Adcetris

Adcetris information, interactions and side effects, 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.

adcetris

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.

INDICATIONS

Classical Hodgkin Lymphoma (HL)

ADCETRIS (brentuximab vedotin) is indicated for treatment of patients with classical HL after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates.

Classical Hodgkin Lymphoma (HL) Post-auto-HSCT Consolidation

ADCETRIS is indicated for the treatment of patients with classical HL at high risk of relapse or progression as post-auto-HSCT consolidation.

Systemic Anaplastic Large Cell Lymphoma (sALCL)

ADCETRIS is indicated for treatment of patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen.

The sALCL indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

DOSAGE AND ADMINISTRATION

Dosage Recommendations

Administer ADCETRIS as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity. See Table 1 for the recommended starting dosage.

For classical HL post-auto-HSCT consolidation treatment, initiate ADCETRIS treatment within 4–6 weeks post-auto-HSCT or upon recovery from auto-HSCT. These patients should continue treatment until a maximum of 16 cycles, disease progression, or unacceptable toxicity.

Table 1: Recommended ADCETRIS Dosage

 

Recommended Starting Dosage
Normal renal and hepatic function 1.8 mg/kg up to 180 mg
Renal impairment
  Mild (creatinine clearance > 50-80 mL/min) or moderate (creatinine clearance 30-50 mL/min) 1.8 mg/kg up to 180 mg
  Severe (creatinine clearance less than 30 mL/min) Avoid use
Hepatic impairment
  Mild (Child-Pugh A) 1.2 mg/kg up to 120 mg
  Moderate (Child-Pugh B) or severe (Child-Pugh C) Avoid use

 

Dose Modification

Peripheral Neuropathy

For new or worsening Grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral neuropathy, ADCETRIS should be discontinued.

Neutropenia

The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower. Consider G-CSF prophylaxis for subsequent cycles in patients who experience Grade 3 or 4 neutropenia in the previous cycle. In patients with recurrent Grade 4 neutropenia despite the use of G-CSF prophylaxis, consider discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg.

Instructions For Preparation And Administration

Administration
  • Administer ADCETRIS as an intravenous infusion only.
  • Do not mix ADCETRIS with, or administer as an infusion with, other medicinal products.
Reconstitution
  • Follow procedures for proper handling and disposal of anticancer drugs.
  • Use appropriate aseptic technique for reconstitution and preparation of dosing solutions.
  • Determine the number of 50 mg vials needed based on the patient’s weight and the prescribed dose.
  • Reconstitute each 50 mg vial of ADCETRIS with 10.5 mL of Sterile Water for Injection, USP, to yield a single-use solution containing 5 mg/mL brentuximab vedotin.
  • Direct the stream toward the wall of vial and not directly at the cake or powder.
  • Gently swirl the vial to aid dissolution. DO NOT SHAKE.
  • Inspect the reconstituted solution for particulates and discoloration. The reconstituted solution should be clear to slightly opalescent, colorless, and free of visible particulates.
  • Following reconstitution, dilute immediately into an infusion bag. If not diluted immediately, store the solution at 2–8°C (36–46°F) and use within 24 hours of reconstitution. DO NOT FREEZE.
  • Discard any unused portion left in the vial.
Dilution
  • Calculate the required volume of 5 mg/mL reconstituted ADCETRIS solution needed.
  • Withdraw this amount from the vial and immediately add it to an infusion bag containing a minimum volume of 100 mL of 0.9% Sodium Chloride Injection, 5% Dextrose Injection or Lactated Ringer’s Injection to achieve a final concentration of 0.4 mg/mL to 1.8 mg/mL brentuximab vedotin.
  • Gently invert the bag to mix the solution.
  • Following dilution, infuse the ADCETRIS solution immediately. If not used immediately, store the solution at 2–8°C (36–46°F) and use within 24 hours of reconstitution. DO NOT FREEZE.

HOW SUPPLIED

Dosage Forms And Strengths

For injection: 50 mg of brentuximab vedotin as a sterile, white to off-white lyophilized, preservative-free cake or powder in a single-use vial for reconstitution.

Storage And Handling

ADCETRIS (brentuximab vedotin) for Injection is supplied as a sterile, white to off-white preservative-free lyophilized cake or powder in individually-boxed single-use vials:

NDC (51144-050-01), 50 mg brentuximab vedotin.

Storage

Store vial at 2–8°C (36–46°F) in the original carton to protect from light.

Special Handling

ADCETRIS is an antineoplastic product. Follow special handling and disposal procedures.

SIDE EFFECTS

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

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

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).

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.

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).

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.

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%).

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%).

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.

Hepatobiliary disorders: hepatotoxicity.

Infections: PML, serious infections and opportunistic infections.

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).

Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, including fatal outcomes.

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.

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. 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. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

PRECAUTIONS

Peripheral Neuropathy

ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. In the relapsed classical HL and sALCL clinical trials, 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. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS.

Anaphylaxis And Infusion Reactions

Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.

Hematologic Toxicities

Prolonged ( ≥ 1 week) severe neutropenia and Grade 3 or Grade 4 thrombocytopenia or anemia can occur with ADCETRIS. Febrile neutropenia has been reported with treatment with ADCETRIS. Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent ADCETRIS doses.

Serious Infections And Opportunistic Infections

Serious infections and opportunistic infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in patients treated with ADCETRIS. Patients should be closely monitored during treatment for the emergence of possible bacterial, fungal, or viral infections.

Tumor Lysis Syndrome

Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures.

Increased Toxicity In The Presence Of Severe Renal Impairment

The frequency of ≥ Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Due to higher MMAE exposure, ≥ Grade 3 adverse reactions may be more frequent in patients with severe renal impairment compared to patients with normal renal function. Avoid the use of ADCETRIS in patients with severe renal impairment [creatinine clearance (CLcr) < 30 mL/min].

Increased Toxicity In The Presence Of Moderate Or Severe Hepatic Impairment

The frequency of ≥ Grade 3 adverse reactions and deaths was greater in patients with moderate and severe hepatic impairment compared to patients with normal hepatic function. Avoid the use of ADCETRIS in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.

Hepatotoxicity

Serious cases of hepatotoxicity, including fatal outcomes, have occurred in patients receiving ADCETRIS. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin. Cases have occurred after the first dose of ADCETRIS or after ADCETRIS rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may also increase the risk. Monitor liver enzymes and bilirubin.

Patients experiencing new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.

Progressive Multifocal Leukoencephalopathy

JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS therapy, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed.

Pulmonary Toxicity

Events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS), some with fatal outcomes, have been reported. Monitor patients for signs and symptoms of pulmonary toxicity, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.

Serious Dermatologic Reactions

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal outcomes, have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.

Embryo-Fetal Toxicity

There are no adequate and well-controlled studies of ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased embryo viability and fetal malformations, in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with classical HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies with brentuximab vedotin or the small molecule (MMAE) have not been conducted.

MMAE was genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism. This effect is consistent with the pharmacological effect of MMAE as a microtubule disrupting agent. MMAE was not mutagenic in the bacterial reverse mutation assay (Ames test) or the L5178Y mouse lymphoma forward mutation assay.

Fertility studies with brentuximab vedotin or MMAE have not been conducted. However, results of repeat-dose toxicity studies in rats indicate the potential for brentuximab vedotin to impair male reproductive function and fertility. In a 4-week repeat-dose toxicity study in rats with weekly dosing at 0.5, 5, or 10 mg/kg brentuximab vedotin, seminiferous tubule degeneration, Sertoli cell vacuolation, reduced spermatogenesis, and aspermia were observed. Effects in animals were seen mainly at 5 and 10 mg/kg of brentuximab vedotin. These doses are approximately 3 and 6-fold the human recommended dose of 1.8 mg/kg, respectively, based on body weight.

Use In Specific Populations

Pregnancy

Pregnancy Category D.

Risk Summary

There are no adequate and well-controlled studies with ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with classical HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.

Animal Data

In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption ( ≥ 99%), post-implantation loss ( ≥ 99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with classical HL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.

Nursing Mothers

It is not known whether brentuximab vedotin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ADCETRIS a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of ADCETRIS have not been established in the pediatric population. Clinical trials of ADCETRIS included only 9 pediatric patients and this number is not sufficient to determine whether they respond differently than adult patients.

Geriatric Use

Clinical trials of ADCETRIS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Safety and efficacy have not been established.

Renal Impairment

Avoid the use of ADCETRIS in patients with severe renal impairment (CLcr < 30 mL/min).

The kidney is a route of excretion for monomethyl auristatin E (MMAE). The pharmacokinetics and safety of brentuximab vedotin and MMAE were evaluated after the administration of 1.2 mg/kg of ADCETRIS to patients with mild (CLcr > 50–80 mL/min; n=4), moderate (CLcr 30–50 mL/min; n=3) and severe (CLcr < 30 mL/min; n=3) renal impairment. In patients with severe renal impairment, the rate of Grade 3 or worse adverse reactions was 3/3 (100%) compared to 3/8 (38%) in patients with normal renal function. Additionally, the AUC of MMAE (component of ADCETRIS) was approximately 2-fold higher in patients with severe renal impairment compared to patients with normal renal function. Due to higher MMAE exposure, ≥ Grade 3 adverse reactions may be more frequent in patients with severe renal impairment compared to patients with normal renal function.

Hepatic Impairment

Avoid the use of ADCETRIS in patients with moderate or severe hepatic impairment.

The liver is a route of clearance for MMAE. The pharmacokinetics and safety of brentuximab vedotin and MMAE were evaluated after the administration of 1.2 mg/kg of ADCETRIS to patients with mild (Child-Pugh A; n=1), moderate (Child-Pugh B; n=5) and severe (Child-Pugh C; n=1) hepatic impairment. In patients with moderate and severe hepatic impairment, the rate of ≥ Grade 3 adverse reactions was 6/6 (100%) compared to 3/8 (38%) in patients with normal hepatic function. Additionally, the AUC of MMAE was approximately 2.2-fold higher in patients with hepatic impairment compared to patients with normal hepatic function.

OVERDOSE

There is no known antidote for overdosage of ADCETRIS. In case of overdosage, the patient should be closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered.

CONTRAINDICATIONS

ADCETRIS is contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation)

589 read