Important Safety Information
Warnings and Precautions
Hepatotoxicity (Boxed WARNING)
Hepatotoxicity, predominantly in the form of asymptomatic increases in the concentrations of serum transaminases, has been observed in clinical trials with KADCYLA.
Serious hepatobiliary disorders, including at least 2 fatal cases of severe drug-induced liver injury and associated hepatic encephalopathy, have been reported in clinical trials with KADCYLA. Some of the observed cases may have been confounded by comorbidities and 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 hepatitis B virus or hepatitis C virus were excluded from EMILIA. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases and/or total bilirubin. Permanently discontinue KADCYLA treatment in patients with serum transaminases >3×ULN and concomitant total bilirubin >2×ULN.
In clinical trials of KADCYLA, cases of nodular regenerative hyperplasia (NRH) of the liver have been identified from liver biopsies (3 cases out of 884 treated patients, 1 of which was fatal). NRH should be considered in all patients with clinical symptoms of portal hypertension and/or cirrhosis-like pattern seen on the computed tomography scan of the liver but with normal transaminases and no manifestations of cirrhosis. Diagnosis can be confirmed only by histopathology. Upon diagnosis, KADCYLA treatment must be permanently discontinued.
Left Ventricular Dysfunction (Boxed WARNING)
Patients treated with KADCYLA are at increased risk of developing left ventricular dysfunction (LVD). A decrease of left ventricular ejection fraction (LVEF) to <40% has been observed in patients treated 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 comparator group.
Assess LVEF prior to initiation of KADCYLA and at regular intervals (eg, every 3 months) during treatment. Treatment with KADCYLA has not been studied in patients with LVEF <50% prior to treatment. 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.
Embryo-Fetal Toxicity (Boxed WARNING)
KADCYLA can cause fetal harm when administered to a pregnant woman. Treatment with trastuzumab, the antibody component of KADCYLA, during pregnancy in the postmarketing setting has resulted in cases of oligohydramnios; oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death were observed in the postmarketing setting in patients treated with trastuzumab. DM1, the cytotoxic component of KADCYLA, can cause embryo-fetal toxicity, based on its mechanism of action.
Verify the pregnancy status of women 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 women of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of KADCYLA.
If KADCYLA is administered during pregnancy or if a patient becomes pregnant while receiving KADCYLA or within 7 months following the last dose of KADCYLA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-25551-888-835-2555.
Encourage women who may be exposed to KADCYLA during pregnancy or within 7 months prior to conception, to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 1-800-690-6720 or visiting http://www.motherpregnancyregistry.com/.
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 EMILIA, the overall frequency of pneumonitis was 1.2%.
Treatment with KADCYLA should be permanently discontinued in patients diagnosed with ILD or pneumonitis.
Patients with dyspnea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of pulmonary events.
Infusion-Related Reactions, Hypersensitivity Reactions
Treatment with KADCYLA has not been studied in patients who had trastuzumab permanently discontinued due to infusion-related reactions (IRR) 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 the randomized trial, the overall frequency of IRRs in patients treated with KADCYLA was 1.4%. 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 IRRs and permanently discontinued in the event of a life-threatening IRR. Patients should be observed closely for IRRs, especially during the first infusion.
One case of a serious, allergic/anaphylactoid-like infusion 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.
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 incidence of ≥Grade 3 hemorrhage was 1.8% in the KADCYLA-treated group and 0.8% in the comparator group.
Although in some of the observed cases the patients were also receiving anticoagulation therapy or antiplatelet therapy, or had thrombocytopenia, in others there were no known additional risk factors. Anticoagulation therapy and antiplatelet agents may increase the risk of bleeding. Use caution with these agents and consider additional monitoring when concomitant use is medically necessary.
Thrombocytopenia was reported in clinical trials of KADCYLA. 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 incidence of ≥Grade 3 thrombocytopenia was 14.5% in the KADCYLA-treated group and 0.4% in the comparator group. In Asian patients, the incidence of ≥Grade 3 thrombocytopenia was 45.1% in the KADCYLA group and 1.3% in the comparator group.
Monitor platelet counts prior to initiation of KADCYLA and 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). Patients with thrombocytopenia (≤100,000/mm3) prior to initiation of KADCYLA and patients on anticoagulant treatment should be closely monitored during treatment with KADCYLA.
Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported in clinical trials of KADCYLA. In EMILIA, the incidence of ≥Grade 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the comparator 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/symptoms of neurotoxicity.
Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA therapy, because these are the only patients studied for whom benefit has been shown. Assessment of HER2 status should be done using an FDA-approved test performed by laboratories with demonstrated proficiency.
In the randomized study, patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC and/or FISH amplification ratio ≥2.0 assessed by a validated test.
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. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration. Specific treatment for KADCYLA extravasation is unknown.
Use in Specific Populations
There is no information regarding the presence of ado-trastuzumab emtansine in human milk, the effects on the breastfed infant, or the effects on milk production. DM1, the cytotoxic component of KADCYLA, may cause serious adverse reactions in breastfed infants, based on its mechanism of action. Advise women not to breastfeed during treatment and for 7 months following the last dose of KADCYLA.
You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-25551-888-835-2555. You may contact the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-10881-800-FDA-1088.
Please see accompanying full Prescribing Information for additional Important Safety Information, including Boxed WARNINGS.