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Hepatotoxicity: Hepatotoxicity, predominantly in the form of asymptomatic, transient increases in the concentrations of serum transaminases, has been observed in clinical trials with KADCYLA [see Clinical Trials Experience under Adverse Reactions]. Serious hepatotoxicity, including 3 fatal cases, has been observed in clinical trials (n=1624) with KADCYLA as single-agent. All fatal cases occurred in MBC clinical trials with KADCYLA, which included severe drug-induced liver injury and associated hepatic encephalopathy. Some of the patients experiencing hepatotoxicity had comorbidities and/or concomitant medications with known hepatotoxic potential.
Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Patients with known active liver disease (such as, hepatitis B virus or hepatitis C virus) were excluded from the EMILIA and KATHERINE studies [see Pharmacology: Pharmacodynamics: Clinical Studies: Metastatic Breast Cancer under Actions]. Reduce the dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases and/or total bilirubin [see Recommended Doses and Schedules under Dosage & Administration]. Permanently discontinue KADCYLA treatment in patients with serum transaminases >3 x ULN and concomitant total bilirubin >2 x ULN. KADCYLA has not been studied in patients with serum transaminases >2.5 x ULN or bilirubin >1.5 x ULN prior to the initiation of treatment.
In clinical trials of KADCYLA, cases of nodular regenerative hyperplasia (NRH) of the liver have been identified from liver biopsies (5 cases out of 1624 treated patients, one of which was fatal). Two of these five cases of NRH were observed in EMILIA and two were observed in KATHERINE [see Clinical Trials Experience under Adverse Reactions]. 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. The 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. A decrease of LVEF to <40% has been observed in patients treated with KADCYLA. Serious cases of heart failure, with no fatal cases, have been observed in clinical trials with KADCYLA. In EMILIA, left ventricular dysfunction occurred in 1.8% of patients in the KADCYLA-treated group and 3.3% of patients in the lapatinib plus capecitabine-treated group. In KATHERINE, left ventricular dysfunction occurred in 0.4% of patients in the KADCYLA-treated group and 0.6% of patients in the trastuzumab-treated group [see Clinical Trials Experience under Adverse Reactions].
Based on limited data from a retrospective observational study, 22% (7 of 32) of patients with HER2-positive metastatic breast cancer (MBC) with a baseline LVEF of 40-49% treated with KADCYLA developed a congestive heart failure (CHF) or a >10% reduction in LVEF [see Post-Marketing Experience under Adverse Reactions].
Assess LVEF prior to initiation of KADCYLA and at regular intervals (e.g. every three months) during treatment to ensure the LVEF is within the institution's normal limits. KADCYLA has not been studied in an adequately controlled study in patients with LVEF<50%.
For patients with MBC, if, at routine monitoring, LVEF is <40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold KADCYLA and repeat LVEF assessment within approximately 3 weeks. Permanently discontinue KADCYLA if the LVEF has not improved or has declined further.
For patients with EBC, if, at routine monitoring, LVEF is <45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold KADCYLA and repeat LVEF assessment within approximately 3 weeks. Permanently discontinue KADCYLA if the LVEF has not improved or has declined further [see Recommended Doses and Schedules under Dosage & Administration].
Patients with a history of symptomatic CHF, serious cardiac arrhythmia, or history of myocardial infarction or unstable angina within 6 months were excluded from the EMILIA and KATHERINE studies [see Pharmacology: Pharmacodynamics: Clinical Studies: Metastatic Breast Cancer under Actions].
Embryo-Fetal Toxicity: KADCYLA can cause fetal harm when administered to a pregnant woman. Cases of oligohydramnios, and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities and neonatal death were observed in the post-marketing setting in patients treated with trastuzumab, the antibody component of KADCYLA. DM1, the cytotoxic component of KADCYLA, can cause embryo-fetal toxicity based on its mechanism of action.
Verify the pregnancy status of females of reproductive potential prior to the initiation of KADCYLA. Advise pregnant women and females of reproductive potential that exposure to KADCYLA during pregnancy or within 7 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of KADCYLA [see Pregnancy and Females and Males of Reproductive Potential under Use in Pregnancy & Lactation].
Pulmonary Toxicity: Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratory distress syndrome or fatal outcome have been reported in clinical trials with KADCYLA. Signs and symptoms include dyspnea, cough, fatigue, and pulmonary infiltrates.
In patients with MBC, pneumonitis was reported at an incidence of 0.8% (7 out of 884 treated patients), with one case of Grade 3 pneumonitis. The overall incidence of pneumonitis was 1.2% in EMILIA. In KATHERINE, pneumonitis was reported at an incidence of 1.1% (8 out of 740 patients treated with KADCYLA), with one case of Grade 3 pneumonitis.
Radiation pneumonitis was reported at an incidence of 1.8% (11 out of 623 patients treated with adjuvant radiotherapy and KADCYLA), with 2 cases of Grade 3 radiation pneumonitis [see Clinical Trials Experience under Adverse Reactions].
Permanently discontinue treatment with KADCYLA in patients diagnosed with ILD or pneumonitis. For patients with radiation pneumonitis in the adjuvant setting, 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 toxicity.
Infusion-Related Reactions, Hypersensitivity Reactions: Treatment with KADCYLA has not been studied in patients who had trastuzumab permanently discontinued due to infusion-related reactions (IRRs) and/or hypersensitivity; 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 EMILIA, the overall incidence of IRRs in patients treated with KADCYLA was 1.4%. In KATHERINE, the overall incidence of IRRs in patients treated with KADCYLA was 1.6% [see Clinical Trials Experience under 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 IRR [see Recommended Doses and Schedules under Dosage & Administration]. Patients should be observed closely for IRR reactions, especially during the first infusion.
One case of a serious, allergic/anaphylactic-like reaction has been observed in clinical trials of single-agent 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 in clinical trials with KADCYLA. Some of these bleeding events resulted in fatal outcomes. In EMILIA, the overall incidence of hemorrhage was 32% in the KADCYLA-treated group and 16% in the lapatinib plus capecitabine-treated group. The incidence of Grade ≥3 hemorrhage was 1.8% in the KADCYLA-treated group and 0.8% in the lapatinib plus capecitabine-treated group. In KATHERINE, the overall incidence of hemorrhage was 29% in the KADCYLA-treated group and 10% in the trastuzumab-treated group. The incidence of Grade ≥3 hemorrhage was 0.4% in the KADCYLA-treated group, with one fatal case of intracranial hemorrhage, and 0.3% in the trastuzumab-treated group [see Clinical Trials Experience under Adverse Reactions]. Although, 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 count, was reported in clinical trials of KADCYLA (145 of 1624 treated patients with Grade ≥3; 494 of 1624 treated patients with any Grade). The majority of these patients had Grade 1 or 2 events (<LLN to ≥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 of KADCYLA, the incidence and severity of thrombocytopenia were higher in Asian patients.
In EMILIA, the overall incidence of thrombocytopenia was 31% in the KADCYLA-treated group and 3.3% in the lapatinib plus capecitabine-treated group [see Clinical Trials Experience under Adverse Reactions]. The incidence of Grade ≥3 thrombocytopenia was 15% in the KADCYLA-treated group and 0.4% in the lapatinib plus capecitabine-treated group. In Asian patients, the incidence of Grade ≥3 thrombocytopenia was 45% in the KADCYLA-treated group and 1.3% in the lapatinib plus capecitabine-treated group.
In KATHERINE, the overall incidence of thrombocytopenia was 29% in the KADCYLA-treated group and 2.4% in the trastuzumab-treated group [see Clinical Trials Experience under Adverse Reactions]. The incidence of Grade ≥3 thrombocytopenia was 6% in the KADCYLA-treated group and 0.3% in the trastuzumab-treated group. In Asian patients, the incidence of Grade ≥3 thrombocytopenia was 19% in the KADCYLA-treated group and 0% in the trastuzumab-treated group. The overall incidence of thrombocytopenia in the KADCYLA-treated group for Asian patients was 50%.
Monitor platelet counts prior to initiation of KADCYLA and prior to each KADCYLA dose [see Recommended Doses and Schedules under Dosage & Administration]. 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 (<50,000/mm3) do not administer KADCYLA until platelet counts recover to Grade 1 (≥75,000/mm3) [see Recommended Doses and Schedules under Dosage & Administration]. Closely monitor patients with thrombocytopenia (<100,000/mm3) and patients on anti-coagulant treatment during treatment with KADCYLA.
Neurotoxicity: Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported in clinical trials of KADCYLA (26 of 1624 treated patients with Grade ≥3; 435 of 1624 treated patients with any Grade). In EMILIA, the overall incidence of peripheral neuropathy was 21% in the KADCYLA-treated group and 14% in the lapatinib plus capecitabine-treated group [see Clinical Trials Experience under Adverse Reactions]. The incidence of Grade ≥3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the lapatinib plus capecitabine-treated group. In KATHERINE, the overall incidence of peripheral neuropathy was 32% in the KADCYLA-treated group and 17% in the trastuzumab-treated group. Peripheral neuropathy, including sensory and motor peripheral neuropathy, for KADCYLA treated patients 30% of cases were not resolved at the time of the primary IDFS analysis for KATHERINE. The incidence of Grade ≥3 peripheral neuropathy was 1.6% in the KADCYLA-treated group and 0.1% in the trastuzumab-treated group.
KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to Grade ≤2. Patients should be clinically monitored on an ongoing basis for signs or symptoms of neurotoxicity [see Pharmacology: Toxicology: Nonclinical Toxicology: Animal Toxicology and/or Pharmacology under Actions].
Extravasation: In KADCYLA clinical studies, reactions secondary to extravasation have been observed. These reactions, observed more frequently within 24 hours of infusion, were usually mild and comprised erythema, tenderness, skin irritation, pain, or swelling at the infusion site. Specific treatment for KADCYLA extravasation is unknown. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration.
Renal Impairment: No dedicated renal impairment trial for KADCYLA has been conducted. Based on the population pharmacokinetics, as well as analysis of Grade 3 or greater adverse reactions and dose modifications, dose adjustments of KADCYLA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 89 mL/min) or moderate (CLcr 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited data available [see Pharmacology: Pharmacokinetics under Actions].
Hepatic Impairment: No adjustment to the starting dose is required for patients with mild or moderate hepatic impairment [see Pharmacology: Pharmacokinetics under Actions]. KADCYLA was not studied in patients with severe hepatic impairment. Closely monitor patients with hepatic impairment due to known hepatotoxicity observed with KADCYLA [see Hepatotoxicity as previously mentioned].
Use in Children: Safety and effectiveness of KADCYLA have not been established in pediatric patients.
Use in the Elderly: Of the 495 patients who were randomized to KADCYLA in EMILIA [see Pharmacology: Pharmacodynamics: Clinical Studies: Metastatic Breast Cancer under Actions], 65 patients (13%) were ≥65 years of age and 11 patients (2%) were ≥75 years of age. In patients ≥65 years old (n=138 across both treatment arms) the hazard ratios for progression-free survival (PFS) and overall survival (OS) were 1.06 (95% CI: 0.68, 1.66) and 1.05 (95% CI: 0.58, 1.91), respectively. No overall differences in the safety of KADCYLA were observed in patients aged ≥65 compared to patients <65 years of age. EMILIA did not include sufficient numbers of patients aged ≥75 years to draw conclusions on the safety or effectiveness of KADCYLA in this age group.
Of the 743 patients who were randomized to KADCYLA in KATHERINE [see Pharmacology: Pharmacodynamics: Clinical Studies: Early Breast Cancer under Actions], 58 patients (8%) were ≥65 years of age and 2 patients (0.3%) were ≥75 years of age. No overall differences in the safety or effectiveness of KADCYLA were observed in patients aged ≥65 compared to patients <65 years of age. KATHERINE did not include sufficient numbers of patients aged ≥75 years to draw conclusions on the safety or effectiveness of KADCYLA in this age group.
Population pharmacokinetic analysis indicates that age does not have a clinically meaningful effect on the pharmacokinetics of trastuzumab emtansine [see Pharmacology: Pharmacokinetics under Actions].
