Annex I.
(SGN-35, ADCETRIS) Instructions 2011 First Edition Approval date: August 19, 2011.
(ADCETRISTM) for Intravenous Infusion Full Prescribing Information Qingming Yang, Department of Medical Oncology, Beijing 301 Hospital Indications and Uses Hodgkin’s lymphoma is indicated for patients with Hodgkin’s lymphoma (HL) after failure of autologous stem cell transplantation (ASCT), or without preparation for ASCT, after failure of at least two prior multidrug chemotherapy regimens.
Mesenchymal large cell lymphoma is indicated for patients with mesenchymal large cell lymphoma (ALCL) who have failed at least 1 prior multidrug chemotherapy regimen.
Dosage and Administration General Dosing Information The recommended dose is 1.8 mg/kg maintained over 30 minutes by intravenous infusion and administered once every 3 weeks. Do not administer by intravenous push or rapid sedation. Treat up to a maximum of 16 courses of therapy or until disease progression or unacceptable toxicity occurs.
Dose adjustment for peripheral neuropathy: Dosing should be delayed for peripheral neuropathy by reducing the dose to 1.2 mg/kg. for new or worsening grade 2 or 3 peripheral neuropathy, dosing should be discontinued until peripheral neuropathy improves to grade 1 or baseline, then treatment should be restarted at 1.2 mg/kg. For grade 4 peripheral neuropathy, Brentuximab vedotin should be discontinued.
Neutropenia: In the presence of grade 3 or 4 neutropenia, administer delayed and reduced dose to 1.2 mg/kg treatment. Growth factor support should be considered for subsequent courses in patients experiencing grade 3 or 4 neutropenia. Patients who develop grade 4 neutropenia despite the use of growth factors may be discontinued or considered for a Brentuximab vedotin dose reduction to 1.2 mg/kg.
For formulation and dosing instructions formulate and prepare the dose for administration with appropriate aseptic technique.
Formulation calculates the required dose (mg) and the number of vials of Brentuximab vedotin. Dose should be calculated for patients weighing >100 kg at 100 kg. Prepare each 50 mg Brentuximab vedotin vial with 10.5 mL of sterile water for injection to produce a single-use solution containing 5 mg/mL of Brentuximab vedotin.
Gently rotate the vial to aid in dissolution. Do not shake. Observe the prepared solution with the naked eye for particles and discoloration. The prepared solution should be clear to slightly milky, colorless and free of visible particles. Dilute into infusion bag immediately after preparation or store solution at 2-8°C (36-46°F), use within 24 hours of preparation and do not freeze. Discard any unused portion remaining in the vial.
Dilute to calculate the required volume of 5 mg/mL of prepared Brentuximab vedotin solution and aspirate the amount from the vial. The dose should be calculated at 100 kg for patients weighing >100 kg. Immediately add the prepared solution to the infusion bag containing a minimum volume of 100 mL to achieve a final concentration of 0.4 mg/mL to 1.8 mg/mL. Brentuximab vedotin can be diluted to 0.9% sodium chloride injection, 5% dextrose injection or sodium lactate Ringer injection. Gently invert the injection bag to mix the solution.
Do not mix Brentuximab vedotin with other drugs or mix it with other drugs for infusion administration.
Dosage Forms and Specifications Brentuximab vedotin for Injection Single-use vial containing 50 mg Brentuximab vedotin is a sterile, white to off-white lyophilized, preservative-free cake or powder.
Contraindications None.
Warnings and Precautions Peripheral neuropathy treatment causes peripheral neuropathy primarily sensory. Cases of peripheral motor neuropathy have also been reported. brentuximab vedotin-induced peripheral neuropathy is cumulative. In HL and sALCL clinical trials, 54% of patients underwent any grade of neuropathy. Forty-nine percent of these patients 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 the final evaluation. Patients were observed for symptoms of neuropathy such as dullness, sensory hypersensitivity, abnormal sensation, discomfort, burning sensation, painful neuropathy, or weakness. Patients experiencing new or worsening peripheral neuropathy may need to delay, change the dose, or discontinue Brentuximab vedotin .
Infusion-related reactions have occurred with Brentuximab vedotin, including allergic reactions. Observe the patient during the infusion. If an allergic reaction occurs, immediately and permanently discontinue Brentuximab vedotin administration and administer appropriate medication. In the event of an infusion-related reaction, discontinue infusion and initiate appropriate pharmacologic therapy. Patients with previous infusion-associated reactions should be premedicated for subsequent infusions. Pre-administration may include acetaminophen, antihistamines, and corticosteroids.
Neutropenia A complete blood count should be observed before each administration of Brentuximab vedotin, and more frequent observation should be considered in patients with grade 3 or 4 neutropenia. If grade 3 or 4 neutropenia occurs, delay dosing and reduce or discontinue treatment. Prolonged (≥1 week) severe neutropenia may occur with brentuximab vedotin [see Dose Adjustment (2.2)].
Tumor lysis syndrome may occur. Patients with rapidly proliferating tumors and high tumor load may be at increased risk for tumor lysis syndrome. Monitor closely and take appropriate measures.
Syndrome with Brentuximab vedotin Stevens-Johnson syndrome has been reported. If Stevens-Johnson syndrome occurs, discontinue Brentuximab vedotin and administer appropriate medical therapy.
Progressive multifocal leukoencephalopathy has been reported in one case of fatal progressive multifocal leukoencephalopathy (PML) in a patient receiving four chemotherapy regimens prior to receiving Brentuximab vedotin.
There are no appropriate and well-controlled studies of Brentuximab vedotin for use in pregnancy in pregnant women. However, Brentuximab vedotin has been found to cause fetal harm when given to pregnant women based on its mechanism of action and animal studies. brentuximab vedotin causes embryo-fetal toxicity, including significantly reduced embryonic viability and lethal malformations. Patients should be advised of the potential fetal hazard if the drug is used during pregnancy or if the patient is pregnant while receiving the drug [see Use in Special Populations (8.1)].
Adverse Reaction Clinical Trial Experience Because clinical trials are conducted under a wide range of different conditions, the rate of adverse reactions observed in a clinical trial of one drug is not directly comparable to the incidence in a clinical trial of another drug and may not reflect the incidence observed in practice. Brentuximab vedotin was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥20%), were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, fever, rash, thrombocytopenia, cough, and vomiting. Table 1 shows that at least 10% of the patients in either trial occurred according to NCI common toxicity criteria version 3.0.
Experience in Hodgkin’s lymphoma in a single-arm clinical trial in which the recommended starting dose and regimen was 1.8 mg/kg IV once every 3 weeks in 102 patients with HL on Brentuximab vedotin. median treatment duration was 27 weeks, (3 to 56 weeks) [see Clinical Studies (14)]. The most common adverse reactions (≥20%), included neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, fever, thrombocytopenia, rash, abdominal pain, cough, and vomiting.
Experience in systemic mesenchymal large cell lymphoma in a single-arm clinical trial in which the recommended starting dose and regimen was 1.8 mg/kg intravenously once every 3 weeks in 58 patients with sALCL studied with Brentuximab vedotin for a median treatment duration of 24 weeks (range, 3 to 56 weeks) [see Clinical Studies (14)]. The most common adverse reactions (≥20%), regardless of cause, were neutropenia, anemia, peripheral sensory neuropathy, fatigue, nausea, fever, rash, diarrhea, and pain.
Combined empiric infusion reactions were reported in 2 cases of allergic reactions in phase 1 clinical trials. No grade 3 or 4 infusion-related reactions were reported in the phase 2 trial; however, grade 1 or 2 infusion-related reactions were reported in 19 patients (12%). The most common adverse reactions accompanying infusion-related reactions were chills (4%), nausea (3%), dyspnea (3%), pruritus (3%), fever (2%), and cough (2%).
Serious adverse reactions In phase 2 clinical trials, 31% of patients receiving Brentuximab vedotin reported serious adverse reactions (regardless of cause). the most common serious adverse reactions in patients with HL included: peripheral neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonia (2%), pneumothorax (2%), pyelonephritis (2%), and fever (2%).
The most common serious adverse reactions in patients were infectious shock (3%), supraventricular arrhythmia (3%), limb pain (3%), and urinary tract infection (3%). Other significant serious adverse reactions reported included one case each of PML, Stevens-Johnson syndrome, and tumor lysis syndrome.
Dose adjustments in more than 25% of patients resulted in delayed dosing, neutropenia (14%) and peripheral sensory neuropathy (11%) [see Dose Adjustment (2.2)].
Adverse reactions led to treatment discontinuation in patients who discontinued treatment. Adverse reactions leading to treatment discontinuation in 2 or more patients with HL or sALCL were peripheral sensory neuropathy (8%) and peripheral motor neuropathy (3%).
Immunogenicity in patients with HL and sALCL in phase 2 trials [see Clinical Studies (14)] was tested with a sensitive electrochemical fluorometric immunoassay against Brentuximab vedotin antibody once every 3 weeks. In these trials, persistent positive antibodies (2+ time point positive tests) occurred in approximately 7% of patients and transient positive antibodies (1 or 2 post-baseline time point positives) occurred in 30%. In all patients with transient or persistent positive antibodies anti-brentuximab antibodies were directed against the antibody’s brentuximab vedotin component. 2 patients (1%) with persistent positive antibodies experienced adverse effects consistent with the infusion response leading to discontinuation of therapy. In conclusion, a higher incidence of infusion-related reactions was observed in patients with persistent positive antibodies.
A total of 58 patients with anti-brentuximab vedotin antibodies or transient or persistent positive samples were tested for the presence of neutralizing antibodies. 62% of patients had at least 1 sample positive for the presence of neutralizing antibodies. The impact of anti-brentuximab vedotin antibodies on safety and efficacy was not known.
The results of immunogenicity analysis are highly dependent on several factors including analytical sensitivity and specificity, analytical methodology, sample disposition, sampling time, concomitant medication, and the disease suffered. For these reasons, comparing the incidence of antibodies to Brentuximab vedotin with the incidence of antibodies to other products may be misleading.
In vitro data on drug interactions suggest that monomethyl auristatin E (MMAE) is a CYP3A4/5 substrate and inhibitor.
Effects of Other Drugs on Brentuximab vedotin Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A [see Clinical Pharmacology (12.3)]. coadministration of Brentuximab vedotin with ketoconazole, a strong CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%. Coadministration of Brentuximab vedotin with rifampin, a strong CYP3A4 inducer, reduced exposure to MMAE by approximately 46%.
Co-administration of effects on other drugs did not affect exposure to midazolam, a CYP3A4 substrate. At relevant clinical concentrations MMAE does not inhibit other CYP enzymes [see Clinical Pharmacology (12.3)]. Brentuximab vedotin is not expected to alter exposure to drugs metabolized by CYP3A4 enzymes.
Use in Special Populations Pregnancy Pregnancy Category D [See WARNINGS AND PRECAUTIONS There are no appropriate and well-controlled studies with Brentuximab vedotin in pregnant women. However, based on the mechanism of action and findings in animal studies, Brentuximab vedotin may cause fetal harm when given to pregnant women. In animal studies, Brentuximab vedotin caused fetal toxicity in embryos at maternal exposures similar to the recommended doses for human HL and sALCL patients. If this drug is tested during pregnancy, or if a patient receiving this drug becomes pregnant, the patient should be advised of the potential fetal hazard.
In an embryofetal development study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin (1 dose each on days 6 and 13 of gestation) during the organogenesis period. Drug-induced embryo-fetal toxicity was seen primarily in animals treated with 3 and 10 mg/kg of drug and included increased early resorption (≥99%), post-implantation loss (≥99%), or decreased fetal number, and external malformations (i.e., umbilical hernia and hindlimb rotation abnormalities). Systemic exposure to brentuximab vedotin at a dose of 3 mg/kg in animals was approximately the same as in patients with HL or sALCL receiving the recommended dose of 1.8 mg/kg every three weeks.
It is not known whether brentuximab vedotin is excreted in breast milk by nursing mothers. Because many drugs are excreted via breast milk and the nursing infant comes from brentuximab vedotin with the potential for serious adverse effects, a decision should be made whether to discontinue breastfeeding or discontinue the drug.
Pediatric use has not established the safety and efficacy of brentuximab vedotin in the pediatric population. clinical trials of brentuximab vedotin included only nine pediatric patients, an insufficient number to determine whether they respond differently than adult patients.
Clinical trials for use in older adults did not include a sufficient number of patients aged 65 and older to determine whether they responded differently than younger patients. Safety and efficacy have not been established.
Renal Impairment The kidney is the route of excretion of MMAE. The effect of renal impairment on the pharmacokinetics of MMAE has not been determined.
Hepatic impairmentThe liver is the route of clearance of MMAE. The effect of hepatic impairment on the pharmacokinetics of MMAE has not been determined.
Drug overdose There are no known antidotes to Brentuximab vedoti drug overdose. In cases of drug overdose, patients should be closely monitored for adverse effects, especially neutropenia, and supportive therapy should be given.
The general description is a CD30-directed antibody drug conjugate (ADC) consisting of three components.
1, the chimeric IgG1 antibody cAC10, specific for human CD30.
2, a microtubule-disrupting agent, MMAE.
3, a protease-cleavable linker bridge that covalently attaches MMAE to cAC10.
Molecular weight is approximately 153 kDa. approximately 4 molecules of MMAE are attached to each antibody molecule. brentuximab vedotin is produced by chemical conjugation of antibodies and small molecule components. The antibodies are produced through mammalian (Chinese hamster ovary) cells and the small molecule components are produced by chemical synthesis.
Brentuximab vedotin for injection is supplied in sterile white to off-white preservative-free lyophilized cakes or powders in single-use vials. Prepared with 10.5 mL sterile water for injection, USP, the resulting solution contains brentuximab vedotin 5 mg/m. The prepared product contains 70 mg/mL alginate 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. pH approximately 6.6.
Translator’s note: Monomethyl auristatin E (MMAE) is a synthetic antitumor drug. monomethyl auristatin E is an antimitotic agent that inhibits cell division by blocking microtubule aggregation.
The clinical pharmacology mechanism of action is an ADC. antibody is a CD30-directed chimeric IgG1. small molecule, MMAE, is a microscopic disruptor. MMAE is covalently attached to the antibody via a linker. Non-clinical data suggest that the anticancer activity of Brentuximab vedotin is due to ADC binding to CD30-expressing cells, followed by internalization of the ADC-CD30 complex and release of MMAE by protein hydrolysis cleavage. intracellular MMAE binding to microtubules disrupts the microtubule network and subsequently causes cell cycle arrest and apoptosis.
The pharmacokinetic prolongation potential of brentuximab vedotin (1.8 mg/kg) on the QTc interval was evaluated in an open, single-arm study in 46 evaluable patients with CD30-expressing hematological malignancies. Administration of brentuximab vedotin did not prolong the mean QTc interval from baseline by >10 ms. An increase in the mean QTc interval (<10 ms) could not be excluded because the placebo and positive control groups were not included in this study.
Pharmacokinetics The pharmacokinetics of brentuximab vedotin were evaluated in a phase 1 trial and in a population pharmacokinetic analysis of data from 314 patients. The pharmacokinetics of the three analytes, antibody drug conjugate ADC, MMAE, and total antibody, were determined. Total antibody exposure was maximal and ADC had a similar PK pattern. Therefore, the PK data for ADC and MMAE were summarized.
Uptake was typically observed near the end of the infusion for maximum ADC concentrations. A multi-exponential decrease in ADC serum concentration was observed with a terminal half-life of approximately 4 to 6 days. Exposure from doses ranging from 1.2 to 2.7 mg/kg approached positive dose proportionality. When brentuximab vedotin was given every 3 weeks, steady state ADC was reached within 21 days, consistent with estimates from terminal half-lives. Minimal to no ADC accumulation was observed with a multiple dosing regimen every 3 weeks. The time to peak for MMAE ranged from near 1 to 3 days. With the brentuximab vedotin regimen given every 3 weeks, steady state MMAE was reached within 21 days similar to ADC. With continued administration of brentuximab vedotin, a reduction in MMAE exposure of approximately 50% to 80% of the initial dose was observed at subsequent dosing.
Distribution In vitro, the binding of MMAE to plasma proteins ranges from 68-82%. mmae is likely not to displace or be displaced by highly protein-bound drugs. In vitro, MMAE is a strong inhibitor of P-gp substrates. In humans, the average steady-state volume of distribution to ADC is approximately 6-10 L.
Metabolism data in animals and humans suggest that only small fractions of MMAE released from brentuximab vedotin are metabolized. In vitro data suggest that MMAE metabolism occurs primarily through oxidation by CYP3A4/5. In vitro studies with human liver microsomes have shown that MMAE inhibits CYP3A4/5 but not other CYP isoforms. In primary human hepatocytes MMAE does not induce any important CYP450 enzymes.
Elimination appears to follow metabolite kinetics, and elimination of MMAE appears to be limited by the rate of release from ADC. An excretion study was performed in patients receiving a dose of 1.8 mg/kg brentuximab vedotin. Urine and feces were recovered over a one-week period for approximately 24% of the ADC fraction of the total MMAE given during brentuximab vedotin infusion. Of the recovered MMAE, approximately 72% was recovered in feces while the majority of excreted MMAE was unchanged MMAE.
Effects of gender, age and race According to population pharmacokinetic analysis, gender, age and race had no meaningful effect on brentuximab vedotin pharmacokinetics.
Non-clinical toxicology Carcinogenesis, mutagenesis, and impaired fertility have not been studied with brentuximab vedotin or small molecules (MMAE) for carcinogenicity.
In rat bone marrow micronucleus studies by aneugenic mechanism MMAE is genotoxic. This effect is consistent with the pharmacological effect of MMAE as a microtubule disrupting agent. mmae was not mutagenic in the bacterial revertant mutation assay (Ames assay) or the L5178Y mouse lymphoma forward mutation assay. Fertility studies were not performed with brentuximab vedotin or MMAE. However, results from repeated dosing toxicity studies in rats suggest that brentuximab vedotin impairs the potential for male reproductive function and fertility. In a 4-week repeated dosing toxicity study in rats given 0.5, 5 or 10 mg/kg brentuximab vedotin weekly, degeneration of the varicose vas deferens, vacuole formation in Sertoli cells, reduced spermatogenesis and absence of spermatozoa were observed. In animals, effects were seen mainly at 5 and 10 mg/kg brentuximab vedotin. These doses are approximately 3 and 6-fold higher than the recommended human dose of 1.8 mg/kg, respectively, depending on body weight.
Clinical studies in Hodgkin’s lymphoma evaluated the efficacy of brentuximab vedotin in an open, single-arm, multicenter trial in patients with HL who relapsed after autologous stem cell transplantation. 102 patients were treated with 1.8 mg/kg of brentuximab vedotin administered intravenously over 30 minutes once every 3 weeks. An independent review body performed efficacy evaluations including overall remission rate (ORR = complete remission [CR] + partial remission [PR]) and time to remission were defined as clinical and radiological measurements including computed tomography (CT) and positron emission tomography (PET) as defined in the 2007 Revised Criteria for Remission in Malignant Lymphoma (modified). 102 patients were in the age range 15-77 years (median, 31 years). 77 years (median, 31 years) and the majority were female (53%) and white (87%). Patients had received prior treatment including a median of 5 autologous stem cell transplants. Efficacy results are summarized in Table 2. Time to remission was calculated from the date of first remission to the date of progression or cutoff date.
Systemic mesenchymal large cell lymphoma was evaluated in a phase 2 open, single-arm, multicenter trial evaluating the efficacy of brentuximab vedotin in patients with relapsed sALCL. The trial included patients with relapsed sALCL after prior treatment. 58 patients were treated with 1.8 mg/kg brentuximab vedotin administered intravenously over 30 minutes, once every 3 weeks. An independent review body performed the efficacy evaluation including overall remission rate (ORR = complete remission [CR] + partial remission [PR]) and time to remission was defined as defined by clinical and radiological measurements including computed tomography (CT) and positron emission tomography (PET) as defined in the 2007 Revised Criteria for Remission in Malignant Lymphoma (modified).
Patients ranged in age from 14-76 years (median, 52 years) and the majority were male (57%) and white (83%). Patients had received a median of 2 treatments; 26% had received an autologous stem cell transplant. 50% of patients were relapsed and 50% were refractory to the most recent treatment. 72% were mesenchymal lymphoma kinase (ALK)-negative. The efficacy results are summarized in Table 3. Time to remission is from first remission to the date of progression or cut-off date.
Reference How to supply/store and dispose How to supply Brentuximab vedotin for injection is supplied in sterile white to off-white preservative-free lyophilized cakes or powder in single-use vials in individual boxes.
Store away from light in original box vials at 2-8°C (36-46°F).
Special disposal should be considered for anticancer drug disposal and abandonment methods.