk of infusion-related reactions.1 Importance of reporting signs and symptoms of such reactions (e.g., fever, chills, rash, breathing difficulty) that occur within 24 hours of an infusion of the drug.1

• Risk of peripheral neuropathy.1 Importance of informing clinician of new or worsening symptoms of peripheral neuropathy (e.g., tingling or numbness of the hands or feet, any muscle weakness).1

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

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

• Risk of pancreatitis.1 Importance of informing clinician of severe abdominal pain.1

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

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

• Anti-CD30 ADC SGN-35
• Anti-CD30 Antibody-Drug Conjugate SGN-35
• Antibody-Drug Conjugate SGN-35
• Brentuximab
• SGN-35

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous [preservative free]:

Adcetris: 50 mg (1 ea) [contains polysorbate 80]

• Antineoplastic Agent, Anti-CD30
• Antineoplastic Agent, Antibody Drug Conjugate
• Antineoplastic Agent, Monoclonal Antibody

Serious side effects have occurred with the use of brentuximab vedotin.

• Nerve damage. This nerve damage mostly involves numbness or tingling in the hands or feet (sensory) and/or weakness in the arms or legs (motor). Symptoms increase with more doses. Your doctor may change or stop brentuximab vedotin depending on the severity of your symptoms.
• Infection in the brain. Brentuximab vedotin may increase the risk that you will develop progressive multifocal leukoencephalopathy (PML; a rare infection of the brain that cannot be treated, prevented or cured and that usually causes death or severe disability). Tell your doctor if you have or have ever had a condition that affects your immune system. Tell your doctor and pharmacist if you are taking any medications that suppress the immune system. If you experience any of the following symptoms, stop receiving brentuximab vedotin and call your doctor immediately: decreased strength or weakness on one side of the body; difficulty walking; loss of coordination; headache; confusion; difficulty thinking clearly; memory loss; changes in mood or usual behavior; difficulty speaking; or vision problems.
• Infections. These may include pneumonia, bacteremia, and sepsis. Tell your doctor if you notice a fever, chills, cough, or other signs of infection. 
• Blood problems: Brentuximab vedotin may lead to a decrease in the number of blood counts. Brentuximab vedotin may lead to low numbers of red blood cells, low numbers of white blood cells. Your doctor will give you a medicine called growth factor with your first dose if you are receiving brentuximab vedotin in combination with chemotherapy for the treatment of advanced cHL. Your blood counts will be checked before each dose, more often if necessary. You will be monitored for fever. If your white blood cell count is too low, your doctor may delay your next infusion, lower your dose, stop your brentuximab vedotin therapy, or give you growth factor with future doses of brentuximab vedotin.
• Serious allergic reactions. Brentuximab vedotin may cause serious allergic reactions, which usually occur during the infusion of the medication or within 24 hours of receiving a dose. You may receive certain medications before your infusion to prevent an allergic reaction if you had a reaction to a previous treatment. Your doctor will watch you carefully while you are receiving brentuximab vedotin. If you experience any of the following symptoms, tell your doctor immediately: fever, chills, rash, hives, itching, or difficulty breathing.
• Liver injury: Liver problems (including deaths) have been reported after the first dose of brentuximab vedotin  and after brentuximab vedotin was stopped and restarted. Your liver function will be monitored. Having liver problems, raised liver enzymes, and some medicines may increase the risk. Your doctor may delay your next infusion, lower your dose, or stop brentuximab vedotin if you have liver problems.
• Skin problems. Although rare, skin conditions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), may occur. These conditions are serious. If either occurs, your doctor will stop brentuximab vedotin and treat you for symptoms. 
• Harm to your unborn baby. It is recommended women do not become pregnant while taking this medication and for at least 6 months after the last dose of brentuximab vedotin. 

Do not take brentuximab vedotin if you are:

• allergic to this medication
• are also taking bleomycin

Brentuximab vedotin comes as a powder to be mixed with fluid and injected over 30 minutes intravenously (into a vein) by a healthcare professional.

It is usually injected once every 3 weeks. This treatment period is called a cycle, and the cycle may be repeated up to 16 times.

Since this medication is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if an overdose is suspected, seek emergency medical attention.

Keep all appointments with your doctor and the laboratory. Your doctor may order certain tests to check your body's response to brentuximab vedotin injection.

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)

JC virus infection resulting in PML and death can occur in patients receiving this medication.