Drug: Adcetris

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.

Source: http://www.rxlist.com

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]
  • Serious Dermatologic Reactions [see WARNINGS AND PRECAUTIONS]
  • Embryo-Fetal Toxicity [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. ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, 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 trial, regardless of causality, using the NCI Common Toxicity Criteria Version 3.0, are shown in Table 2. Experience in Hodgkin Lymphoma ADCETRIS was studied in 102 patients with 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 27 weeks (range, 3 to 56 weeks) [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. Pulmonary Toxicity In another clinical trial in patients with 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]. 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 24 weeks (range, 3 to 56 weeks) [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. Combined Experience Table 2: Most Commonly Reported ( ≥ 10%) Adverse Reactions
Adverse Reaction 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 Infusion Reactions Two cases of anaphylaxis were reported in phase 1 trials. There were no Grade 3 or 4 infusion-related reactions reported in the phase 2 trials, however, Grade 1 or 2 infusion-related reactions were reported for 19 patients (12%). 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%). Serious Adverse Reactions In the phase 2 trials, serious adverse reactions, regardless of causality, were reported in 31% of patients receiving ADCETRIS. The most common serious adverse reactions experienced by patients with 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. Dose Modifications Adverse reactions that led to dose delays in more than 5% of patients were neutropenia (14%) and peripheral sensory neuropathy (11%) [see DOSAGE AND ADMINISTRATION]. Discontinuations Adverse reactions led to treatment discontinuation in 21% of patients. Adverse reactions that led to treatment discontinuation in 2 or more patients with HL or sALCL were peripheral sensory neuropathy (8%) and peripheral motor neuropathy (3%). 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. Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, including fatal outcomes [see WARNINGS AND PRECAUTIONS]. Immunogenicity Patients with HL and sALCL in the phase 2 trials [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 effectsLearn More »

Source: http://www.rxlist.com

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. 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 [seeWARNINGS AND PRECAUTIONS] 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 [see WARNINGS AND PRECAUTIONS] 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 [see REFERENCES].
  • 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 [see Dosage Recommendations].
  • 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.

Source: http://www.rxlist.com

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 Learn More »

Source: http://www.rxlist.com

Hodgkin Lymphoma ADCETRIS (brentuximab vedotin) is indicated for treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates. This indication is approved under accelerated approval based on overall response rate [see Clinical Studies]. An improvement in patient-reported outcomes or survival has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Systemic Anaplastic Large Cell Lymphoma ADCETRIS is indicated for treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen. This indication is approved under accelerated approval based on overall response rate [see Clinical Studies]. An improvement in patient-reported outcomes or survival has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Source: http://www.rxlist.com

ADCETRIS is contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation) [see ADVERSE REACTIONS]. Last reviewed on RxList: 12/11/2014
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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.

Source: http://www.rxlist.com

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 procedures1. REFERENCES 1. OSHA Hazardous Drugs. OSHA. [Accessed on 30 July 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html] Manufactured by: Seattle Genetics, Inc. Bothell, WA 98021. 1-855-473-2436. Revised: Nov 2014 Last reviewed on RxList: 12/11/2014
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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 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 [see Dose Modification]. 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 [see Dose Modification]. 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] [see Use in Specific Populations]. 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 [see Use in Specific Populations]. 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. 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. 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 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 [see Use in Specific Populations]. 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 [see WARNINGS AND PRECAUTIONS]. 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 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 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) [See WARNINGS AND PRECAUTIONS]. 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 3050 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 events 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 [See WARNINGS AND PRECAUTIONS]. 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. Last reviewed on RxList: 12/11/2014
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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