September 3, 2015
Recommended Topic Related To:

Adcetris

"The U.S. Food and Drug Administration today expanded the approved use of Opdivo (nivolumab) to treat patients with advanced (metastatic) squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

L"...

Adcetris




Side Effects
Interactions

SIDE EFFECTS

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

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

Summary of Clinical Trial Experience in Relapsed Classical HL (Study 1)

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.

Summary of Clinical Trial Experience in Classical HL Post-auto-HSCT Consolidation (Study 3)

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

Summary of Clinical Trial Experience in Relapsed sALCL (Study 2)

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

Adverse Reaction Classical HL Total
N = 102 % of patients
sALCL Total
N = 58 % of patients
Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4
Blood and lymphatic system disorders
  Neutropenia* 54 15 6 55 12 9
  Anemia* 33 8 2 52 2 -
  Thrombocytopenia* 28 7 2 16 5 5
  Lymphadenopathy 11 - - 10 - -
Nervous system disorders
  Peripheral sensory neuropathy 52 8 - 53 10 -
  Peripheral motor neuropathy 16 4 - 7 3 -
  Headache 19 - - 16 2 -
  Dizziness 11 - - 16 - -
General disorders and administration site conditions
  Fatigue 49 3 - 41 2 2
  Pyrexia 29 2 - 38 2 -
  Chills 13 - - 12 - -
  Pain 7 - - 28 - 5
  Edema peripheral 4 - - 16 - -
Infections and infestations
  Upper respiratory tract infection 47 - - 12 - -
Gastrointestinal disorders
  Nausea 42 - - 38 2 -
  Diarrhea 36 1 - 29 3 -
  Abdominal pain 25 2 1 9 2 -
  Vomiting 22 - - 17 3 -
  Constipation 16 - - 19 2 -
Skin and subcutaneous tissue disorders
  Rash 27 - - 31 - -
  Pruritus 17 - - 19 - -
  Alopecia 13 - - 14 - -
  Night sweats 12 - - 9 - -
  Dry skin 4 - - 10 - -
Respiratory, thoracic and mediastinal disorders
  Cough 25 - - 17 - -
  Dyspnea 13 1 - 19 2 -
  Oropharyngeal pain 11 - - 9 - -
Musculoskeletal and connective tissue disorders
  Arthralgia 19 - - 9 - -
  Myalgia 17 - - 16 2 -
  Back pain 14 - - 10 2 -
  Pain in extremity 10 - - 10 2 2
  Muscle spasms 9 - - 10 2 -
Psychiatric disorders
  Insomnia 14 - - 16 - -
  Anxiety 11 2 - 7 - -
Metabolism and nutrition disorders
  Decreased appetite 11 - - 16 2 -
Investigations
  Weight decreased 6 - - 12 3 -
*Derived from laboratory values and adverse reaction data

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

Adverse Reaction ADCETRIS Total
N = 167 % of patients
Placebo Total
N = 160 % of patients
Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4
Blood and lymphatic system disorders
  Neutropenia* 78 30 9 34 6 4
  Thrombocytopenia* 41 2 4 20 3 2
  Anemia* 27 4 - 19 2 -
Nervous system disorders
  Peripheral sensory neuropathy 56 10 - 16 1 -
  Peripheral motor neuropathy 23 6 - 2 1 -
  Headache 11 2 - 8 1 -
Infections and infestations
  Upper respiratory tract infection 26 - - 23 1 -
General disorders and administration site conditions
  Fatigue 24 2 - 18 3 -
  Pyrexia 19 2 - 16 - -
  Chills 10 - - 5 - -
Gastrointestinal disorders
  Nausea 22 3 - 8 - -
  Diarrhea 20 2 - 10 1 -
  Vomiting 16 2 - 7 - -
  Abdominal pain 14 2 - 3 - -
  Constipation 13 2 - 3 - -
Respiratory, thoracic and mediastinal disorders
  Cough 21 - - 16 - -
  Dyspnea 13 - - 6 - 1
  Investigations
  Weight decreased 19 1 - 6 - -
Musculoskeletal and connective tissue disorders
  Arthralgia 18 1 - 9 - -
  Muscle spasms 11 - 6 - -
  Myalgia 11 1 - 4 - -
Skin and subcutaneous tissue disorders
  Pruritus 12 1 - 8 - -
Metabolism and nutrition disorders
  Decreased appetite 12 1 - 6 - -
*Derived from laboratory values and adverse reaction data

Additional Important Adverse Reactions

Peripheral Neuropathy

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.

Infusion Reactions

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%).

Pulmonary Toxicity

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.

Serious Adverse Reactions

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%).

Dose Modifications

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].

Discontinuations

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].

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.

Gastrointestinal disorders: Pancreatitis (including fatal outcomes). Consider the diagnosis of pancreatitis for patients presenting with severe abdominal pain.

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

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.

Read the Adcetris (brentuximab vedotin) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5. In vitro data indicate that MMAE is also a substrate of the efflux transporter P-glycoprotein (P-gp).

Effect Of Other Drugs On ADCETRIS

CYP3A4 Inhibitors/Inducers

MMAE is primarily metabolized by CYP3A [see CLINICAL PHARMACOLOGY]. Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%. Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions. Co-administration of ADCETRIS with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%.

P-gp Inhibitors

Co-administration of ADCETRIS with P-gp inhibitors may increase exposure to MMAE. Patients who are receiving P-gp inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions.

Effect Of ADCETRIS On Other Drugs

Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate. MMAE does not inhibit other CYP enzymes at relevant clinical concentrations [see CLINICAL PHARMACOLOGY]. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

Read the Adcetris Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 8/31/2015
This monograph has been modified to include the generic and brand name in many instances.

Side Effects
Interactions

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Cancer

Get the latest treatment options.

Related Drugs
Health Resources
Use Pill Finder Find it Now See Interactions

Pill Identifier on RxList

  • quick, easy,
    pill identification

Find a Local Pharmacy

  • including 24 hour, pharmacies

Interaction Checker

  • Check potential drug interactions
Search the Medical Dictionary for Health Definitions & Medical Abbreviations