KADCYLA

KADCYLA (ado-trastuzumab emtansine) is a HER2-targeted antibody-drug conjugate (ADC) 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. The antibody trastuzumab, is a well characterized recombinant monoclonal antibody product produced by mammalian (Chinese hamster ovary) cells, and the small molecule components (DM1 and MCC) are produced by chemical synthesis. Ado-trastuzumab emtansine contains an average of 3.5 DM1 molecules per antibody. Ado-trastuzumab emtansine has the following chemical structure: Note: The bracketed structure is DM1 plus MCC which represents the emtansine component. The n is, on average, 3.5 DM1 molecules per trastuzumab (Mab) molecule. KADCYLA (ado-trastuzumab emtansine) is a sterile, white to off-white preservative free lyophilized powder in single-dose vials. Each vial contains 100 mg or 160 mg ado-trastuzumab emtansine. Following reconstitution, each single-dose vial contains ado-trastuzumab emtansine (20 mg/mL), polysorbate 20 [0.02% (w/v)], sodium succinate (10 mM), and sucrose [6% (w/v)] with a pH of 5.0. The resulting solution containing 20 mg/mL ado-trastuzumab emtansine is administered by intravenous infusion following dilution. Chemical Structure

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 ) 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 ) Select patients for therapy based on an FDA-approved companion diagnostic for KADCYLA [see Dosage and Administration (2.1) ] 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) ]. 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) ].

Do not substitute KADCYLA for or with trastuzumab. HER2 Testing: Perform using FDA-approved tests by laboratories with demonstrated proficiency. ( 2.1 ) For intravenous infusion only . Do not administer as an intravenous push or bolus. Do not use Dextrose (5%) solution. ( 2.4 ) 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 ) 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 ) 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. 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. 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 1 and 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/mm 3 ) Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm 3 ), and then treat at the same dose level Grade 4 (< 25,000/mm 3 ) Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm 3 ), 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/mm 3 ) Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm 3 ), 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/mm 3 Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm 3 ), 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 baseline Prior 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 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.

None. None. ( 4 )

The following adverse reactions are discussed in greater detail in other sections of the label: Hepatotoxicity [See Warnings and Precautions (5.1) ] Left Ventricular Dysfunction [See Warnings and Precautions (5.2) ] Embryo-Fetal Toxicity [See Warnings and Precautions (5.3) ] Pulmonary Toxicity [See Warnings and Precautions (5.4) ] Infusion-Related Reactions, Hypersensitivity Reactions [See Warnings and Precautions (5.5) ] Hemorrhage [See Warnings and Precautions (5.6) ] Thrombocytopenia [See Warnings and Precautions (5.7) ] Neurotoxicity [See Warnings and Precautions (5.8) ] Metastatic Breast Cancer The most common adverse reactions (≥ 25%) with KADCYLA were fatigue, nausea, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, increased transaminases, constipation and epistaxis. ( 6.1 ) Early Breast Cancer The most common adverse reactions (≥ 25%) with KADCYLA were fatigue, nausea, increased transaminases, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, peripheral neuropathy, and arthralgia. To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in the WARNINGS AND PRECAUTIONS reflect exposure to KADCYLA as a single agent at 3.6 mg/kg given as an intravenous infusion every 3 weeks (21-day cycle) in 1624 patients including 884 patients with HER2-positive metastatic breast cancer and 740 patients with HER2-positive early breast cancer (KATHERINE trial). Metastatic Breast Cancer In clinical trials, KADCYLA has been evaluated as single-agent in 884 patients with HER2-positive metastatic breast cancer. The most common (≥ 25%) adverse reactions were fatigue, nausea, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, increased transaminases, constipation and epistaxis. The adverse reactions described in Table 3 were identified in patients with HER2-positive metastatic breast cancer treated in the EMILIA trial [see Clinical Studies (14.1) ] . Patients were randomized to receive KADCYLA or lapatinib plus capecitabine. The median duration of study treatment was 7.6 months for patients in the KADCYLA-treated group and 5.5 months and 5.3 months for patients treated with lapatinib and capecitabine, respectively. In the EMILIA trial, 43% of patients experienced Grade ≥ 3 adverse reactions in the KADCYLA-treated group compared with 59% of patients in the lapatinib plus capecitabine-treated group. Dose adjustments for KADCYLA were permitted [see Dosage and Administration (2.2) ] . Thirty-two patients (7%) discontinued KADCYLA due to an adverse reaction, compared with 41 patients (8%) who discontinued lapatinib, and 51 patients (10%) who discontinued capecitabine due to an adverse reaction. The most common adverse reactions leading to KADCYLA discontinuation were thrombocytopenia and increased transaminases. Eighty patients (16%) treated with KADCYLA had adverse reactions leading to dose reductions. The most frequent adverse reactions leading to dose reduction of KADCYLA (in ≥ 1% of patients) included thrombocytopenia, increased transaminases, and peripheral neuropathy. Adverse reactions that led to dose delays occurred in 116 (24%) of KADCYLA treated patients. The most frequent adverse reactions leading to a dose delay of KADCYLA (in ≥ 1% of patients) were neutropenia, thrombocytopenia, leukopenia, fatigue, increased transaminases and pyrexia. Table 3 reports the adverse reactions that occurred in patients in the KADCYLA-treated group (n=490) of the EMILIA trial. Selected laboratory abnormalities are shown in Table 4 . The most common adverse reactions seen with KADCYLA in the randomized trial (frequency > 25%) were nausea, fatigue, musculoskeletal pain, hemorrhage, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI–CTCAE (version 3) Grade ≥ 3 adverse reactions (frequency > 2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue. Table 3 Adverse Reactions Occurring in ≥ 10% of Patients on the KADCYLA Treatment Arm in the EMILIA Trial Grouped terms were used for the following Adverse Reactions: Thrombocytopenia: thrombocytopenia, platelet count decreased Anemia: anemia, hemoglobin decreased Abdominal pain: abdominal pain, abdominal pain upper Stomatitis: stomatitis, mucosal inflammation, oropharyngeal pain Transaminases Increased: transaminases increased, aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyltransferase increased, liver function test abnormal, hepatic enzyme increased, hepatic function abnormal Hypokalemia: hypokalemia, blood potassium decreased Musculoskeletal Pain: muscle spasms, musculoskeletal discomfort, musculoskeletal chest pain, back pain, pain in extremity, bone pain, musculoskeletal pain Peripheral neuropathy: neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia Hemorrhage: Hemorrhage terms (excl laboratory terms) (SMQ, wide), Hemorrhage laboratory terms (SMQ, narrow). Adverse Reactions KADCYLA (3.6 mg/kg) n=490 Lapatinib (1250 mg) + Capecitabine (2000 mg/m 2 ) n=488 All Grades (%) Grade 3 – 4 (%) All Grades (%) Grade 3 – 4 (%) SMQ=standardized MedDRA queries Blood and Lymphatic System Disorders Thrombocytopenia 31 15 3.3 0.4 Anemia 14 4.1 11 2.5 Gastrointestinal Disorders Nausea 40 0.8 45 2.5 Constipation 27 0.4 11 0 Diarrhea 24 1.6 80 21 Vomiting 19 0.8 30 4.5 Abdominal pain 19 0.8 18 1.6 Dry Mouth 17 0 4.9 0.2 Stomatitis 14 0.2 33 2.5 General Disorders and Administration Fatigue 36 2.5 28 3.5 Pyrexia 19 0.2 8 0.4 Asthenia 18 0.4 18 1.6 Investigations Transaminases increased 29 8.0 14 2.5 Metabolism and Nutrition Disorders Hypokalemia 10 2.7 9 4.7 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 36 1.8 31 1.4 Arthralgia 19 0.6 8 0 Myalgia 14 0.6 3.7 0 Nervous System Disorders Headache 28 0.8 15 0.8 Peripheral neuropathy 21 2.2 14 0.2 Dizziness 10 0.4 11 0.2 Psychiatric Disorders Insomnia 12 0.4 9 0.2 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 23 0.2 8 0 Cough 18 0.2 13 0.2 Dyspnea 12 0.8 8 0.4 Skin and Subcutaneous Tissue Disorders Rash 12 0 28 1.8 Vascular Disorders Hemorrhage 32 1.8 16 0.8 The following clinically relevant adverse reactions were reported in < 10% of patients in the KADCYLA-treated group in EMILIA: dyspepsia (9%), urinary tract infection (9%), chills (8%), dysgeusia (8%), neutropenia (7%), peripheral edema (7%), pruritus (6%), hypertension (5%), blood alkaline phosphatase increased (4.7%), vision blurred (4.5%), conjunctivitis (3.9%), dry eye (3.9%), lacrimation increased (3.3%), drug hypersensitivity (2.2%), left ventricular dysfunction (1.8%), infusion-related reaction (1.4%), pneumonitis (1.2%), nodular regenerative hyperplasia (0.4%), portal hypertension (0.4%). Table 4 Selected Laboratory Abnormalities (EMILIA) Parameter KADCYLA (3.6 mg/kg) Lapatinib (1250 mg) + Capecitabine (2000 mg/m 2 ) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Chemistry Increased AST 98 7 0.5 65 3 0 Increased ALT 82 5 0.2 54 3 0 Decreased potassium 33 3 0 31 6 0.8 Increased bilirubin 17 0.6 0 57 2 0 Hematology Decreased platelet count 83 14 3 21 0.4 0.6 Decreased hemoglobin 60 4 1 64 3 0.2 Decreased neutrophils 39 3 0.6 38 6 2 Early Breast Cancer KADCYLA has been evaluated as a single-agent in 740 patients with HER2-positive early breast cancer. The adverse reactions described in Table 5 were identified in patients with HER2-positive early breast cancer treated in the KATHERINE trial [see Clinical Studies (14.2) ] . Patients were randomized to receive KADCYLA or trastuzumab. The median duration of study treatment was 10 months for patients in the KADCYLA-treated group and 10 months for patients treated with trastuzumab. One hundred and ninety (26%) patients experienced Grade ≥ 3 adverse reactions in the KADCYLA-treated group compared with 111 (15%) patients in the trastuzumab group. One hundred and thirty-three patients (18%) discontinued KADCYLA due to an adverse reaction, compared with 15 patients (2.1%) who discontinued trastuzumab due to an adverse reaction. The most common adverse reactions leading to KADCYLA discontinuation (in ≥ 1% of patients) were platelet count decreased, blood bilirubin increased, ejection fraction decreased, AST increased, ALT increased, and peripheral neuropathy. Dose adjustments for KADCYLA were permitted [see Dosage and Administration (2.2) ] . One hundred and six patients (14%) treated with KADCYLA had dose reductions. The most frequent adverse reactions leading to dose reduction of KADCYLA (in ≥ 1% of patients) included thrombocytopenia, increased transaminases, blood bilirubin and fatigue. Adverse reactions that led to dose delays occurred in 106 (14%) of KADCYLA treated patients. The most frequent adverse reactions leading to a dose delay of KADCYLA (in ≥ 1% of patients) were neutropenia, thrombocytopenia and AST increased. Selected laboratory abnormalities are shown in Table 6 . The most common adverse reactions seen with KADCYLA in the randomized trial (frequency > 25%) were fatigue, nausea, increased transaminases, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, peripheral neuropathy, and arthralgia. The most common NCI–CTCAE (version 3) Grade ≥ 3 adverse reactions (> 2%) were thrombocytopenia and hypertension. Table 5 Adverse Reactions Occurring in ≥ 10% of Patients in the KATHERINE Trial Grouped terms were used for the following Adverse Reactions: Thrombocytopenia: thrombocytopenia, platelet count decreased Anemia: anemia, hemoglobin decreased Stomatitis: stomatitis, mucosal inflammation, oropharyngeal pain Abdominal pain: abdominal pain, abdominal pain upper Urinary Tract Infection: urinary tract infection, cystitis Transaminases Increased: transaminases increased, aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyltransferase increased, liver function test abnormal, hepatic enzyme increased, hepatic function abnormal Musculoskeletal Pain: muscle spasms, musculoskeletal discomfort, musculoskeletal chest pain, back pain, pain in extremity, bone pain, musculoskeletal pain Peripheral neuropathy: neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia Hemorrhage: Hemorrhage terms (excl laboratory terms) (SMQ, wide), Hemorrhage laboratory terms (SMQ, narrow) Adverse Reactions KADCYLA n=740 Trastuzumab n=720 All grades (%) Grade 3 – 4 (%) All grades (%) Grade 3 – 4 (%) SMQ=standardized MedDRA queries Blood and Lymphatic System Disorders Thrombocytopenia 29 6 2.4 0.3 Anemia 10 1.1 9 0.1 Gastrointestinal Disorders Nausea 42 0.5 13 0.3 Constipation 17 0.1 8 0 Stomatitis 15 0.1 8 0.1 Vomiting 15 0.5 5 0.3 Dry Mouth 14 0.1 1.3 0 Diarrhea 12 0.8 13 0.3 Abdominal pain 11 0.4 7 0.3 General Disorders and Administration Fatigue 50 1.1 34 0.1 Pyrexia 10 0 4 0 Infections and Infestations Urinary tract infection 10 0.3 6 0.1 Investigations Transaminases increased 32 1.5 8 0.4 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 30 0.7 29 0.7 Arthralgia 26 0.1 21 0 Myalgia 15 0.4 11 0 Nervous System Disorders Headache 28 0 17 0.1 Peripheral neuropathy 28 1.6 14 0.1 Dizziness 10 0.1 8 0.3 Psychiatric Disorders Insomnia 14 0 12 0.1 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 22 0 3.5 0 Cough 14 0.1 12 0 Vascular Disorders Hemorrhage 29 0.4 Included one fatal hemorrhage. 10 0.3 The following clinically relevant adverse reactions were reported in < 10% of patients in the KADCYLA-treated group in KATHERINE: blood alkaline phosphatase increased (8%), dysgeusia (8%), dyspnea (8%), neutropenia (8%), blood bilirubin increased (7%), hypokalemia (7%), pruritus (7%), hypertension (6%), lacrimation increased (6%), chills (5%), dry eye (4.5%), dyspepsia (4.3%), peripheral edema (3.9%),vision blurred (3.9%), conjunctivitis (3.5%), left ventricular dysfunction (3.0%), drug hypersensitivity (2.7%), infusion-related reaction (1.6%), radiation pneumonitis (1.5%), pneumonitis (1.1%), rash (1.1%), asthenia (0.4%), nodular regenerative hyperplasia (0.3%). Table 6 Selected Laboratory Abnormalities (KATHERINE) Parameter KADCYLA n=740 Trastuzumab n=720 All Grade (%) Grade 3 (%) Grade 4 (%) All Grade (%) Grade 3 (%) Grade 4 (%) Chemistry Increased AST 79 0.8 0 21 0.1 0 Increased ALT 55 0.7 0 21 0.1 0 Decreased potassium 26 2 0.5 9 0.7 0.1 Increased bilirubin 12 0 0 4 0.7 0 Hematology Decreased platelet count 51 4 2 13 0.1 0.1 Decreased hemoglobin 31 1 0 29 0.3 0 Decreased neutrophils 24 1 0 19 0.6 0.6 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of KADCYLA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse Reactions from Observational Studies CHF and > 10% reduction in LVEF in patients with HER2-positive metastatic breast cancer with a baseline LVEF of 40-49% treated with KADCYLA [see Warnings and Precautions (5.2) ] . Adverse Reactions from Postmarketing Spontaneous Reports Tumor lysis syndrome (TLS) Skin/tissue necrosis after extravasation

No formal drug-drug interaction studies with KADCYLA have been conducted. In vitro studies indicate that DM1, the cytotoxic component of KADCYLA, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5. Concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) with KADCYLA should be avoided due to the potential for an increase in DM1 exposure and toxicity. Consider an alternate medication with no or minimal potential to inhibit CYP3A4. If concomitant use of strong CYP3A4 inhibitors is unavoidable, consider delaying KADCYLA treatment until the strong CYP3A4 inhibitors have cleared from the circulation (approximately 3 elimination half-lives of the inhibitors) when possible. If a strong CYP3A4 inhibitor is coadministered and KADCYLA treatment cannot be delayed, patients should be closely monitored for adverse reactions.

16.1 How Supplied/Storage KADCYLA (ado-trastuzumab emtansine) is supplied as: Carton Contents NDC One 100 mg vial, single-dose vial NDC 50242-088-01 One 160 mg vial, single-dose vial NDC 50242-087-01 Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of reconstitution. Do not freeze or shake.