Kadcyla (Ado-Trastuzumab Emtansine)

• Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin. (

  2.3 Dose Modifications

  Do not re-escalate the KADCYLA dose after a dose reduction is made.

  If a planned dose is delayed or missed, administer as soon as possible; do not wait until the next planned cycle. Adjust the schedule of administration to maintain a 3-week interval between doses. Administer the infusion at the dose and rate the patient tolerated in the most recent infusion.

  Slow or interrupt the infusion rate of KADCYLA if the patient develops an infusion-related reaction. Permanently discontinue KADCYLA for life-threatening infusion-related reactions

  [see Warnings and Precautions (5.5)]

  .

  Management of increased serum transaminases, hyperbilirubinemia, left ventricular dysfunction, thrombocytopenia, pulmonary toxicity or peripheral neuropathy may require temporary interruption, dose reduction or treatment discontinuation of KADCYLA as per guidelines provided in Tables 1and 2.

  Table 1 Recommended Dose Reduction Schedule for Adverse Reactions

  Dose Reduction Schedule	Dose Level
  Starting dose	3.6 mg/kg
  First dose reduction	3 mg/kg
  Second dose reduction	2.4 mg/kg
  Requirement for further dose reduction	Discontinue treatment

  Table 2 Dose Modification Guidelines for KADCYLA

  ALT = alanine transaminase; AST = aspartate transaminase, CHF = congestive heart failure, DILI = Drug Induced Liver Injury; LVEF = left ventricular ejection fraction, LVSD = left ventricular systolic dysfunction, TBILI = Total Bilirubin, ULN = upper limit of normal
  Dose Modifications for Patients with MBC
  Adverse reaction	Severity	Treatment modification
  Increased Transaminase (AST/ALT)	Grade 2 (> 2.5 to ≤ 5× the ULN)	Treat at the same dose level.
  	Grade 3 (> 5 to ≤ 20× the ULN)	Do not administer KADCYLA until AST/ALT recovers to Grade ≤ 2, and then reduce one dose level
  	Grade 4 (> 20× the ULN)	Discontinue KADCYLA
  Hyperbilirubinemia	Grade 2 (> 1.5 to ≤ 3× the ULN)	Do not administer KADCYLA until total bilirubin recovers to Grade ≤ 1, and then treat at the same dose level.
  	Grade 3 (> 3 to ≤ 10× the ULN)	Do not administer KADCYLA until total bilirubin recovers to Grade ≤ 1 and then reduce one dose level.
  	Grade 4 (> 10× the ULN)	Discontinue KADCYLA
  Drug Induced Liver Injury (DILI)	Serum transaminases > 3 × ULN and concomitant total bilirubin > 2 × ULN	Permanently discontinue KADCYLA in the absence of another likely cause for the elevation of liver enzymes and bilirubin, e.g. liver metastasis or concomitant medication
  Nodular Regenerative Hyperplasia (NRH)	All Grades	Permanently discontinue KADCYLA
  Thrombocytopenia	Grade 3 (25,000 to < 50,000/mm3)	Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm3), and then treat at the same dose level
  	Grade 4 (< 25,000/mm3)	Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm3), and then reduce one dose level
  Left Ventricular Dysfunction	Symptomatic CHF	Discontinue KADCYLA
  	LVEF < 40%	Do not administer KADCYLA Repeat LVEF assessment within 3 weeks. If LVEF < 40% is confirmed, discontinue KADCYLA
  	LVEF 40% to ≤ 45% and decrease is ≥ 10% points from baseline	Do not administer KADCYLA Repeat LVEF assessment within 3 weeks. If the LVEF has not recovered to within 10% points from baseline, discontinue KADCYLA
  	LVEF 40% to ≤ 45% and decrease is < 10% points from baseline	Continue treatment with KADCYLA . Repeat LVEF assessment within 3 weeks.
  	LVEF > 45%	Continue treatment with KADCYLA .
  Pulmonary Toxicity	Interstitial lung disease (ILD) or pneumonitis	Permanently discontinue KADCYLA
  Peripheral Neuropathy	Grade 3-4	Do not administer KADCYLA until resolution Grade ≤ 2
  Dose Modification Guidelines for EBC
  Adverse reaction	Severity	Treatment modification
  Increased Alanine Transaminase (ALT)	Grade 2-3 (> 3.0 to ≤ 20 × ULN on day of scheduled treatment)	Do not administer KADCYLA until ALT recovers to Grade ≤ 1, and then reduce one dose level
  	Grade 4 (> 20 × ULN at any time)	Discontinue KADCYLA
  Increased Aspartate Transaminase (AST)	Grade 2 (> 3.0 to ≤ 5 × ULN on day of scheduled treatment)	Do not administer KADCYLA until AST recovers to Grade ≤ 1, and then treat at the same dose level
  	Grade 3 (> 5 to ≤ 20 × ULN on day of scheduled treatment)	Do not administer KADCYLA until AST recovers to Grade ≤ 1, and then reduce one dose level
  	Grade 4 (> 20 × ULN at any time)	Discontinue KADCYLA
  Hyperbilirubinemia	TBILI > 1.0 to ≤ 2.0 × the ULN on day of scheduled treatment	Do not administer KADCYLA until total bilirubin recovers to ≤ 1.0 × ULN, and then reduce one dose level
  	TBILI > 2 × ULN at any time	Discontinue KADCYLA
  Nodular Regenerative Hyperplasia (NRH)	All Grades	Permanently discontinue KADCYLA
  Thrombocytopenia	Grade 2-3 on day of scheduled treatment (25,000 to < 75,000/mm3)	Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm3), and then treat at the same dose level. If a patient requires 2 delays due to thrombocytopenia, consider reducing dose by one level.
  	Grade 4 at any time < 25,000/mm3	Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm3), and then reduce one dose level.
  Left Ventricular Dysfunction	LVEF < 45%	Do not administer KADCYLA Repeat LVEF assessment within 3 weeks. If LVEF < 45% is confirmed, discontinue KADCYLA.
  	LVEF 45% to < 50% and decrease is ≥ 10% points from baselinePrior to starting KADCYLA treatment	Do not administer KADCYLA Repeat LVEF assessment within 3 weeks. If the LVEF remains < 50% and has not recovered to < 10% points from baseline, discontinue KADCYLA.
  	LVEF 45% to < 50% and decrease is < 10% points from baseline	Continue treatment with KADCYLA. Repeat LVEF assessment within 3 weeks.
  	LVEF ≥ 50%	Continue treatment with KADCYLA.
  Heart Failure	Symptomatic CHF, Grade 3-4 LVSD or Grade 3-4 heart failure, or Grade 2 heart failure accompanied by LVEF < 45%	Discontinue KADCYLA
  Peripheral Neuropathy	Grade 3-4	Do not administer KADCYLA until resolution Grade ≤ 2
  Pulmonary Toxicity	Interstitial lung disease (ILD) or pneumonitis	Permanently discontinue KADCYLA
  Radiotherapy-Related Pneumonitis	Grade 2	Discontinue KADCYLA if not resolving with standard treatment
  	Grade 3-4	Discontinue KADCYLA

  ,

  5.1 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 Adverse Reactions (6.1)]

  . 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 Clinical Studies (14.1)]

  . Reduce the dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases and/or total bilirubin

  [see Dosage and Administration (2.2)]

  . Permanently discontinue KADCYLA treatment in patients with serum transaminases > 3 × ULN and concomitant total bilirubin > 2 × ULN. KADCYLA has not been studied in patients with serum transaminases > 2.5 × ULN or bilirubin > 1.5 × 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 Adverse Reactions (6.1)]

  . 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.

  )
• Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function. (

  2.3 Dose Modifications

  Do not re-escalate the KADCYLA dose after a dose reduction is made.

  If a planned dose is delayed or missed, administer as soon as possible; do not wait until the next planned cycle. Adjust the schedule of administration to maintain a 3-week interval between doses. Administer the infusion at the dose and rate the patient tolerated in the most recent infusion.

  Slow or interrupt the infusion rate of KADCYLA if the patient develops an infusion-related reaction. Permanently discontinue KADCYLA for life-threatening infusion-related reactions

  [see Warnings and Precautions (5.5)]

  .

  Management of increased serum transaminases, hyperbilirubinemia, left ventricular dysfunction, thrombocytopenia, pulmonary toxicity or peripheral neuropathy may require temporary interruption, dose reduction or treatment discontinuation of KADCYLA as per guidelines provided in Tables 1and 2.

  Table 1 Recommended Dose Reduction Schedule for Adverse Reactions

  Dose Reduction Schedule	Dose Level
  Starting dose	3.6 mg/kg
  First dose reduction	3 mg/kg
  Second dose reduction	2.4 mg/kg
  Requirement for further dose reduction	Discontinue treatment

  Table 2 Dose Modification Guidelines for KADCYLA

  ALT = alanine transaminase; AST = aspartate transaminase, CHF = congestive heart failure, DILI = Drug Induced Liver Injury; LVEF = left ventricular ejection fraction, LVSD = left ventricular systolic dysfunction, TBILI = Total Bilirubin, ULN = upper limit of normal
  Dose Modifications for Patients with MBC
  Adverse reaction	Severity	Treatment modification
  Increased Transaminase (AST/ALT)	Grade 2 (> 2.5 to ≤ 5× the ULN)	Treat at the same dose level.
  	Grade 3 (> 5 to ≤ 20× the ULN)	Do not administer KADCYLA until AST/ALT recovers to Grade ≤ 2, and then reduce one dose level
  	Grade 4 (> 20× the ULN)	Discontinue KADCYLA
  Hyperbilirubinemia	Grade 2 (> 1.5 to ≤ 3× the ULN)	Do not administer KADCYLA until total bilirubin recovers to Grade ≤ 1, and then treat at the same dose level.
  	Grade 3 (> 3 to ≤ 10× the ULN)	Do not administer KADCYLA until total bilirubin recovers to Grade ≤ 1 and then reduce one dose level.
  	Grade 4 (> 10× the ULN)	Discontinue KADCYLA
  Drug Induced Liver Injury (DILI)	Serum transaminases > 3 × ULN and concomitant total bilirubin > 2 × ULN	Permanently discontinue KADCYLA in the absence of another likely cause for the elevation of liver enzymes and bilirubin, e.g. liver metastasis or concomitant medication
  Nodular Regenerative Hyperplasia (NRH)	All Grades	Permanently discontinue KADCYLA
  Thrombocytopenia	Grade 3 (25,000 to < 50,000/mm3)	Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm3), and then treat at the same dose level
  	Grade 4 (< 25,000/mm3)	Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm3), and then reduce one dose level
  Left Ventricular Dysfunction	Symptomatic CHF	Discontinue KADCYLA
  	LVEF < 40%	Do not administer KADCYLA Repeat LVEF assessment within 3 weeks. If LVEF < 40% is confirmed, discontinue KADCYLA
  	LVEF 40% to ≤ 45% and decrease is ≥ 10% points from baseline	Do not administer KADCYLA Repeat LVEF assessment within 3 weeks. If the LVEF has not recovered to within 10% points from baseline, discontinue KADCYLA
  	LVEF 40% to ≤ 45% and decrease is < 10% points from baseline	Continue treatment with KADCYLA . Repeat LVEF assessment within 3 weeks.
  	LVEF > 45%	Continue treatment with KADCYLA .
  Pulmonary Toxicity	Interstitial lung disease (ILD) or pneumonitis	Permanently discontinue KADCYLA
  Peripheral Neuropathy	Grade 3-4	Do not administer KADCYLA until resolution Grade ≤ 2
  Dose Modification Guidelines for EBC
  Adverse reaction	Severity	Treatment modification
  Increased Alanine Transaminase (ALT)	Grade 2-3 (> 3.0 to ≤ 20 × ULN on day of scheduled treatment)	Do not administer KADCYLA until ALT recovers to Grade ≤ 1, and then reduce one dose level
  	Grade 4 (> 20 × ULN at any time)	Discontinue KADCYLA
  Increased Aspartate Transaminase (AST)	Grade 2 (> 3.0 to ≤ 5 × ULN on day of scheduled treatment)	Do not administer KADCYLA until AST recovers to Grade ≤ 1, and then treat at the same dose level
  	Grade 3 (> 5 to ≤ 20 × ULN on day of scheduled treatment)	Do not administer KADCYLA until AST recovers to Grade ≤ 1, and then reduce one dose level
  	Grade 4 (> 20 × ULN at any time)	Discontinue KADCYLA
  Hyperbilirubinemia	TBILI > 1.0 to ≤ 2.0 × the ULN on day of scheduled treatment	Do not administer KADCYLA until total bilirubin recovers to ≤ 1.0 × ULN, and then reduce one dose level
  	TBILI > 2 × ULN at any time	Discontinue KADCYLA
  Nodular Regenerative Hyperplasia (NRH)	All Grades	Permanently discontinue KADCYLA
  Thrombocytopenia	Grade 2-3 on day of scheduled treatment (25,000 to < 75,000/mm3)	Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm3), and then treat at the same dose level. If a patient requires 2 delays due to thrombocytopenia, consider reducing dose by one level.
  	Grade 4 at any time < 25,000/mm3	Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm3), and then reduce one dose level.
  Left Ventricular Dysfunction	LVEF < 45%	Do not administer KADCYLA Repeat LVEF assessment within 3 weeks. If LVEF < 45% is confirmed, discontinue KADCYLA.
  	LVEF 45% to < 50% and decrease is ≥ 10% points from baselinePrior to starting KADCYLA treatment	Do not administer KADCYLA Repeat LVEF assessment within 3 weeks. If the LVEF remains < 50% and has not recovered to < 10% points from baseline, discontinue KADCYLA.
  	LVEF 45% to < 50% and decrease is < 10% points from baseline	Continue treatment with KADCYLA. Repeat LVEF assessment within 3 weeks.
  	LVEF ≥ 50%	Continue treatment with KADCYLA.
  Heart Failure	Symptomatic CHF, Grade 3-4 LVSD or Grade 3-4 heart failure, or Grade 2 heart failure accompanied by LVEF < 45%	Discontinue KADCYLA
  Peripheral Neuropathy	Grade 3-4	Do not administer KADCYLA until resolution Grade ≤ 2
  Pulmonary Toxicity	Interstitial lung disease (ILD) or pneumonitis	Permanently discontinue KADCYLA
  Radiotherapy-Related Pneumonitis	Grade 2	Discontinue KADCYLA if not resolving with standard treatment
  	Grade 3-4	Discontinue KADCYLA

  ,

  5.2 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 Adverse Reactions (6.1)]

  .

  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 Adverse Reactions (6.2)].

  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 Dosage and Administration (2.2)]

  .

  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 Clinical Studies (14.1)]

  .

  )
• Embryo-Fetal Toxicity: Exposure to KADCYLA during pregnancy can result in embryo-fetal harm. Advise patients of these risks and the need for effective contraception. (

  5.3 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 Use in Specific Populations (8.1, 8.3)].

  ,

  8.1 Pregnancy

  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, health care providers and patients should immediately report KADCYLA exposure to Genentech at 1-888-835-2555.

  Risk Summary

  KADCYLA can cause fetal harm when administered to a pregnant woman. There are no available data on the use of KADCYLA in pregnant women. Cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death were observed in the postmarketing setting in patients treated with trastuzumab, the antibody component of KADCYLA

  [see Data]

  . Based on its mechanism of action, the DM1 component of KADCYLA can also cause embryo-fetal harm when administered to a pregnant woman [

  see Data

  ]. Apprise the patient of the potential risks to a fetus. There are clinical considerations if KADCYLA is used in a pregnant woman, or if a patient becomes pregnant within 7 months following the last dose of KADCYLA

  [see Clinical Considerations].

  The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

  Clinical Considerations

  Fetal/Neonatal Adverse Reactions

  Monitor women who received KADCYLA during pregnancy or within 7 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care.

  Data

  Human Data

  There are no available data on the use of KADCYLA in pregnant women. In the post-marketing setting, cases of oligohydramnios, and of oligohydramnios sequence, manifesting in the fetus as pulmonary hypoplasia, skeletal abnormalities and neonatal death were observed after treatment with trastuzumab during pregnancy. These case reports described oligohydramnios in pregnant women who received trastuzumab either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after trastuzumab was stopped. In one case, trastuzumab therapy resumed after amniotic index improved, and oligohydramnios recurred.

  Animal Data

  There were no reproductive and developmental toxicology studies conducted with ado-trastuzumab emtansine. DM1, the cytotoxic component of KADCYLA, disrupts microtubule function. DM1 is toxic to rapidly dividing cells in animals and is genotoxic, suggesting it has the potential to cause embryotoxicity and teratogenicity. In studies where trastuzumab was administered to pregnant cynomolgus monkeys during the period of organogenesis at doses up to 25 mg/kg given twice weekly (about 7 times the clinical dose), trastuzumab crossed the placental barrier during the early (Gestation Days 20 to 50) and late (Gestation Days 120 to 150) phases of gestation. The resulting concentrations of trastuzumab in fetal serum and amniotic fluid were approximately 33% and 25%, respectively, of those present in the maternal serum but were not associated with adverse developmental effects.

  ,

  8.3 Females and Males of Reproductive Potential

  Pregnancy Testing

  Verify the pregnancy status of females of reproductive potential prior to the initiation of KADCYLA.

  Contraception

  Females

  KADCYLA can cause embryo-fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of KADCYLA [

  see Use in Specific Populations (8.1)

  ].

  Males

  Because of the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment with KADCYLA and for 4 months following the last dose.

  Infertility

  Based on results from animal toxicity studies, KADCYLA may impair fertility in females and males of reproductive potential. It is not known if the effects are reversible

  [see Nonclinical Toxicology (13.1)].

  )

KADCYLA is a HER2-targeted antibody and microtubule inhibitor conjugate indicated, as a single agent, for:

• the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either:
  • received prior therapy for metastatic disease, or
  • developed disease recurrence during or within six months of completing adjuvant therapy. (
    1.1 Metastatic Breast Cancer (MBC)

    KADCYLA

    ^®

    , as a single agent, is indicated for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either:

    • Received prior therapy for metastatic disease, or
    • Developed disease recurrence during or within six months of completing adjuvant therapy.

    Select patients for therapy based on an FDA-approved companion diagnostic for KADCYLA [

    see Dosage and Administration (2.1)

    ].
    )
• the adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment. (
  1.2 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 invasive disease after neoadjuvant taxane and trastuzumab -based treatment.

  Select patients for therapy based on an FDA-approved companion diagnostic for KADCYLA [

  see Dosage and Administration (2.1)

  ].
  )

Select patients for therapy based on an FDA-approved companion diagnostic for KADCYLA

• Do not substitute KADCYLA for or with trastuzumab.
• HER2 Testing: Perform using FDA-approved tests by laboratories with demonstrated proficiency. (
  2.1 Patient Selection

  Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens

  [see Indications and Usage (1), Clinical Studies (14)].

  Assessment of HER2 protein overexpression and/or HER2 gene amplification should be performed using FDA-approved tests specific for breast cancers by laboratories with demonstrated proficiency. Information on the FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at: http://www.fda.gov/CompanionDiagnostics.

  Improper assay performance, including use of sub-optimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.
  )
• For intravenous infusion only
  . Do not administer as an intravenous push or bolus. Do not use Dextrose (5%) solution. (
  2.4 Preparation for Administration

  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 (ado-trastuzumab emtansine) and not trastuzumab.

  Administration:

  • Administer KADCYLA as an intravenous infusion only with a 0.2 or 0.22 micron in-line polyethersulfone (PES) filter. Do not administer as an intravenous push or bolus.
  • Do not mix KADCYLA, or administer as an infusion, with other medicinal products.

  Reconstitution:

  • Use aseptic technique for reconstitution and preparation of dosing solution. Appropriate procedures for the preparation of chemotherapeutic drugs should be used.
  • Using a sterile syringe, slowly inject 5 mL of Sterile Water for Injection or 0.45% sodium chloride into the 100 mg KADCYLA vial, or 8 mL of Sterile Water for Injection or 0.45% sodium chloride into the 160 mg KADCYLA vial to yield a solution containing 20 mg/mL. Swirl the vial gently until completely dissolved.
    Do not shake.
    Inspect the reconstituted solution for particulates and discoloration.
  • The reconstituted solution should be clear to slightly opalescent and free of visible particulates. The color of the reconstituted solution should be colorless to pale brown. Do not use if the reconstituted solution contains visible particulates or is cloudy or discolored.
  • The reconstituted lyophilized vials should be used immediately following reconstitution with Sterile Water for Injection or 0.45% sodium chloride. If not used immediately, the reconstituted KADCYLA vials can be stored for up to 120 hours (5 days) in a refrigerator at 2ºC to 8ºC (36°F to 46°F); discard unused KADCYLA after 120 hours (5 days) if stored at 2ºC to 8ºC (36°F to 46°F).
    Do not freeze.
  • The reconstituted product contains no preservative and is intended for single-dose only.

  Dilution:

  Determine the correct dose (mg) of KADCYLA

  [see Dosage and Administration (2.1)]

  .

  • Calculate the volume of the 20 mg/mL reconstituted KADCYLA solution needed.
  • Withdraw this amount from the vial and add it to an infusion bag containing 250 mL of
    0.9%
    Sodium Chloride Injection.
    Do not use Dextrose (5%) solution.
  • Gently invert the bag to mix the solution in order to avoid foaming.
  • The diluted KADCYLA infusion solution should be used immediately. If not used immediately, the solution may be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours prior to use. This storage time is additional to the time allowed for the reconstituted vials.
    Do not freeze or shake.
  )
• The recommended dose of KADCYLA is 3.6 mg/kg given as an intravenous infusion every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity, or a total of 14 cycles for patients with EBC.
  Do not administer KADCYLA at doses greater than 3.6 mg/kg.
  (
  2.2 Recommended Doses and Schedules

  Do not substitute trastuzumab for or with KADCYLA.

  The recommended dose of KADCYLA is 3.6 mg/kg given as an intravenous infusion every 3 weeks (21-day cycle).

  Do not administer KADCYLA at doses greater than 3.6 mg/kg

  .

  Closely monitor the infusion site for possible subcutaneous infiltration during drug administration

  [see Warnings and Precautions (5.9)]

  .

  First infusion: Administer infusion over 90 minutes. Observe patients during the infusion and for at least 90 minutes following the initial dose for fever, chills, or other infusion-related reactions

  [see Warnings and Precautions (5.5)]

  .

  Subsequent infusions: Administer over 30 minutes if prior infusions were well tolerated. Observe patients during the infusion and for at least 30 minutes after infusion.

  Metastatic Breast Cancer (MBC)

  Patients with MBC should receive treatment until disease progression or unmanageable toxicity.

  Early Breast Cancer (EBC)

  Patients with EBC should receive treatment for a total of 14 cycles unless there is disease recurrence or unmanageable toxicity.
  )
• Management of adverse reactions (infusion-related reactions, hepatotoxicity, left ventricular cardiac dysfunction, thrombocytopenia, pulmonary toxicity or peripheral neuropathy) may require temporary interruption, dose reduction, or treatment discontinuation of KADCYLA. (
  2.3 Dose Modifications

  Do not re-escalate the KADCYLA dose after a dose reduction is made.

  If a planned dose is delayed or missed, administer as soon as possible; do not wait until the next planned cycle. Adjust the schedule of administration to maintain a 3-week interval between doses. Administer the infusion at the dose and rate the patient tolerated in the most recent infusion.

  Slow or interrupt the infusion rate of KADCYLA if the patient develops an infusion-related reaction. Permanently discontinue KADCYLA for life-threatening infusion-related reactions

  [see Warnings and Precautions (5.5)]

  .

  Management of increased serum transaminases, hyperbilirubinemia, left ventricular dysfunction, thrombocytopenia, pulmonary toxicity or peripheral neuropathy may require temporary interruption, dose reduction or treatment discontinuation of KADCYLA as per guidelines provided in Tables 1and 2.

  Table 1 Recommended Dose Reduction Schedule for Adverse Reactions

  Dose Reduction Schedule	Dose Level
  Starting dose	3.6 mg/kg
  First dose reduction	3 mg/kg
  Second dose reduction	2.4 mg/kg
  Requirement for further dose reduction	Discontinue treatment

  Table 2 Dose Modification Guidelines for KADCYLA

  ALT = alanine transaminase; AST = aspartate transaminase, CHF = congestive heart failure, DILI = Drug Induced Liver Injury; LVEF = left ventricular ejection fraction, LVSD = left ventricular systolic dysfunction, TBILI = Total Bilirubin, ULN = upper limit of normal
  Dose Modifications for Patients with MBC
  Adverse reaction	Severity	Treatment modification
  Increased Transaminase (AST/ALT)	Grade 2 (> 2.5 to ≤ 5× the ULN)	Treat at the same dose level.
  	Grade 3 (> 5 to ≤ 20× the ULN)	Do not administer KADCYLA until AST/ALT recovers to Grade ≤ 2, and then reduce one dose level
  	Grade 4 (> 20× the ULN)	Discontinue KADCYLA
  Hyperbilirubinemia	Grade 2 (> 1.5 to ≤ 3× the ULN)	Do not administer KADCYLA until total bilirubin recovers to Grade ≤ 1, and then treat at the same dose level.
  	Grade 3 (> 3 to ≤ 10× the ULN)	Do not administer KADCYLA until total bilirubin recovers to Grade ≤ 1 and then reduce one dose level.
  	Grade 4 (> 10× the ULN)	Discontinue KADCYLA
  Drug Induced Liver Injury (DILI)	Serum transaminases > 3 × ULN and concomitant total bilirubin > 2 × ULN	Permanently discontinue KADCYLA in the absence of another likely cause for the elevation of liver enzymes and bilirubin, e.g. liver metastasis or concomitant medication
  Nodular Regenerative Hyperplasia (NRH)	All Grades	Permanently discontinue KADCYLA
  Thrombocytopenia	Grade 3 (25,000 to < 50,000/mm3)	Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm3), and then treat at the same dose level
  	Grade 4 (< 25,000/mm3)	Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm3), and then reduce one dose level
  Left Ventricular Dysfunction	Symptomatic CHF	Discontinue KADCYLA
  	LVEF < 40%	Do not administer KADCYLA Repeat LVEF assessment within 3 weeks. If LVEF < 40% is confirmed, discontinue KADCYLA
  	LVEF 40% to ≤ 45% and decrease is ≥ 10% points from baseline	Do not administer KADCYLA Repeat LVEF assessment within 3 weeks. If the LVEF has not recovered to within 10% points from baseline, discontinue KADCYLA
  	LVEF 40% to ≤ 45% and decrease is < 10% points from baseline	Continue treatment with KADCYLA . Repeat LVEF assessment within 3 weeks.
  	LVEF > 45%	Continue treatment with KADCYLA .
  Pulmonary Toxicity	Interstitial lung disease (ILD) or pneumonitis	Permanently discontinue KADCYLA
  Peripheral Neuropathy	Grade 3-4	Do not administer KADCYLA until resolution Grade ≤ 2
  Dose Modification Guidelines for EBC
  Adverse reaction	Severity	Treatment modification
  Increased Alanine Transaminase (ALT)	Grade 2-3 (> 3.0 to ≤ 20 × ULN on day of scheduled treatment)	Do not administer KADCYLA until ALT recovers to Grade ≤ 1, and then reduce one dose level
  	Grade 4 (> 20 × ULN at any time)	Discontinue KADCYLA
  Increased Aspartate Transaminase (AST)	Grade 2 (> 3.0 to ≤ 5 × ULN on day of scheduled treatment)	Do not administer KADCYLA until AST recovers to Grade ≤ 1, and then treat at the same dose level
  	Grade 3 (> 5 to ≤ 20 × ULN on day of scheduled treatment)	Do not administer KADCYLA until AST recovers to Grade ≤ 1, and then reduce one dose level
  	Grade 4 (> 20 × ULN at any time)	Discontinue KADCYLA
  Hyperbilirubinemia	TBILI > 1.0 to ≤ 2.0 × the ULN on day of scheduled treatment	Do not administer KADCYLA until total bilirubin recovers to ≤ 1.0 × ULN, and then reduce one dose level
  	TBILI > 2 × ULN at any time	Discontinue KADCYLA
  Nodular Regenerative Hyperplasia (NRH)	All Grades	Permanently discontinue KADCYLA
  Thrombocytopenia	Grade 2-3 on day of scheduled treatment (25,000 to < 75,000/mm3)	Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm3), and then treat at the same dose level. If a patient requires 2 delays due to thrombocytopenia, consider reducing dose by one level.
  	Grade 4 at any time < 25,000/mm3	Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm3), and then reduce one dose level.
  Left Ventricular Dysfunction	LVEF < 45%	Do not administer KADCYLA Repeat LVEF assessment within 3 weeks. If LVEF < 45% is confirmed, discontinue KADCYLA.
  	LVEF 45% to < 50% and decrease is ≥ 10% points from baselinePrior to starting KADCYLA treatment	Do not administer KADCYLA Repeat LVEF assessment within 3 weeks. If the LVEF remains < 50% and has not recovered to < 10% points from baseline, discontinue KADCYLA.
  	LVEF 45% to < 50% and decrease is < 10% points from baseline	Continue treatment with KADCYLA. Repeat LVEF assessment within 3 weeks.
  	LVEF ≥ 50%	Continue treatment with KADCYLA.
  Heart Failure	Symptomatic CHF, Grade 3-4 LVSD or Grade 3-4 heart failure, or Grade 2 heart failure accompanied by LVEF < 45%	Discontinue KADCYLA
  Peripheral Neuropathy	Grade 3-4	Do not administer KADCYLA until resolution Grade ≤ 2
  Pulmonary Toxicity	Interstitial lung disease (ILD) or pneumonitis	Permanently discontinue KADCYLA
  Radiotherapy-Related Pneumonitis	Grade 2	Discontinue KADCYLA if not resolving with standard treatment
  	Grade 3-4	Discontinue KADCYLA
  )

Lyophilized powder in single-dose vials: 100 mg per vial or 160 mg per vial of ado-trastuzumab emtansine.

• Lactation: Advise not to breastfeed. (
  8.2 Lactation

  Risk Summary

  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

  [see Data]

  . Advise women not to breastfeed during treatment and for 7 months following the last dose of KADCYLA.

  Data

  There were no animal lactation studies conducted with ado-trastuzumab emtansine or the cytotoxic component of KADCYLA (DM1). In lactating cynomolgus monkeys, trastuzumab was present in breast milk at about 0.3% of maternal serum concentrations after pre- (beginning Gestation Day 120) and post-partum (through Post-partum Day 28) doses of 25 mg/kg administered twice weekly (about 7 times the clinical dose of KADCYLA). Infant monkeys with detectable serum levels of trastuzumab did not exhibit any adverse effects on growth or development from birth to 1 month of age.
  )
• Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of KADCYLA. (
  8.3 Females and Males of Reproductive Potential

  Pregnancy Testing

  Verify the pregnancy status of females of reproductive potential prior to the initiation of KADCYLA.

  Contraception

  Females

  KADCYLA can cause embryo-fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of KADCYLA [

  see Use in Specific Populations (8.1)

  ].

  Males

  Because of the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment with KADCYLA and for 4 months following the last dose.

  Infertility

  Based on results from animal toxicity studies, KADCYLA may impair fertility in females and males of reproductive potential. It is not known if the effects are reversible

  [see Nonclinical Toxicology (13.1)].
  )