Kadcyla

Trastuzumab emtansine.

Dosage Preparations: 100 mg single-use vial containing powder for concentrate for infusion solution designed to deliver 5 ml of 20 mg/ml of trastuzumab emtansine.
160 mg single-use vial containing powder for concentrate for infusion solution designed to deliver 8 ml of 20 mg/ml of trastuzumab emtansine.
Sterile/Radioactive Statement: Sterile product.
Excipients/Inactive Ingredients: Sodium succinate, Sucrose, Polysorbate 20.

Therapeutic/Pharmacologic Class of Drug: Antibody drug conjugate antineoplastic agent. ATC Code: L01XC14.
Pharmacology: Pharmacodynamics: Mechanism of Action: Kadcyla, trastuzumab emtansine, is a HER2-targeted antibody-drug conjugate which contains the humanized anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitory drug DM1 (a maytansine derivative) via the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate). Emtansine refers to the MCC-DM1 complex. An average of 3.5 DM1 molecules are conjugated to each molecule of trastuzumab.
Conjugation of DM1 to trastuzumab confers selectivity of the cytotoxic agent for HER2-overexpressing tumor cells, thereby increasing intracellular delivery of DM1 directly to malignant cells. Upon binding to HER2, trastuzumab emtansine undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in release of DM1-containing cytotoxic catabolites (primarily lysine-MCC-DM1).
Kadcyla has the mechanisms of action of both trastuzumab and DM1: Trastuzumab emtansine, like trastuzumab, binds to domain IV of the HER2 extracellular domain (ECD), as well as to Fcγ receptors and complement C1q. In addition, Kadcyla, like trastuzumab, inhibits shedding of the HER2 ECD, inhibits signaling through the phosphatidylinositol 3-kinase (PI3-K) pathway, and mediates antibody-dependent cell-mediated cytotoxicity (ADCC) in human breast cancer cells that overexpress HER2.
DM1, the cytotoxic drug component of Kadcyla, binds to tubulin. By inhibiting tubulin polymerization, both DM1 and Kadcyla cause cells to arrest in the G2/M phase of the cell cycle, ultimately leading to apoptotic cell death. Results from in vitro cytotoxicity assays show that DM1 is 20-200 times more potent than taxanes and vinca alkaloids.
The MCC linker is designed to limit systemic release and increase targeted delivery of DM1, as demonstrated by detection of very low levels of free DM1 in plasma.
Clinical/Efficacy Studies: Efficacy: Early Breast Cancer: KATHERINE (BO27938) was a randomized, multicenter, open-label trial of 1486 patients with HER2-positive, early breast cancer with residual invasive tumor in the breast and/or axillary lymph nodes following taxane and trastuzumab-based therapy as part of a neoadjuvant regimen before trial enrollment. Patients received radiotherapy and/or hormonal therapy concurrent with study treatment as per local guidelines. Breast tumor samples were required to show HER2 overexpression defined as 3+ IHC or ISH amplification ratio ≥ 2.0 determined at a central laboratory. Patients were randomized (1:1) to receive trastuzumab or KADCYLA. Randomization was stratified by clinical stage at presentation, hormone receptor status, preoperative HER2-directed therapy (trastuzumab, trastuzumab plus additional HER2-directed agent[s]), and pathological nodal status evaluated after preoperative therapy.
KADCYLA was given intravenously at 3.6 mg/kg on Day 1 of a 21-day cycle. Trastuzumab was given intravenously at 6 mg/kg on Day 1 of a 21-day cycle. Patients were treated with KADCYLA or trastuzumab for a total of 14 cycles unless there was recurrence of disease, withdrawal of consent, or unacceptable toxicity, whichever occurred first. At the time of the primary analysis, median treatment duration was 10 months (range: 1-12) for KADCYLA, and median treatment duration 10 months (range: 1-13) for trastuzumab. Patients who discontinued KADCYLA could complete the duration of their intended study treatment up to 14 cycles of HER2-directed therapy with trastuzumab, if appropriate, based on toxicity considerations and investigator discretion.
The primary efficacy endpoint of the study was Invasive Disease Free Survival (IDFS). IDFS was defined as the time from the date of randomization to first occurrence of ipsilateral invasive breast tumor recurrence, ipsilateral local or regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause. Additional endpoints included IDFS including second primary non-breast cancer, disease free survival (DFS), overall survival (OS), and distant recurrence-free interval (DRFI).
Patient demographics and baseline tumor characteristics were balanced between treatment arms. The median age was approximately 49 years (range 23-80 years), 72.8% were White, 8.7% were Asian and 2.7% were Black or African American. All but 5 patients were women. 22.5 percent of patients were enrolled in North America, 54.2% in Europe and 23.3% throughout the rest of the world. Tumor prognostic characteristics including hormone receptor status (positive: 72.3%, negative: 27.7%), clinical stage at presentation (inoperable: 25.3%, operable: 74.8%) and pathological nodal status after preoperative therapy (node positive: 46.4%, node negative not evaluated: 53.6%) were similar in the study arms.
The majority of the patients (76.9%) had received an anthracycline-containing neoadjuvant chemotherapy regimen. 19.5% of patients received another HER2-targeted agent in addition to trastuzumab as a component of neoadjuvant therapy. Pertuzumab was the second therapy in 93.8% of patients who received a second neoadjuvant HER2-directed agent.
A clinically meaningful and statistically significant improvement in IDFS was observed in patients who received trastuzumab emtansine compared with trastuzumab (HR = 0.50, 95% CI [0.39, 0.64], p <0.0001), corresponding to a 50% reduction in risk of an IDFS event. Estimates of 3 years IDFS rates were 88.3% vs. 77.0% in trastuzumab emtansine vs. trastuzumab arms, respectively. See Table 1 and Figures 1 and 2.

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

In KATHERINE, consistent treatment benefit of Kadcyla for IDFS was seen in all the pre specified subgroups evaluated, supporting the robustness of the overall result (see Figure 3). In the subgroup of patients with hormone receptor-negative disease (n=412, 27.7%), the hazard ratio for IDFS was 0.50 (95% CI: 0.33, 0.74). In the subgroup of patients with hormone receptor-positive disease (n=1074, 72.3%), the hazard ratio for IDFS was 0.48 (95% CI: 0.35, 0.67). In the subgroup of patients who received neoadjuvant trastuzumab with chemotherapy (n=1196, 80.5%), the hazard ratio for IDFS was 0.49 (95% CI: 0.37, 0.65). In the subgroup of patients who received neoadjuvant trastuzumab plus a second HER2- directed therapy with chemotherapy (n=290, 19.5%), the hazard ratio for IDFS was 0.54 (95% CI: 0.27, 1.06). Patients who received Perjeta as a second neoadjuvant HER2-directed agent (n=272, 93.8%), had an IDFS hazard ratio of 0.50 (95% CI: 0.25, 1.00). The IDFS hazard ratio in patients who were node-positive after preoperative therapy (n=689, 46.4%) was 0.52 (95% CI: 0.38, 0.71). In patients who were node-negative or not evaluated after preoperative therapy (n=797, 53.6%), the hazard ratio for IDFS was 0.44 (95% CI: 0.28, 0.68). (See Figure 3.)

Click on icon to see table/diagram/image

Patient reported outcomes included the assessment of patient-reported global health status, role and physical function, and treatment symptoms using the EORTC QLQ-C30 and EORTC QLQ-BR23. In the analyses of patient-reported outcomes, a 10-point difference was considered clinically meaningful.
Patients' function, global health status, and symptom scores showed no clinically meaningful change from baseline over the course of treatment or during follow-up. Mean change from baseline at Cycle 11 for physical function was -0.6 (95% CI -1.9-0.7) in the trastuzumab emtansine arm and 1.8 (95% 0.6-3.1) in the trastuzumab arm; global health status was 0.4 (95% CI -2.2-1.3) in the trastuzumab emtansine arm and 1.4 (95% CI -0.2-3.0) in the trastuzumab arm. No clear differences were observed in function, global health status, or symptoms between the two treatment arms and at no timepoint during the study were the average scores on those scales of patients in the trastuzumab emtansine arm clinically worse than those of patients in the trastuzumab arm.
Metastatic Breast Cancer: A Phase III, randomized, multicenter, international, open-label clinical trial (TDM4370g/BO21977) was conducted in patients with HER2-positive unresectable locally advanced breast cancer or MBC who had received prior taxane and trastuzumab-based therapy, including patients who received prior therapy with trastuzumab and a taxane in the adjuvant setting and who relapsed within six months of completing adjuvant therapy. Prior to enrollment, breast tumor samples were required to be centrally confirmed for HER2-positive disease defined as a score of 3+ by IHC or gene amplification by ISH. Baseline patient and tumor characteristics were well balanced between treatment groups. For patients randomized to Kadcyla, the median age was 53 years, most patients were female (99.8%), the majority were Caucasian (72%), and 57% had estrogen-receptor and/or progesterone-receptor positive disease. The study compared the safety and efficacy of Kadcyla with that of lapatinib plus capecitabine. A total of 991 patients were randomized with Kadcyla or lapatinib plus capecitabine as follows: Kadcyla Arm: Kadcyla 3.6 mg/kg intravenously (IV) over 30-90 minutes on Day 1 of a 21-day cycle.
Control Arm (lapatinib plus capecitabine): lapatinib 1250 mg/day orally once per day of a 21-day cycle plus capecitabine 1000 mg/m² orally twice daily on Days 1-14 of a 21-day cycle.
The co-primary efficacy endpoints of the study were progression-free survival (PFS) as assessed by an independent review committee (IRC), and overall survival (OS) and landmark (1-year and 2-year) survival rates.
Time to symptom progression, as defined by a 5-point decrease in the score derived from the trials outcome index-breast (TOI-B) subscale of the Functional Assessment of Cancer Therapy-Breast Quality of Life (FACT-B QoL) questionnaire was also assessed during the clinical trial. A change of 5 points in the TOI-B is considered clinically significant. (See Table 2.)

Click on icon to see table/diagram/image

A treatment benefit was seen in the subgroup of patients who had not received any prior systemic anti-cancer therapy in the metastatic setting (n=118); hazard ratios for PFS and OS were 0.51 (95% CI: 0.30, 0.85) and 0.61 (95% CI: 0.32, 1.16), respectively. The median PFS and OS for the KADCYLA group were 10.8 months and not reached, respectively, compared with 5.7 months and 27.9 months, respectively, for the lapatinib plus capecitabine group. (See Figures 4 and 5.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

A randomized, multicenter, open-label phase II, study (TDM4450g/BO21976) evaluated the effects of Kadcyla versus trastuzumab plus docetaxel in patients with HER2-positive MBC who had not received prior chemotherapy for metastatic disease. Patients were randomized to receive Kadcyla 3.6 mg/kg IV every 3 weeks (n=67) or trastuzumab 8 mg/kg IV loading dose followed by 6 mg/kg IV every 3 weeks plus docetaxel 75-100 mg/m² IV every 3 weeks (n=70).
The primary endpoint was PFS assessed by investigator. The median PFS was 9.2 months in the trastuzumab plus docetaxel arm and 14.2 months in the Kadcyla arm (hazard ratio, 0.59; p = 0.035), with a median follow-up of approximately 14 months in both arms. The ORR was 58.0% with trastuzumab plus docetaxel and 64.2% with Kadcyla. The median duration of response was not reached with Kadcyla vs. median duration 9.5 months in the control arm.
The worsening of the FACT-B TOI scores was delayed in the Kadcyla arm compared with the control arm (median time to symptom progression was 7.5 months in the Kadcyla arm vs. 3.5 months in the control arm; hazard ratio, 0.58; p = 0.022).
A Phase II, single-arm, open-label study (TDM4374g) evaluated the effects of Kadcyla in patients with HER2-positive incurable locally advanced, or MBC. All patients were previously treated with HER2-directed therapies (trastuzumab and lapatinib), and chemotherapy (anthracycline, taxane, and capecitabine) in the neoadjuvant, adjuvant, locally advanced, or metastatic setting. The median number of anti-cancer agents that patients received in any setting was 8.5 (range, 5-19) and in the metastatic setting was 7.0 (range, 3-17), including all agents intended for the treatment of breast cancer.
Patients (n=110) received 3.6 mg/kg of Kadcyla intravenously every 3 weeks until disease progression or unacceptable toxicity.
The key efficacy analyses were ORR based on independent radiologic review and duration of objective response. The ORR was 32.7% (95% CI: 24.1, 42.1), n=36 responders, by both IRC and investigator review. The median duration of response by IRC was not reached (95% CI, 4.6 months to not estimable).
Immunogenicity: As with all therapeutic proteins, there is the potential for an immune response to Kadcyla. A total of 1243 patients from seven clinical studies were tested at multiple time points for anti-drug antibody (ADA) responses to Kadcyla. Following Kadcyla dosing, 5.1% (63/1243) of patients tested positive for anti-Kadcyla antibodies at one or more post-dose time points. In the Phase I and Phase II studies, 6.4% (24/376) of patients tested positive for anti-Kadcyla antibodies. In the EMILIA study (TDM4370g/BO21977), 5.2% (24/466) of patients tested positive for anti-Kadcyla antibodies, of which 13 were also positive for neutralizing antibodies. In the KATHERINE (BO27938) study, 3.7% (15/401) of patients tested positive for anti-Kadcyla antibodies, of which 5 of were also positive for neutralizing antibodies. Due to the low incidence of ADA, conclusions cannot be made on the impact of anti-Kadcyla antibodies on the pharmacokinetics, safety, and efficacy of Kadcyla.
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 Kadcyla with the incidence of antibodies to other products may be misleading.
Pharmacokinetics: The population pharmacokinetic analysis of trastuzumab emtansine suggested no difference in Kadcyla exposure based on disease status (adjuvant vs. metastatic setting).
Absorption: Kadcyla is administered IV. There have been no studies performed with other routes of administration.
Distribution: Kadcyla when administered intravenously every 3 weeks exhibited linear pharmacokinetics across doses ranging from 2.4 to 4.8 mg/kg; patients who received doses less than or equal to 1.2 mg/kg had faster clearance.
Patients in Study TDM4370g/BO21977 and Study BO29738 who received 3.6 mg/kg of Kadcyla intravenously every 3 weeks had a mean maximum serum concentration (Cmax) of trastuzumab emtansine in Cycle 1 of 83.4 (± 16.5) μg/mL and 72.6 (± 24.3) μg/mL, respectively. Based on population pharmacokinetic analysis, following intravenous administration, the central volume of distribution of trastuzumab emtansine was (3.13 L) and approximated that of plasma volume.
Metabolism: Kadcyla is expected to undergo catabolism by means of proteolysis in cellular lysosomes, with no significant involvement of cytochrome P450 isoenzymes. Catabolites including Lys-MCC-DM1, MCC-DM1 and DM1 are detected at low levels in human plasma. In Study TDM4370g/BO21977 and Study BO29738, mean maximum DM1 levels in Cycle 1 following Kadcyla administration were consistently low and averaged 4.61 (± 1.61) ng/mL and 4.71 (± 2.25) ng/mL, respectively.
In vitro metabolism studies in human liver microsomes suggest that DM1, a component of trastuzumab emtansine, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5.
Elimination: Based on population pharmacokinetic (PK) analysis, following IV administration of Kadcyla in patients with HER2-positive metastatic breast cancer, the clearance of trastuzumab emtansine was 0.68 L/day and the elimination half-life (t_1/2) was approximately 4 days. No accumulation of trastuzumab emtansine was observed after repeated dosing of IV infusion every 3 weeks.
Based on a population PK analysis (n=671), body weight, albumin, sum of longest diameter of target lesions by RECIST, HER2 ECD, baseline trastuzumab concentrations and AST were identified as statistically significant covariates for trastuzumab emtansine pharmacokinetic parameters. However, the magnitude of effect of these covariates on trastuzumab emtansine exposure suggests that, with the exception of body weight, these covariates are unlikely to have any clinically meaningful effect on trastuzumab emtansine exposure. Therefore, the body weight based dose of 3.6 mg/kg every 3 weeks without correction for other covariates is considered appropriate. In nonclinical studies, catabolites of trastuzumab emtansine including DM1, Lys-MCC-DM1, and MCC-DM1 are mainly excreted in the bile with minimal elimination in urine.
Pharmacokinetics in Special Populations: The population pharmacokinetic analysis of trastuzumab emtansine showed that race did not appear to influence the pharmacokinetics of Kadcyla. Because most of the patients in Kadcyla clinical studies were females, effect of gender on the pharmacokinetics of Kadcyla was not formally evaluated.
Geriatric Population: The population pharmacokinetic analysis of trastuzumab emtansine showed that age did not affect the pharmacokinetics of Kadcyla. No significant difference was observed in the pharmacokinetics of trastuzumab emtansine among patients <65 years (n=577), patients between 65-75 years (n=78) and patients >75 years (n=16).
Renal impairment: The population pharmacokinetic analysis of trastuzumab emtansine showed that creatinine clearance does not affect pharmacokinetics of Kadcyla. Pharmacokinetics of trastuzumab emtansine in patients with mild (creatinine clearance CLcr 60-89 mL/min, n=254) or moderate (CLcr 30 to 59 mL/min, n=53) renal impairment were similar to those in patients with normal renal function (CLcr ≥90 mL/min, n=361). Pharmacokinetic data in patients with severe renal impairment (CLcr 15-29 mL/min) is limited (n=1), therefore no dosage recommendations can be made.
Hepatic impairment: The liver is a primary organ for eliminating DM1 and DM1-containing catabolites. The pharmacokinetics of trastuzumab emtansine and DM1-containing catabolites were evaluated after the administration of 3.6 mg/kg of Kadcyla to metastatic HER2-positive breast cancer patients with normal hepatic function (n=10), mild (Child-Pugh A; n=10) and moderate (Child-Pugh B; n=8) hepatic impairment.
Plasma concentrations of DM1 and DM1-containing catabolites (Lys-MCC-DM1 and MCC-DM1) were low and comparable between patients with and without hepatic impairment.
Systemic exposures (AUC) of trastuzumab emtansine at Cycle 1 in patients with mild and moderate hepatic impairment were approximately 38% and 67% lower than that of patients with normal hepatic function, respectively. Trastuzumab emtansine exposure (AUC) at Cycle 3 after repeated dosing in patients with mild or moderate hepatic dysfunction was within the range observed in patients with normal hepatic function.
No formal pharmacokinetic study has been conducted and no population PK data was collected in patients with severe hepatic impairment (Child-Pugh class C).
Toxicology: Nonclinical Safety: Carcinogenicity: No carcinogenicity studies have been performed to establish the carcinogenic potential of Kadcyla.
Genotoxicity: No evidence of mutagenic activity was observed in an in vitro bacterial reverse mutation assay of DM1. In an in vivo micronucleus assay of trastuzumab emtansine in cynomolgus monkeys, no evidence of chromosomal damage to bone marrow cells was observed. However, in a rat bone marrow micronucleus assay, DM1 was positive for micronuclei formation after a single low dose in the DM1 concentration range measured in humans given trastuzumab emtansine, confirming that Kadcyla is an aneugen and/or clastogen.
Impairment of Fertility: No fertility studies in animals have been performed to evaluate the effect of Kadcyla. However, based on results from general animal toxicity studies, adverse effects on fertility can be expected.
Reproductive toxicity: Dedicated embryo-fetal development studies have not been conducted in animals with trastuzumab emtansine. Developmental toxicity of trastuzumab has been identified in the clinical setting although it was not predicted in the non-clinical program. In addition, developmental toxicity of maytansine has been identified in non-clinical studies which suggests that DM1, the microtubule-inhibiting cytotoxic maytansinoid drug component of trastuzumab emtansine, will be similarly teratogenic and potentially embryotoxic.
Other: Not applicable.

Breast Cancer: Metastatic Breast Cancer (MBC): Kadcyla, as a single agent, is indicated for the treatment of patients with HER2-positive, unresectable locally advanced or metastatic breast cancer who have received prior treatment with trastuzumab and a taxane.
Early Breast Cancer (EBC): Kadcyla, as a single agent, is indicated for the adjuvant treatment of patients with HER2-positive early breast cancer who have residual disease, after pre-operative systemic treatment that included HER2 targeted therapy.

In order to prevent medication errors it is important to check the vial labels to ensure that the drug being prepared and administered is Kadcyla (trastuzumab emtansine) and not trastuzumab.
Kadcyla therapy should only be administered under the supervision of a healthcare professional experienced in the treatment of cancer patients.
Patients treated with Kadcyla should have HER2 positive tumor status, defined as a score of 3+ by immunohistochemistry (IHC) or a ratio of ≥2.0 by in situ hybridization (ISH) or by fluorescence in situ hybridization (FISH) assessed by a validated test.
Substitution by any other biological medicinal product requires the consent of the prescribing physician.
The safety and efficacy of alternating or switching between Kadcyla and products that are biosimilar but not deemed interchangeable has not been established. Therefore, the benefit-risk of alternating or switching needs to be carefully considered.
Kadcyla must be reconstituted and diluted by a healthcare professional and administrated as an intravenous infusion (see Special Instructions for Use, Handling and Disposal under Cautions for Usage). Do not administer as an intravenous push or bolus.
Schedule: The recommended dose of Kadcyla is 3.6 mg/kg given as an intravenous infusion every 3 weeks (21-day cycle).
Administer the initial dose as a 90 minutes intravenous infusion. Patients should be observed during the infusion and for at least 90 minutes following the initial dose for fever, chills, or other infusion related reactions. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration (see General: Extravasation under Precautions).
If prior infusions were well tolerated, subsequent doses of Kadcyla may be administered as 30 minute infusions and patients should be observed during the infusions and for at least 30 minutes after infusion.
The infusion rate of Kadcyla should be slowed or interrupted if the patient develops infusion-related symptoms (see General under Precautions). Discontinue Kadcyla for life-threatening infusion reactions.
Duration of treatment: Patients with EBC should receive treatment for a total of 14 cycles unless there is disease recurrence or unmanageable toxicity.
Patients with MBC should receive treatment until disease progression or unmanageable toxicity.
Delayed or Missed Dose: If a planned dose of Kadcyla is missed, it should be administered as soon as possible; do not wait until the next planned cycle. The schedule of administration should be adjusted to maintain a 3-week interval between doses. The infusion may be administered at the rate the patient tolerated the most recent infusion.
Dose Modifications: Management of symptomatic adverse events may require temporary interruption, dose reduction, or treatment discontinuation of Kadcyla as per guidelines provided in Tables 3 and 4.
Kadcyla dose should not be re-escalated after a dose reduction is made.(See Tables 3 and 4.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Special Dosage Instructions: Geriatric Use: No dose adjustment of Kadcyla is required in patients aged ≥65 years (see Precautions).
Pediatric Use: The safety and efficacy of Kadcyla in children and adolescents (<18 years) have not been established.
Renal Impairment: No adjustment to the starting dose of Kadcyla is needed in patients with mild or moderate renal impairment (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions). The potential need for dose adjustment in patients with severe renal impairment cannot be determined due to insufficient data.
Hepatic Impairment: No adjustment to the starting dose is required for patients with mild or moderate hepatic impairment (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions). Kadcyla has not been studied in patients with severe hepatic impairment. Treatment of patients with hepatic impairment should be undertaken with caution due to known hepatotoxicity observed with Kadcyla (see General: Hepatotoxicity under Precautions).

There is no known antidote for trastuzumab emtansine overdose. In case of overdose, the patient should be closely monitored. Cases of overdose have been reported with trastuzumab emtansine treatment, most associated with thrombocytopenia, and there was one death. In the fatal case, the patient incorrectly received trastuzumab emtansine 6 mg/kg and died approximately 3 weeks following the overdose; a cause of death and a causal relationship to Kadcyla were not established.

Kadcyla is contraindicated in patients with known hypersensitivity to Kadcyla or any of the excipients.

General: Patients treated with Kadcyla must have confirmed HER2-positive tumor status as assessed by either HER2 protein over-expression or gene amplification.
In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded (or stated) in the patient file.
Pulmonary Toxicity: Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratory distress syndrome or a fatal outcome, have been reported in clinical trials with Kadcyla (see Adverse Reactions). Signs and symptoms include dyspnea, cough, fatigue, and pulmonary infiltrates.
It is recommended that treatment with Kadcyla be permanently discontinued in patients who are diagnosed with ILD or pneumonitis, except for radiation pneumonitis in the adjuvant setting, where KADCYLA should be permanently discontinued for ≥Grade 3 or for Grade 2 not responding to standard treatment (see Dose Modifications under Dosage & Administration).
Patients with dyspnea at rest due to complications of advanced malignancy, co-morbidities, and receiving concurrent pulmonary radiation therapy may be at increased risk of pulmonary events.
Hepatotoxicity: Hepatotoxicity, predominantly in the form of asymptomatic increases in the concentrations of serum transaminases (Grade 1-4 transaminitis), has been observed while on treatment with Kadcyla in clinical trials (see Adverse Reactions). Transaminase elevations were generally transient with peak elevation at day 8 after therapy and subsequent recovery to Grade 1 or less prior to the next cycle. A cumulative effect of Kadcyla on transaminases has also been observed. Patients with elevated transaminases improved to Grade 1 or normal within 30 days of the last dose of Kadcyla in the majority of the cases. Serious hepatobiliary disorders, including nodular regenerative hyperplasia (NRH) of the liver and some with a fatal outcome due to drug-induced liver injury have been observed in patients treated with Kadcyla in clinical trials. Observed cases may have been confounded by comorbidities and/or concomitant medications with known hepatotoxic potential.
Liver function should be monitored prior to initiation of treatment and each Kadcyla dose. Dose reductions or discontinuation for increased serum transaminases and total bilirubin are specified in Dose Modifications under Dosage & Administration.
Kadcyla has not been studied in patients with serum transaminases >2.5x ULN or total bilirubin >1.5x ULN prior to initiation of treatment. Kadcyla treatment in patients with serum transaminases >3x ULN and concomitant total bilirubin >2x ULN should be permanently discontinued.
Cases of nodular regenerative hyperplasia (NRH) of the liver have been identified from liver biopsies in patients treated with Kadcyla. NRH is a rare liver condition characterized by widespread benign transformation of hepatic parenchyma into small regenerative nodules; NRH may lead to non-cirrhotic portal hypertension. Diagnosis of NRH can be confirmed only by histopathology. NRH should be considered in all patients with clinical symptoms of portal hypertension and/or cirrhosis-like pattern seen on the computed tomography (CT) scan of the liver but with normal transaminases and no other manifestations of cirrhosis. Upon diagnosis of NRH, Kadcyla treatment must be permanently discontinued.
Left Ventricular Dysfunction: Patients treated with Kadcyla are at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) < 40% has been observed in patients treated with Kadcyla, and therefore symptomatic congestive heart failure (CHF) is a potential risk. Standard cardiac function testing (echocardiogram or multigated acquisition (MUGA) scanning) should be performed prior to initiation and at regular intervals (e.g. every three months) during treatment with Kadcyla. Treatment with Kadcyla has not been studied in patients with LVEF <50% prior to initiation of treatment. Specific guidelines regarding dose modifications and discontinuation are provided in Dose Modifications under Dosage & Administration.
Infusion-Related Reactions: Treatment with Kadcyla has not been studied in patients who had trastuzumab permanently discontinued due to infusion-related reactions (IRR); treatment with Kadcyla is not recommended for these patients.
Infusion-related reactions, characterized by one or more of the following symptoms - flushing, chills, pyrexia, dyspnea, hypotension, wheezing, bronchospasm, and tachycardia-have been reported in clinical trials of Kadcyla. In general, these symptoms were not severe (see Adverse Reactions). In most patients, these reactions resolved over the course of several hours to a day after the infusion was terminated. Kadcyla treatment should be interrupted in patients with severe IRR. Kadcyla treatment should be permanently discontinued in the event of a life threatening infusion-related reaction (see Dose Modifications under Dosage & Administration).
Hypersensitivity Reactions: Patients should be observed closely for hypersensitivity reactions, especially during the first infusion. Hypersensitivity, including serious anaphylactic-like reactions, has been observed in clinical trials with treatment of Kadcyla. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use.
Hemorrhage: Cases of hemorrhagic events, including central nervous system, respiratory, and gastrointestinal hemorrhage, have been reported with Kadcyla. Some of these bleeding events resulted in fatal outcomes. In some of the observed cases the patients were also receiving anti-coagulation therapy, antiplatelet therapy, or had thrombocytopenia, in others there were no known additional risk factors. Use caution with these agents and consider additional monitoring when concomitant use is medically necessary.
Thrombocytopenia: Thrombocytopenia, or decreased platelet counts, was reported in patients in clinical trials of Kadcyla. The majority of these patients had Grade 1 or 2 events (≥50,000/mm³), with the nadir occurring by day 8 and generally improving to grade 0 or 1 (≥75,000/mm³) by the next scheduled dose. In clinical trials, the incidence and severity of thrombocytopenia were higher in Asian patients.
Patients with thrombocytopenia (<100,000/mm³) and patients on anti-coagulant treatment should be monitored closely while on Kadcyla treatment. It is recommended that platelet counts are monitored prior to each Kadcyla dose. Kadcyla has not been studied in patients with platelet counts <100,000/mm³ prior to initiation of treatment. In the event of decreased platelet count to Grade 3 or greater (<50,000/mm³), do not administer Kadcyla until platelet counts recover to Grade 1 (≥75,000/mm³). Please see Dose Modifications under Dosage & Administrations.
Neurotoxicity: Peripheral neuropathy, mainly Grade 1 and predominantly sensory, has been reported in clinical trials of Kadcyla. Treatment with Kadcyla should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until symptoms resolve or improve to ≤Grade 2. Patients should be clinically monitored on an ongoing basis for signs/symptoms of neurotoxicity.
Extravasation: In Kadcyla clinical studies, reactions secondary to extravasation have been observed. These reactions were usually mild and comprised erythema, tenderness, skin irritation, pain, or swelling at the infusion site. These reactions have been observed more frequently within 24 hours of infusion. Specific treatment for Kadcyla extravasation is unknown at this time. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration.
Drug Abuse and Dependence: No data to report.
Ability to Drive and Use Machines: Kadcyla has no or negligible influence on the ability to drive and use machines. The significance of reported adverse reactions such as fatigue, headache, dizziness and blurred vision on the ability to drive or use machines is unknown. Patients experiencing symptoms of infusion related reactions (flushing, shivering fits, fever, trouble breathing, low blood pressure or a rapid heartbeat) should be advised not to drive and use machines until symptoms abate.
Renal Impairment: See Special Dosage Instructions under Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetic in Special Populations under Actions.
Hepatic Impairment: See Special Dosage Instructions under Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetic in Special Populations under Actions.
Females and Males of Reproductive Potential: Contraception: Women of child bearing potential and female partners of male patients of child bearing potential should use effective contraception while receiving Kadcyla and for at least 7 months following the last dose of Kadcyla.
Use in Children: Safety and efficacy in pediatric patients below the age of 18 have not been established.
Use in the Elderly: There are insufficient data to establish the safety and efficacy of Kadcyla in patients 75 years of age or older.

Pregnancy: No clinical studies of Kadcyla in pregnant women have been performed. No reproductive and developmental toxicology studies have been conducted with Kadcyla.
Trastuzumab, a component of Kadcyla, can cause fetal harm or death when administered to a pregnant woman. In the post-marketing setting, cases of oligohydramnios, some associated with fatal pulmonary hypoplasia, have been reported in pregnant women receiving trastuzumab. Animal studies of maytansine, a closely related chemical entity of the same maytansinoid class as DM1, suggest that DM1, the microtubule inhibiting cytotoxic drug component of Kadcyla, is expected to be teratogenic and potentially embryotoxic.
Administration of Kadcyla to pregnant women is not recommended. Women who become pregnant must contact their doctor and should be advised of the possibility of harm to the fetus. If a pregnant woman is treated with Kadcyla, close monitoring by a multidisciplinary team is recommended.
Labor and Delivery: The safe use of Kadcyla during labor and delivery has not been established.
Lactation: It is not known whether Kadcyla is excreted in human breast milk. Since many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Kadcyla, women should discontinue nursing prior to initiating treatment with Kadcyla. Women may begin nursing 7 months following the last dose of Kadcyla.

Clinical Trials: Early Breast Cancer: The safety of Kadcyla has been evaluated in 740 patients with EBC in Study BO27938 KATHERINE. Adverse drug reactions from KATHERINE (Table 5) are listed by MedDRA system organ class. The corresponding frequency category for each adverse drug reaction is based on the following convention: 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). (See Table 5.)

Click on icon to see table/diagram/image

Laboratory Abnormalities: The following table displays laboratory abnormalities observed in patients treated with Kadcyla in clinical trial BO27938 (KATHERINE). (See Table 6.)

Click on icon to see table/diagram/image

Metastatic Breast Cancer: The safety of Kadcyla has been evaluated in 1871 patients in clinical trials. Adverse drug reactions from clinical trials (Table 7) are listed by MedDRA system organ class. The corresponding frequency category for each adverse drug reaction is based on the following convention: 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). (See Table 7.)

Click on icon to see table/diagram/image

Laboratory Abnormalities: The following table displays laboratory abnormalities observed in patients treated with Kadcyla in clinical trial TDM4370g/BO21977. (See Table 8.)

Click on icon to see table/diagram/image

Postmarketing Experience: Not applicable.

No formal drug-drug interaction studies with Kadcyla in humans have been conducted. In vitro metabolism studies in human liver microsomes suggest that DM1, a component of trastuzumab emtansine, is metabolized mainly by CYP3A4 and, to a lesser extent, by CYP3A5. DM1 does not induce or inhibit P450-mediated metabolism in vitro. Caution should be taken when Kadcyla is co-administered with potent CYP3A inhibitors.

Special Instructions for Use, Handling and Disposal: Appropriate aseptic technique should be used. Appropriate procedures for the preparation of chemotherapeutic drugs should be used.
The reconstituted product contains no preservative and is intended for single use only. Discard any unused portion.
Using a sterile syringe, slowly inject 5 ml of Sterile Water for Injection into the 100 mg vial, or 8 mL of sterile water for injection into the 160 mg Kadcyla vial.
Swirl the vial gently until completely dissolved. DO NOT SHAKE!
Store reconstituted Kadcyla at 2-8ºC; discard unused Kadcyla after 24 hours.
Reconstituted solution should be inspected visually for particulate matter and discoloration prior to administration. The reconstituted solution should be free of visible particulates, clear to slightly opalescent. The color of the reconstituted solution should be colorless to pale brown. Do not use if reconstituted solution contains visible particulates, or is cloudy, or is discolored.
Instructions for Dilution: Determine the volume of the solution required based on a dose of 3.6 mg Kadcyla/kg body weight (see Dose Reduction Schedule under Dosage & Administration):

Click on icon to see table/diagram/image

The appropriate amount of solution should be withdrawn from the vial and added to an infusion bag containing 250 ml of 0.45% sodium chloride or 0.9% sodium chloride. Dextrose (5%) solution should not be used. 0.45% sodium chloride may be used without a 0.2 or 0.22 micron in-line polyethersulfone (PES) filter. If 0.9% sodium chloride is used for infusion, a 0.2 or 0.22 micron in-line polyethersulfone (PES) filter is required. Once the infusion is prepared it should be administered immediately. If not used immediately, the infusion can be stored for up to 24 hours in a refrigerator at 2°C-8°C. Do not freeze or shake the infusion during storage.
Disposal of unused/expired medicines: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Use established "collection systems", if available in the location.
The following points should be strictly adhered to regarding the use and disposal of syringes and other medicinal sharps: Needles and syringes should never be reused.
Place all used needles and syringes into a sharps container (puncture-proof disposable container).
Local requirements should be followed for the disposal process of unused/expired medicines or waste material.
Incompatibilities: Dextrose (5%) solution should not be used since it causes aggregation of the protein.
Kadcyla should not be mixed or diluted with other drugs.

Vials: Store vials at 2-8°C.
Shelf-life of the reconstituted solution: Product vials reconstituted with sterile water for injection should be used immediately following reconstitution. If not used immediately, the reconstituted vials can be stored for up to 24 hours at 2-8°C, and must be discarded thereafter.
Do not freeze the reconstituted solution.
Shelf-life of the solution for infusion containing the reconstituted product: The reconstituted Kadcyla solution diluted in polyvinyl chloride (PVC) or latex-free PVC-free polyolefin bags containing 0.9% Sodium Chloride Injection, or 0.45% Sodium Chloride Injection, may be stored at 2-8°C for up to 24 hours prior to use. Particulates may be observed on storage if diluted in 0.9% Sodium Chloride Injection, therefore, a 0.2 or 0.22 micron in-line polyethersulfone (PES) filter is required for administration (see Special Instructions for Use, Handling and Disposal under Cautions for Usage).
Do not freeze the solution for infusion containing the reconstituted product.

Targeted Cancer Therapy

L01FD03 - trastuzumab emtansine ; Belongs to the class of HER2 (Human Epidermal Growth Factor Receptor 2) inhibitors. Used in the treatment of cancer.

S