Adcetris

Adcetris

brentuximab vedotin

Manufacturer:

Takeda
Full Prescribing Info
Contents
Brentuximab vedotin.
Description
Each single-use vial contains 50 mg of brentuximab vedotin.
Each mL contains 5 mg of brentuximab vedotin, after reconstitution.
Brentuximab vedotin is an antibody-drug conjugate composed of a CD30-directed monoclonal antibody (recombinant chimeric immunoglobulin G1 (IgG1), produced by recombinant DNA technology in Chinese Hamster ovary cells) that is covalently linked to the antimicrotubule agent monomethyl auristatin E (MMAE).
Excipients/Inactive Ingredients: (weight per 50 mg vial; concentration after reconstitution): Citric acid monohydrate; Sodium citrate dihydrate; α,α-Trehalose dihydrate; Polysorbate 80.
Action
Pharmacotherapeutic group: monoclonal antibodies. ATC code: L01XC12.
Pharmacology: Pharmacodynamics: Pharmacologic class: CD30-directed class antibody-drug conjugate.
Mechanism of Action: ADCETRIS is an Antibody Drug Conjugate (ADC) that delivers an antineoplastic agent that results in apoptotic cell death selectively in CD30-expressing tumor cells. Nonclinical data suggest that the biological activity of ADCETRIS results from a multi-step process. Binding of the ADC to CD30 on the cell surface initiates internalization of the ADC-CD30 complex, which then trafficks to the lysosomal compartment. Within the cell, a single defined active species, MMAE, is released via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, induces cell cycle arrest and results in apoptotic death of the CD30-expressing tumor cell.
Contributions to the mechanism of action by other antibody associated functions have not been excluded.
General: No primary pharmacodynamic relationships have been identified.
Cardiac Electrophysiology: Forty-six (46) patients with CD30-expressing hematologic malignancies were evaluable of the 52 patients who received 1.8 mg/kg of ADCETRIS every 3 weeks as part of a phase 1, single-arm, open-label, multicenter cardiac safety study. The primary objective was to evaluate the effect of brentuximab vedotin on cardiac ventricular repolarization and the predefined primary analysis was the change in QTc from baseline to multiple time points in Cycle 1.
The upper 90% confidence interval (CI) was <10 msec at each of the Cycle 1 post-baseline time-points. These data indicate the absence of clinically relevant QT prolongation due to brentuximab vedotin administered at a dose of 1.8 mg/kg in patients with CD30-expressing malignancies.
Clinical Studies: Hodgkin Lymphoma: Study SG035-0003: The efficacy and safety of brentuximab vedotin as a single agent was evaluated in an open-label, single- arm, multicenter study in 102 patients with relapsed or refractory HL. (See Table 1.)


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All patients had a histologically confirmed CD30-expressing disease and had at least one prior autologous stem cell transplant (ASCT). Seventy-two patients (71%) had primary refractory HL, defined as a failure to achieve a complete response to, or progressed within 3 months of completing frontline therapy; 43 patients (42%) were refractory and 59 patients (58%) had relapsed following their most recent prior therapy. Patients had received a median of 3.5 prior systemic chemotherapies. The median time from ASCT to first post-transplant relapse was 6.7 months. Patients received up to 16 cycles of therapy; the median number of cycles received was 9 (ranging from 1 to 16). The primary endpoint, Objective Response Rate, was 74.5%. See Table 2 as follows for other pre-specified endpoints.


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No clinically meaningful differences in the objective response rate were observed within the subgroups analyzed among the following subgroups analyzed: gender, baseline weight (≤100 kg versus >100 kg), baseline B symptoms, number of treatments prior to ASCT (≤2 versus >2), number of treatments post-ASCT (0 versus ≥1), relapsed versus refractory to last therapy, primary refractory disease, and time from ASCT to relapse post-ASCT (≤1 year versus >1 year).
Tumor reduction was achieved in 94% of patients. See Figure 1 for waterfall chart of tumor reduction, ORR and CR.


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Per IRF, median time to first response was 1.3 months, and median time to CR was 2.8 months. Median duration of objective response was 6.7 months (95% CI [3.6, 14.8]) with a range of 1.2+ to 26.1+ months. Of the patients treated, 7 responding patients went on to receive an allogeneic stem cell transplant.
Of the 35 patients who had B symptoms at baseline, 27 patients (%) experienced resolution of all B symptoms at a median time from initiation of ADCETRIS of 0.7 months.
Per IRF, the median PFS for patients treated with ADCETRIS was 5.6 months (95% CI [5.0, 9.0]) (the median follow-up time from first dose for patients who were censored on PFS was 5.8 months). Patients who attained a CR achieved a median PFS of 29.2 months while those who attained a PR achieved a median PFS of 5.1 months and those who attained SD achieved a median PFS of 3.5 months. See Figure 2 for median PFS by best clinical response.


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Patients who received ADCETRIS achieved a PFS improvement versus their most recent post ASCT therapy (7.8 months [5.2, 9.9] versus 4.1 months [3.4, 4.9] as assessed by investigator). See Figure 3 for a KM plot of PFS with ADCETRIS compared to PFS from the most recent post-ASCT therapy.


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In addition, patients experienced a greater overall and complete response rate compared to their most recent post-ASCT therapy. The median overall survival was 40.5 months.
An exploratory intra-patient analysis showed that approximately 64% of the HL patients treated with brentuximab vedotin as part of the SG035-0003 clinical study experienced an improvement in clinical benefit as measured by longer progression free survival (PFS) compared with their most recent prior line of therapy.
Data in HL Patients Who Are Not Stem Cell Transplant (SCT) Candidates: Study C25007: A phase 4 single-arm study was conducted in patients with relapsed or refractory HL (n=60) who had received at least one prior chemotherapeutic regimen and at the time of treatment initiation with brentuximab vedotin were not considered candidates for SCT or multiagent chemotherapy. The median number of cycles was 7 (range 1 to 16 cycles). Patients were treated with 1.8 mg/kg of brentuximab vedotin every 3 weeks. Per IRF, the overall response rate (ORR) in the ITT population was 50% (95% CI, 37; 63%). A best overall response of CR was reported for 7 patients (12%); PR was reported for 23 patients (38%). Twenty eight patients (47%) went on to receive SCT after a median of 7 cycles (range 4 to 16 cycles) of brentuximab vedotin treatment. The 32 patients (53%) who did not receive subsequent SCT also received brentuximab vedotin for a median of 7 cycles (range 1 to 16 cycles). Eleven patients (18%) had received one prior chemotherapeutic regimen. Per IRF, the overall response rate (ORR) in these patients was 45% (95% CI, 17; 77%). A best overall response of CR was reported for 1 patient (9%); PR was reported for 4 patients (36%).
Data were also collected from patients (n=15) in phase 1 dose escalation and clinical pharmacology studies, and from patients (n=26) in a Named Patient Program (NPP), with relapsed or refractory HL who had not received an ASCT, and who were treated with 1.8 mg/kg of brentuximab vedotin every 3 weeks.
Baseline patient characteristics showed failure from multiple prior chemotherapy regimens (median of 3 with a range of 1 to 7) before first administration with brentuximab vedotin. Fifty nine percent (59%) of patients had advanced stage disease (stage III or IV) at initial diagnosis.
Results from these phase 1 studies and from the NPP experience showed, that in patients with relapsed or refractory HL without prior ASCT, clinically meaningful responses can be achieved as evidenced by an investigator-assessed, objective response rate of 54% and a complete remission rate of 22% after a median of 5 cycles of brentuximab vedotin.
Study SGN35-005: The efficacy and safety of brentuximab vedotin were evaluated in a randomized, double-blinded, placebo-controlled, 2-arm multicenter trial in 329 patients with HL at risk of relapse or progression following ASCT. See Table 3 for patient characteristics. Of the 329 patients, 165 patients were randomized to the treatment arm and 164 patients were randomized to the placebo arm. The safety population in the ADCETRIS arm (N=167) included two additional patients who received at least one dose of ADCETRIS but were not randomized to the treatment arm. In the study, patients were to receive their first dose after recovery from ASCT (between days 30-45 following ASCT). Patients were treated with 1.8 mg/kg of ADCETRIS or matching placebo intravenously over 30 minutes every 3 weeks for up to 16 cycles.
The median number of cycles received in both arms was 15 cycles.
Eligible patients were required to have at least one of the following risk factors: HL that was refractory to frontline treatment; Relapsed or progressive HL that occurred <12 months from the end of frontline treatment; Extranodal involvement at time of pre-ASCT relapse, including extranodal extension of nodal masses into adjacent vital organs. (See Table 3, Table 4 and Figure 4 and Figure 5.)


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Pre-specified subgroup analyses of PFS per IRF were performed by patients' best response to pre-ASCT salvage therapy, HL status after frontline therapy, age, gender, baseline weight, baseline ECOG performance status, number of treatments pre-ASCT, geographic region, pre-ASCT PET status, B symptom status after failure of frontline therapy, and pre-ASCT extranodal disease status. The analyses showed a consistent trend towards benefit for patients who received brentuximab vedotin compared with patients who received placebo with the exception of patients ≥65 years of age (n=8).
At the time of primary PFS analysis, an interim OS analysis was performed and there was no significant difference in OS between the treatment and placebo arms. Fifty-three patients had died; 28/165 patients in the brentuximab vedotin arm versus 25/164 patients in the placebo arm.
Quality of life was assessed using the EQ-5D instrument. No clinically meaningful differences were observed between the treatment and placebo arms.
Post-hoc Risk Factor Analyses: Post-hoc analyses were performed to evaluate the impact of increased risk (number of risk factors) on clinical benefit (Table 5). Representative risk factors for these analyses were: HL that occurred <12 months or HL that was refractory to frontline therapy;
Best response of PR or SD to most recent salvage therapy as determined by CT and/or PET scanning;
Extranodal disease at pre-ASCT relapse;
B symptoms at pre-ASCT relapse;
Two or more prior salvage therapies.
The results of these post-hoc analyses suggest increased clinical benefit for patients with two or more risk factors but no difference based on any of the individual risk factors. No benefit in terms of PFS or OS has been observed in patients with one risk factor for relapse or progression. (See Table 5.)


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At the time of the updated analysis (3 years of follow-up) for patients with 2 or more risk factors, the hazard ratio for PFS per IRF was 0.49 (95% CI [0.34, 0.71]) and the hazard ratio for PFS per investigator was 0.41 (95% CI [0.29, 0.58]) (see Figure 6 and Figure 7).


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Study SGN35-006 (Retreatment Study): The efficacy of retreatment in patients who had previously responded (CR or PR) to treatment with ADCETRIS was evaluated in a phase 2, open-label, multicenter trial. Twenty patients with relapsed or refractory HL received a starting dose of 1.8 mg/kg and one patient received a starting dose of 1.2 mg/kg of ADCETRIS administered intravenously over 30 minutes every 3 weeks. The median number of cycles was 7 (range 2 to 37 cycles). Of the 20 evaluable patients with HL, 6 patients (30%) achieved a CR and 6 patients (30%) achieved a PR with ADCETRIS retreatment, for an ORR of 60%. The median duration of response was 9.2 and 9.4 months in patients who achieved OR (CR+PR) and CR, respectively.
Systemic Anaplastic Large Cell Lymphoma: Study SG035-0004: The efficacy and safety of brentuximab vedotin as a single agent was evaluated in an open-label, single-arm, multicenter study in 58 patients with relapsed or refractory sALCL. (See Table 6.)


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All patients had a histologically confirmed CD30-expressing disease and had received front-line chemotherapy with curative intent. A total of 58 patients were treated: 36 patients (62%) had primary refractory sALCL, defined as a failure to achieve a complete response to, or progressed within 3 months of completing frontline therapy; 29 patients (50%) were relapsed and 29 patients (50%) were refractory to most recent prior therapy; 42 patients (72%) had anaplastic lymphoma kinase (ALK)-negative disease. Patients had received a median of 2 prior systemic chemotherapies. Fifteen patients (26%) had received a prior ASCT. The median time from initial sALCL diagnosis to first dose with brentuximab vedotin was 16.8 months. Patients received up to 16 cycles of therapy; the median number of cycles received was 7 (range, 1 to 16). The primary endpoint, Objective Response Rate, was 86.2%. See Table 7 as follows for other prespecified endpoints.


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No clinically meaningful differences in the objective response rate were observed among the following subgroups analyzed: gender, baseline weight (≤100 kg versus >100 kg), baseline B symptoms, prior autologus stem cell transplantation (ASCT), and post-treatment ASCT. The ORR for relapsed patients was higher than those who were refractory (97% vs. 76%). Tumor reduction was achieved in 97% of patients. See Figure 8 for waterfall chart of tumor reduction, ORR and CR.


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Per IRF, median time to first objective response was 1.4 months (range, 1.0-3.2 months) and the median time to CR was 2.7 months (range, 1.2-11.6 months). Median duration of objective response was 13.2 months (95% CI [5.7, NE]) with a range of 0.1+ to 21.7+ months (the median follow-up time from first dose was 11.8 months). Of the patients treated, 9 responding patients went on to receive an allogeneic stem cell transplant (SCT) and 7 responding patients went onto autologous SCT.
Of the 17 patients who had B symptoms at baseline, 14 patients (82%) experienced resolution of all B symptoms in a median time from initiation of ADCETRIS of 0.7 months.
Per IRF, the median PFS for patients treated with ADCETRIS was 14.6 months (the median follow-up time from first dose was 14.2 months). Patients who attained a CR achieved a median PFS of 27.4 months while those who attained a PR achieved a PFS of 3.9 months. See Figure 9 for median PFS by best clinical response. (See Figure 9.)


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Patients who received ADCETRIS achieved a PFS improvement versus last therapy received prior to study entry (19.6 months [9.1, NE] versus 5.9 months [3.9, 8.3] as assessed by investigator). See Figure 10 for a KM plot of PFS with ADCETRIS compared to PFS from last therapy received prior to study.


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In addition, patients experienced a greater overall and CR rate compared to their most recent therapy. The median overall survival was not reached. The estimated 36 month overall survival was 63% (95% CI [51, 76]).
An exploratory intra-patient analysis showed that approximately 69% of the sALCL patients treated with brentuximab vedotin as part of the SG035-0004 clinical study experienced an improvement in clinical benefit as measured by longer progression free survival (PFS) compared with their most recent prior line of therapy.
Study SGN35-006 (Retreatment study): The efficacy of retreatment in patients who had previously responded (CR or PR) to treatment with ADCETRIS was evaluated in a phase 2, open-label, multicenter trial. Seven patients with relapsed sALCL received a starting dose of 1.8 mg/kg and one patient received a starting dose of 1.2 mg/kg of ADCETRIS administered intravenously over 30 minutes every 3 weeks. The median number of cycles was 8.5 (range, 2 to 30 cycles). Of the 8 sALCL patients, 3 were retreated twice for a total of 11 retreatment experiences. Retreatment with ADCETRIS resulted in 6 CRs (55%) and 4 PRs (36%), for an ORR of 91%. The median duration of response was 8.8 and 12.3 months in patients who achieved OR (CR+PR) and CR, respectively.
Cutaneous T-Cell Lymphoma: Study C25001: The efficacy and safety of ADCETRIS as a single agent was evaluated in a pivotal phase 3, open-label, randomized, multicenter study in 128 patients with histologically confirmed CD30-expressing CTCL.
Patients were stratified by disease subtype (mycosis fungoides [MF] or primary cutaneous anaplastic large cell lymphoma [pcALCL]) and randomized 1:1 to receive either ADCETRIS or the physician's choice of either methotrexate or bexarotene. Patients with pcALCL received either prior radiation therapy or at least 1 prior systemic therapy and patients with MF received at least 1 prior systemic therapy. Patients were treated with 1.8 mg/kg of ADCETRIS intravenously over 30 minutes every 3 weeks for up to 16 cycles or physician's choice for up to 48 weeks. The median number of cycles was approximately 12 cycles in the ADCETRIS arm. In the physician's choice arm, the median duration of treatment (number of cycles) for patients receiving bexarotene was approximately 16 weeks (5.5 cycles) and 11 weeks (3 cycles) for patients receiving methotrexate. Table 8 provides a summary of the baseline patient and disease characteristics. (See Table 8.)


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Pharmacokinetics: General Introduction: The pharmacokinetics of ADCETRIS were evaluated in phase 1 studies and in a population pharmacokinetic analysis of data from 314 patients.
Absorption and Bioavailability: The serum pharmacokinetics of ADC following an intravenous dose of ADCETRIS were similar to other antibody products. Maximum concentrations were typically observed at the end of infusion or the sampling time point closest to the end of infusion. A multiexponential decline in ADC serum concentrations was observed with a terminal half-life of approximately 4 to 6 days. Exposures were approximately dose proportional. After multiple-dose administration of ADCETRIS, ADC steady-state was achieved by 21 days, consistent with the terminal half-life estimate. Minimal to no accumulation of ADC was observed with multiple doses at the every 3-week schedule.
The elimination of MMAE was limited by its rate of release from ADC. The time to maximum concentration ranged from approximately 1 to 3 days after each infusion. MMAE exposures decreased after multiple doses of ADCETRIS with approximately 50% to 80% of the exposure of the first dose being observed at subsequent doses.
Distribution: In vitro, the binding of MMAE to human serum plasma proteins ranged from 68-82%. MMAE is not likely to displace or to be displaced by highly protein-bound drugs. In vitro, MMAE was a substrate of P-gp and was not a potent inhibitor of P-gp.
In humans, the mean steady state volume of distribution was approximately 6-10 L for ADC.
Metabolism: In vivo data in animals and humans suggests that only a small fraction of MMAE released from ADCETRIS is metabolized. In vitro data indicate that the MMAE metabolism that occurs is primarily via oxidation by CYP3A4/5. In vitro studies using human liver microsomes indicate that MMAE inhibits CYP3A4/5 but not other isoforms. MMAE did not induce any major CYP450 enzymes in primary cultures of human hepatocytes.
Elimination: An excretion study was undertaken in patients who received a dose of 1.8 mg/kg of ADCETRIS (brentuximab vedotin). Approximately 24% of the total MMAE administered as part of the ADC during a ADCETRIS infusion was recovered in both urine and feces over a 1-week period. Of the recovered MMAE, approximately 72% was recovered in the feces and the majority of the excreted MMAE was unchanged. A lesser amount of MMAE (28%) was excreted in the urine and the majority was excreted unchanged.
Pediatric: Clinical studies of ADCETRIS did not include sufficient numbers of subjects below 18 years of age to determine whether they respond differently from older subjects. Safety and efficacy have not been established.
Elderly: The population pharmacokinetics of ADCETRIS were examined from several studies, including data from 380 patients up to 87 years old. The influence of age on pharmacokinetics was investigated and it was not a significant covariate. The safety profile in elderly patients with CTCL was consistent with that of adult patients, therefore dosing recommendations for patients aged 65 and older are the same as for adults.
Renal impairment: A study evaluated the pharmacokinetics of ADCETRIS and MMAE after the administration of 1.2 mg/kg of ADCETRIS to patients with mild (n=4), moderate (n=3) and severe (n=3) renal impairment. Compared to patients with normal renal function, MMAE exposure increased approximately 1.9-fold in patients with severe renal impairment.
Hepatic impairment: A study evaluated the pharmacokinetics of ADCETRIS and MMAE 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. Compared to patients with normal hepatic function, MMAE exposure increased approximately 2.3-fold in patients with hepatic impairment.
Toxicology: Carcinogenicity: Carcinogenicity studies with ADCETRIS (brentuximab vedotin) or MMAE have not been conducted.
Mutagenicity: MMAE was negative for mutagenicity in the bacterial reverse mutation assay (Ames test) and the mouse lymphoma forward mutation assay. The in vivo rat bone marrow micronucleus study revealed aneugenic rather than clastogenic micronuclear formation. These results were consistent with the pharmacological effect of MMAE on the mitotic apparatus (disruption of the microtubule network) in cells.
Impairment of Fertility: The effects of ADCETRIS on human male and female fertility have not been studied. However, results of repeat-dose toxicity studies in rats indicate the potential for brentuximab vedotin to impair male reproductive function and fertility. Testicular atrophy and degeneration were observed in a 4-week rat study when brentuximab vedotin was given weekly at intravenous doses of 5 or 10 mg/kg. These changes were partially reversible following a 16-week treatment-free period.
Indications/Uses
ADCETRIS is indicated for the treatment of patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL).
ADCETRIS is indicated for the treatment of patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL) following Autologous Stem Cell Transplant (ASCT) or at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option.
ADCETRIS is indicated for the treatment of patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL).
ADCETRIS is indicated for the treatment of adult patients with histologically confirmed CD30+ mycosis fungoides (MF) or primary cutaneous anaplastic large cell lymphoma (pcALCL) after at least 1 prior systemic therapy.
Dosage/Direction for Use
The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks.
For patients with HL at risk of relapse or progression following ASCT, ADCETRIS treatment should start following recovery from ASCT based on medical judgment. These patients should receive up to 16 cycles (see Pharmacology: Clinical Studies under Actions).
The recommended starting dose for the retreatment of patients with relapsed or refractory HL or sALCL who have previously responded to treatment with ADCETRIS is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Alternatively, treatment may be started at the last tolerated dose (see Pharmacology: Clinical Studies under Actions).
Patients with histologically confirmed CD30+ mycosis fungoides (MF) or primary cutaneous anaplastic large cell lymphoma (pcALCL) should receive up to 16 cycles.
The recommended starting dose in patients with severe renal impairment is 1.2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Patients with renal impairment should be closely monitored for adverse events (see Pharmacology: Pharmacokinetics under Actions).
The recommended starting dose in patients with hepatic impairment is 1.2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Patients with hepatic impairment should be closely monitored for adverse events (see Pharmacology: Pharmacokinetics under Actions).
Do not administer as an IV push or bolus.
If patient's weight is more than 100 kg, the dose calculation should use 100 kg.
Continue treatment until disease progression or unacceptable toxicity (see Precautions).
Patients who achieve stable disease or better should receive a minimum of 8 cycles.
There is clinical experience with treating patients through 16 cycles (approximately 1 year).
Dose Modification and/or Dose Discontinuation: Continue treatment as long as the patient continues to benefit from and tolerates the therapy. See as follows for recommendations for peripheral neuropathy and neutropenia.
Peripheral Neuropathy: If peripheral sensory or motor neuropathy emerges or worsens during treatment see Table 9 as follows for appropriate recommendations.


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Neutropenia: If neutropenia develops during treatment it should be managed by dose delays (see Precautions). See Table 10 as follows for appropriate dosing recommendations.


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Elderly: Based upon population PK analyses and the safety profile in elderly patients, which are consistent with that of adult patients, the dosing recommendations for patients aged 65 and older are the same as for adults.
Paediatric population: The safety and efficacy of children less than 18 years have not yet been established. No data are available.
In nonclinical studies, thymus depletion has been observed.
Instructions for Reconstitution: General Precautions: Follow proper aseptic technique throughout the handling of ADCETRIS.
Recommended safety measures for handling and preparation include protective clothing, gloves, and vertical laminar airflow safety cabinets.
ADCETRIS vials are single-use containers. Any partially used vials or diluted dosing solutions are to be discarded using appropriate institutional drug disposal procedures.
Determining Dosage Amount: Calculate the dose (mg) and number of vials of ADCETRIS required.
Dose calculation to prepare infusion solution for a normal dose: (1.8 mg/kg) X patient's weight in kg = dose in mg.
Note: If patient's weight is more than 100 kg, the dose calculation should use 100 kg.
To calculate amount of mLs: (Dose in mg) divided by (5 mg/mL which is the final concentration in a reconstituted vial) = dose in mL.
Since 10-mL can be withdrawn from each vial, calculate the number of vials needed to prepare infusion solution: (Dose in mL) divided by (10-mL/vial) = Number of vials that should be used.
Dose calculation to prepare infusion solution for a reduced dose: (1.2 mg/kg) X pts weight in kg = dose in mg.
Note: If patient's weight is more than 100 kg, the dose calculation should use 100 kg.
To calculate amount of mLs: (Dose in mg) divided by (5 mg/mL which is the final concentration a reconstituted vial) = dose in mL.
Since 10-mL can be withdrawn from each vial, calculate the number of vials needed to prepare infusion solution: (Dose in mL) divided by (10-mL/vial) = Number of vials that should be used.
Instructions for reconstitution: Each 50 mg single-use vial must be reconstituted with 10.5 ml of Water for Injection only. Direct the stream toward the wall of the vial and not directly at the cake. Gently swirl the vial to aid dissolution. DO NOT SHAKE. The reconstituted solution in the vial is a clear to slightly opalescent, colorless solution with a final pH of 6.6. The reconstituted solution should be inspected visually for any particulate matter or discoloration. If any discoloration or particulate matter is observed, the reconstituted solution must be discarded. If not used immediately, the reconstituted solution may be stored at 2-8˚C (DO NOT FREEZE) for no more than 24 hours. ADCETRIS contains no bacteriostatic preservatives; Discard any unused portion left in the vial.
Preparation of Infusion Solution: There are no known incompatibilities between ADCETRIS and polyvinylchloride bags, ethylene vinylacetate (EVA), polyolefin, polyethylene (PE), or polypropylene (PP).
The appropriate amount of reconstituted ADCETRIS will be withdrawn from the vial(s) and added to an infusion bag containing 0.9% Sodium Chloride Injection, USP or equivalent, in order to achieve a final concentration of 0.4-1.8 mg/mL brentuximab vedotin. The already reconstituted ADCETRIS can also be diluted into 5% dextrose in water (D5W), USP or equivalent, or Lactated Ringers Solution, USP or equivalent.
Gently invert the bag to mix the solution containing ADCETRIS. DO NOT SHAKE. Excess agitation may cause aggregate formation.
Do not add other medications to the prepared ADCETRIS infusion solution or IV infusion set. Infusion line should be flushed following administration with 0.9% Sodium Chloride Injection, 5% dextrose in water (D5W), or Lactated Ringers Solution.
Following dilution, infuse the ADCETRIS solution immediately at the recommended infusion rate, or store the solution at 2-8°C (DO NOT FREEZE) and use within 24 hours.
Total storage time of the solution from reconstitution to infusion must not exceed 24 hours.
*Sterile water for injection (preservative free).
Overdosage
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 (see Neutropenia under Precautions).
Contraindications
Combination use of bleomycin and ADCETRIS due to pulmonary toxicity.
Hypersensitivity to the active substance or to any of the excipients listed in Description.
Special Precautions
Progressive Multifocal Leukoencephalopathy: JC virus (JCV) infection resulting in progressive multifocal leukoencephalopathy (PML) and death can occur in ADCETRIS-treated patients. PML has been reported in patients who received ADCETRIS after receiving multiple prior chemotherapy regimens. PML is a rare demyelinating disease of the central nervous system that results from reactivation of latent JCV and is often fatal.
New or worsening neurological, cognitive, or behavioral signs or symptoms may be suggestive of PML. ADCETRIS dosing should be held for any suspected case of PML. Suggested evaluation of PML includes neurology consultation, gadolinium-enhanced magnetic resonance imaging of the brain and cerebrospinal fluid analysis for JCV DNA by polymerase chain reaction or a brain biopsy for evidence of JCV. ADCETRIS dosing should be permanently discontinued if a diagnosis of PML is confirmed.
The physician should be particularly alert to symptoms suggestive of PML that the patient may not notice (e.g., cognitive, neurological, or psychiatric symptoms).
Pancreatitis: Acute pancreatitis has been observed in patients treated with ADCETRIS. Fatal outcomes have been reported.
Patients should be closely monitored for new or worsening abdominal pain, which may be suggestive of acute pancreatitis. Patient evaluation may include physical examination, laboratory evaluation for serum amylase and serum lipase, and abdominal imaging, such as ultrasound and other appropriate diagnostic measures. Brentuximab vedotin should be held for any suspected case of acute pancreatitis. ADCETRIS should be discontinued if a diagnosis of acute pancreatitis is confirmed.
Pulmonary Toxicity: Cases of pulmonary toxicity, including pneumonitis, interstitial lung diseases, and acute respiratory distress syndrome (ARDS), some with fatal outcomes have been reported in patients receiving ADCETRIS. Although a causal association with ADCETRIS has not been established, the risk of pulmonary toxicity cannot be ruled out. In the event of new or worsening pulmonary symptoms (e.g., cough, dyspnea), a prompt diagnostic evaluation should be performed and patients should be treated appropriately. Consider holding ADCETRIS dosing during evaluation and until symptomatic improvement.
Serious Infections and Opportunistic Infections: Serious and opportunistic infections such as pneumonia, bacteremia, and sepsis/septic shock (including fatal outcomes) have been reported in patients treated with ADCETRIS. Patients should be carefully monitored during treatment for the emergence of possible bacterial, fungal or viral infections.
Infusion-Related Reactions: Infusion-related reactions can occur with ADCETRIS. Carefully monitor patients during infusion. 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 paracetamol (acetaminophen), an antihistamine and a corticosteroid.
Anaphylaxis has been reported with ADCETRIS. Carefully monitor patients during infusion. If anaphylaxis occurs, immediately discontinue administration of ADCETRIS and administer appropriate medical therapy. There are limited data with retreatment of patients who have experienced an anaphylactic reaction with ADCETRIS.
Peripheral Neuropathy: ADCETRIS treatment may cause peripheral neuropathy, both sensory and motor. ADCETRIS-induced peripheral neuropathy is typically cumulative and generally reversible. In clinical trials, the majority of patients had improvement or resolution of some of their symptoms. Patients should be monitored 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 and a change in dose of ADCETRIS or ADCETRIS discontinuation (see Dose Modification under Dosage & Administration). Neuropathy appeared to be mitigated by dose delay and subsequent reduction or ADCETRIS discontinuation.
Hematological Toxicities: Grade 3 or Grade 4 anemia, thrombocytopenia, and prolonged (≥1 week) neutropenia can occur with ADCETRIS. Febrile neutropenia has been reported with treatment with ADCETRIS. Complete blood counts should be monitored prior to administration of each dose of ADCETRIS. Patients should be monitored closely for fever. If Grade 3 or 4 neutropenia develops, manage by dose modifications or discontinuations (see Dose Modification under Dosage & Administration).
Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with ADCETRIS. Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome. These patients should be monitored closely and appropriate measures taken.
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. Fatal outcomes have been reported. If SJS or TEN occur, discontinue ADCETRIS and administer appropriate medical therapy.
Gastrointestinal Complications: Gastrointestinal (GI) complications including intestinal obstruction, ileus, enterocolitis, neutropenic colitis,erosion, ulcer, perforation and haemorrhage, some with fatal outcomes, have been reported in patients treated with ADCETRIS. Some cases of GI perforations were reported in patients with GI involvement of underlying lymphoma. In the event of new or worsening GI symptoms, perform a prompt diagnostic evaluation and treat appropriately.
Hepatotoxicity: Hepatotoxicity in the form of elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) has been reported with ADCETRIS. Serious cases of hepatotoxicity, including fatal outcomes, have also occurred. Pre-existing liver disease, comorbidities and concomitant medications may also increase the risk. Liver function should be routinely monitored in patients receiving ADCETRIS. Patient experiencing hepatotoxicity may require a delay, change in dose or discontinuation of ADCETRIS. (See Adverse Reactions.)
Renal and Hepatic Impairment: There is limited experience in patients with renal and hepatic impairment. Available data indicate that MMAE clearance might be affected by severe renal impairment, hepatic impairment, and by low serum albumin concentrations. (See Pharmacology: Pharmacokinetics under Actions).
Use in Pregnancy: ADCETRIS may cause fetal harm when administered to pregnant women (See Use in Pregnancy & Lactation).
Use In Pregnancy & Lactation
Pregnancy: There are no adequate and well-controlled studies with ADCETRIS in pregnant women. ADCETRIS may cause fetal harm when administered to pregnant women; therefore women who are pregnant should not begin treatment with ADCETRIS. Women of childbearing potential should be advised not to become pregnant while taking this medicine, and must use effective methods to prevent pregnancy from the start of treatment with ADCETRIS and must continue for 6 months following the last dose of ADCETRIS. If the patient becomes pregnant while taking ADCETRIS, the patient should be apprised of the potential hazard to the fetus.
ADCETRIS was studied for effects on embryo-fetal development in pregnant female rats. The no-observed-adverse-effect-level of ADCETRIS when administered to pregnant rats was 1 mg/kg/dose.
It is not known if using ADCETRIS will affect human spermatogenesis. In nonclinical studies, ADCETRIS resulted in testicular toxicity which was partially resolved 16-weeks post last dose administration. Therefore, due to this potential risk, men should be advised not to impregnate their partner during treatment with ADCETRIS. Men of reproductive potential must use an appropriate method of barrier contraception throughout treatment with ADCETRIS and for at least 6 months following the last dose of ADCETRIS (see Precautions).
Lactation (Breastfeeding): It is not known whether ADCETRIS or MMAE are 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 ADCETRIS to the mother.
Adverse Reactions
Summary of the safety profile: The safety profile of ADCETRIS is based on available clinical trial data, the Named Patient Program (NPP), and post-marketing experience to date. Frequencies of adverse reactions described as follows and in Table 11 have been determined based on data generated from clinical studies.
In the pooled dataset of Adcetris as monotherapy across HL, sALCL and CTCL studies (SG035-0003, SG035-0004, SGN35-005, SGN35-006, C25001 and C25007, see Contraindications) the most frequent adverse reactions (≥10%) were infections, peripheral sensory neuropathy, nausea, fatigue, diarrhoea, pyrexia, upper respiratory tract infection, neutropenia, rash, cough, vomiting, arthralgia, peripheral motor neuropathy, infusion-related reactions, pruritus, constipation, dyspnoea, weight decreased, myalgia and abdominal pain.
Serious adverse drug reactions occurred in 12% of patients. The frequency of unique serious adverse drug reactions was ≤1%.
Adverse events led to treatment discontinuation in 24% of patients receiving brentuximab vedotin.
The safety data in patients retreated with ADCETRIS (SGN35-006) were consistent with those observed in the combined pivotal phase 2 studies, with the exception of peripheral motor neuropathy, which had a higher incidence (28% vs. 9% in the pivotal phase 2 studies) and was primarily Grade 2. Patients also had a higher incidence of arthralgia, Grade 3 anaemia, and back pain compared to patients observed in the combined pivotal phase 2 studies.
The safety data in patients with relapsed or refractory HL who had not received an autologous stem cell transplant and were treated with the recommended dose of 1.8 mg/kg every three weeks in the phase 1 dose escalation and clinical pharmacology studies (n=15 patients) and in the NPP (n=26 patients) (see Contraindications) were consistent with the safety profile of the pivotal clinical studies.
Tabulated list of adverse reactions: Adverse reactions for ADCETRIS are listed by MedDRA System Organ Class and Preferred Term (see Table 11). Within each System Organ Class, adverse reactions are listed under frequency categories of: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000); not known (cannot be estimated from the available data). (See Table 11.)


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Description of selected adverse reactions: Neutropenia: In clinical trials, neutropenia led to dose delays in 14% of patients. Grade 3 neutropenia was reported in 13% and Grade 4 neutropenia was reported in 5% of patients. No patients required dose reduction or discontinued treatment for neutropenia.
Severe and prolonged (≥1 week) neutropenia can occur with this treatment which may increase the risk of patients developing serious infections. Febrile neutropenia reported in <1% of the patients.
In the pivotal phase 2 population (SG035-0003 and SG035-0004), the median duration of Grade 3 or Grade 4 neutropenia was limited (1 week); 2% of patients had Grade 4 neutropenia that lasted ≥7 days. Less than half of the patients in the pivotal phase 2 population with Grade 3 or Grade 4 neutropenia had temporally associated infections, and the majority of temporally associated infections were Grade 1 or Grade 2.
Serious infections and opportunistic infections: In clinical trials, serious infections and opportunistic infections occurred in 10% of patients, sepsis or septic shock occurred in <1% of the patients. The most commonly reported opporunistic infections were herpes zoster and herpes simplex.
Peripheral neuropathy: In clinical trials treatment emergent neuropathy occurred in 59% of the population, peripheral motor neuropathy occurred in 14% of patients. Peripheral neuropathy led to treatment discontinuation in 15%, dose reductions in 15%, and dose delays in 17% of patients. For patients who experienced peripheral neuropathy the median time of onset of peripheral neuropathy was 12 weeks. The median duration of treatment for patients who discontinued due to peripheral neuropathy was 12 cycles.
Among patients who experienced peripheral neuropathy in the pivotal phase 2 studies (SG035-0003 and SG035-0004) and randomized phase 3 studies (SGN35-005 and C25001), the median follow up time from end of treatment until last evaluation ranged from 48.9 to 98 weeks. At the time of last evaluation, most of the patients (82-85%) who experienced peripheral neuropathy had resolution or improvement of their peripheral neuropathy symptoms. The median time from onset to resolution or improvement for all events ranged from 16 to 23.4 weeks.
In patients with relapsed or refractory HL or sALCL who were retreated with brentuximab vedotin (SGN35-006), the majority of patients (80%) also had improvement or resolution of their peripheral neuropathy symptoms at the time of last evaluation.
PML has been reported of the pivotal phase 2 clinical trials.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with brentuximab vedotin in clinical trials and post-marketing use. Fatal outcomes have been reported.
Infusion-related reactions: IRRs, such as headache, rash, back pain, vomiting, chills, nausea, dyspnoea, pruritus and cough were reported in 13% of patients. Anaphylactic reactions have been reported. Symptoms of an anaphylactic reaction may include, but are not limited to, urticaria, angioedema, hypotension and bronchospasm.
Immunogenicity: In clinical trials, patients were periodically tested for antibodies to brentuximab vedotin using a sensitive electrochemiluminescent immunoassay. There was a higher incidence of infusion-related reactions observed in patients with antibodies to brentuximab vedotin relative to patients who tested transiently positive or negative.
The presence of antibodies to brentuximab vedotin did not correlate with a clinically meaningful reduction in serum brentuximab vedotin levels and did not result in a decrease in the efficacy of brentuximab vedotin. While the presence of antibodies to brentuximab vedotin does not necessarily predict the development of an IRR, there was a higher incidence of IRRs observed in patients with persistently positive ATA relative to patients with transiently positive ATA and never positive ATA.
Drug Interactions
CYP3A4 Inhibitors, Inducers and Substrates: Co-administration of ADCETRIS with ketoconazole, a strong CYP3A4 inhibitor and P-gp inhibitor, did not alter exposure to ADCETRIS; however, a moderate increase to the exposure to MMAE was observed. Patients who are receiving strong CYP3A4 inhibitors and P-gp inhibitors concomitantly with ADCETRIS should be closely monitored for adverse events.
Co-administration of ADCETRIS with rifampicin, a strong CYP3A4 inducer, did not alter exposure to ADCETRIS; however, a moderate reduction to the exposure to MMAE was observed. Co-administration of ADCETRIS with CYP3A4 inducers is not expected to have an impact on safety or efficacy.
Co-administration of midazolam, a CYP3A4 substrate, with ADCETRIS did not alter the metabolism of midazolam; therefore ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes (see Pharmacology: Pharmacokinetics under Actions).
Caution For Usage
Special Precautions for Storage and Transportation: Reconstituted ADCETRIS vial: Chemical and physical in-use stability has been demonstrated for 24 hours at 2-8°C. From a microbiological point of view, the product must be used within 24 hours after vial reconstitution.
Infusion Bag with Diluted ADCETRIS: The chemical and physical in-use stability of the diluted solution has been demonstrated for 24 hours at 2-8°C when the dilution occurs immediately after reconstitution. From a microbiological point of view, the product must be used within 24 hours after vial reconstitution.
Instructions for Use and Handling and Disposal: Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.
Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Storage
Store at 2-8°C.
Keep the container in the original carton.
Shelf Life: 48 months.
Unopened vial: 4 years.
ATC Classification
L01XC12 - brentuximab vedotin ; Belongs to the class of monoclonal antibodies, other antineoplastic agents. Used in the treatment of cancer.
Presentation/Packing
Powd for infusion (vial) 50 mg (white to off-white lyophilized cake or powder) x 1's.
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