PHESGO

(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.

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. 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-authorized test for KADCYLA 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-authorized test for KADCYLA. 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-authorized test for KADCYLA.

Mechanism of Action Ado-trastuzumab emtansine is a HER2-targeted antibody-drug conjugate.

The antibody is the humanized anti-HER2 IgG1, trastuzumab.

The small molecule cytotoxin, DM1, is a microtubule inhibitor.

Upon binding to sub-domain IV of the HER2 receptor, ado-trastuzumab emtansine undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in intracellular release of DM1-containing cytotoxic catabolites.

Binding of

DM1 to tubulin disrupts microtubule networks in the cell, which results in cell cycle arrest and apoptotic cell death.

In addition, in vitro studies have shown that similar to trastuzumab, ado-trastuzumab emtansine inhibits HER2 receptor signaling, mediates antibody-dependent cell-mediated cytotoxicity and inhibits shedding of the HER2 extracellular domain in human breast cancer cells that overexpress HER2. 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of multiple doses of KADCYLA (3.6 mg/kg every 3 weeks) on the QTc interval was evaluated in an open label, single arm study in 51 patients with HER2-positive metastatic breast cancer.

No large changes in the mean

QT interval (i.e., > 20 ms) were detected in the study. 12.3 Pharmacokinetics The pharmacokinetics of KADCYLA was evaluated in a phase 1 study and in a population pharmacokinetic analysis for the ado-trastuzumab emtansine conjugate (ADC) using pooled data from 5 trials in patients with breast cancer.

A linear two-compartment model with first-order elimination from the central compartment adequately describes the ADC concentration-time profile.

In addition to

ADC, the pharmacokinetics of total antibody (conjugated and unconjugated trastuzumab), DM1 were also determined.

The population pharmacokinetic analysis of

ADC suggested no difference in KADCYLA exposure based on disease status (adjuvant vs. metastatic setting).

The pharmacokinetics of

KADCYLA are summarized below.

Maximum concentrations (C max ) of ADC and DM1 were observed close to the end of infusion.

In EMILIA, mean (SD) ADC and DM1 Cycle 1 C max following KADCYLA administration was 83.4 µg/mL and 4.61 ng/mL, respectively.

In KATHERINE, mean (SD) ADC and DM1 Cycle 1 C max following KADCYLA administration was 72.6 µg/mL and 4.71 ng/mL, respectively.

In vitro, the mean binding of DM1 to human plasma proteins was 93%.

In vitro, DM1 was a substrate of P-glycoprotein (P-gp).

Based on population pharmacokinetic analysis, the central volume of distribution of ADC was 3.13 L. Metabolism In vitro studies indicate that DM1, the small molecule component of KADCYLA, undergoes metabolism by CYP3A4/5.

DM1 did not inhibit or induce major CYP450 enzymes in vitro.

In human plasma, ado-trastuzumab emtansine catabolites MCC-DM1, Lys-MCC-DM1, and DM1 were detected at low levels.

Based on population pharmacokinetic analysis, following intravenous infusion of KADCYLA, the clearance of the ADC was 0.68 L/day and the elimination half-life (t 1/2 ) was approximately 4 days.

No accumulation of

KADCYLA was observed after repeated dosing of intravenous infusion every 3 weeks.

Based on population pharmacokinetic analysis (n=671), body weight, sum of longest diameter of target lesions by RECIST, HER2 extracellular domain (ECD) concentrations, AST, albumin, and baseline trastuzumab concentrations were identified as statistically significant covariates for ado-trastuzumab emtansine clearance.

However, the magnitude of effect of these covariates on ado-trastuzumab emtansine exposure suggests that, with the exception of body weight, these covariates are unlikely to have a clinically meaningful effect on KADCYLA exposure.

Therefore, the body weight based dose of 3.6 mg/kg every 3 weeks without correction for other covariates is considered appropriate.

Based on population pharmacokinetic analysis in 668 patients, including moderate (CLcr 30 - 59 mL/min, n=53) and mild (CLcr 60 - 89 mL/min, n=254) renal impairment, indicate that pharmacokinetics of the ADC is not affected by mild to moderate renal impairment as compared to normal renal function (CLcr ≥ 90 mL/min, n=361).

Data from only one patient with severe renal impairment (CLcr < 30 mL/min) is available.

The liver is a primary organ for eliminating DM1 and DM1-containing catabolites.

The pharmacokinetics of ado-trastuzumab emtansine and

DM1-containing catabolites were evaluated after the administration of 3.6 mg/kg of KADCYLA to metastatic HER2-positive breast cancer patients with normal hepatic function (n=10), mild (Child-Pugh A; n=10) and moderate (Child-Pugh B; n=8) hepatic impairment. – Plasma concentrations of DM1 and DM1-containing catabolites (Lys-MCC-DM1 and MCC-DM1) were low and comparable between patients with and without hepatic impairment. – Systemic exposures (AUC) of ado-trastuzumab emtansine at Cycle in patients with mild and moderate hepatic impairment were approximately 38% and 67% lower than that of patients with normal hepatic function, respectively.

Ado-trastuzumab emtansine exposure (AUC) at Cycle 3 after repeated dosing in patients with mild or moderate hepatic dysfunction was within the range observed in patients with normal hepatic function.

KADCYLA has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

Based on population pharmacokinetic analysis, age (< 65 [n=577]; 65 - 75 (n=78); > 75 [n=16]) and race (Asian [n=73]; non-Asian [n=598]) do not have a clinically meaningful effect on the pharmacokinetics of ado-trastuzumab emtansine. 12.6 Immunogenicity The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay.

Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of ado-trastuzumab emtansine or of other ado-trastuzumab emtansine products.

Among patients who received

KADCYLA as a single agent for a median duration of 10 months in seven clinical trials, 5% (64/1243) of patients tested positive for antibodies against ado-trastuzumab emtansine at one or more post-dose timepoints.

Neutralizing antibodies against ado-trastuzumab emtansine were detected in 45% (18/40) of evaluable patients who were ADA positive.

Because of the low occurrence of

ADA, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of ado-trastuzumab emtansine is unknown.

The presence of ado-trastuzumab emtansine in patient serum at the time of ADA sampling may interfere with the ability of this assay to detect anti-ado-trastuzumab emtansine antibodies.

As a result, data may not accurately reflect the true incidence of anti-ado-trastuzumab emtansine antibody development.

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The following adverse reactions are discussed in greater detail in other sections of the label: Hepatotoxicity Left Ventricular Dysfunction Embryo-Fetal Toxicity Pulmonary Toxicity Infusion-Related Reactions, Hypersensitivity Reactions Hemorrhage Thrombocytopenia Neurotoxicity Metastatic Breast Cancer The most common adverse reactions (≥ 25%) with KADCYLA were fatigue, nausea, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, increased transaminases, constipation and epistaxis.

The most common adverse reactions (≥ 25%) with KADCYLA were fatigue, nausea, increased transaminases, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, peripheral neuropathy, and arthralgia.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).

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 were identified in patients with HER2-positive metastatic breast cancer treated in the EMILIA trial.

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.

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).

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.

Table were identified in patients with HER2-positive early breast cancer treated in the KATHERINE trial.

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.

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.

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.

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.

There is no known antidote for overdose of KADCYLA.

In clinical trials, overdose of KADCYLA has been reported at approximately two times the recommended dose which resulted in Grade 2 thrombocytopenia (resolved 4 days later) and one death.

In the fatal case, the patient incorrectly received KADCYLA at 6 mg/kg and died approximately 3 weeks following the overdose; a cause of death and a causal relationship to KADCYLA were not established.

Do not substitute

KADCYLA for or with trastuzumab.

HER2 Testing: Perform using FDA-authorized tests by laboratories with demonstrated proficiency.

For intravenous infusion only.

Do not administer as an intravenous push or bolus.

Do not use

Dextrose (5%) solution.

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. 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. 2.1 Patient Selection Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens.

Assessment of

HER2 protein overexpression and/or HER2 gene amplification should be performed using FDA-authorized tests specific for breast cancers by laboratories with demonstrated proficiency.

Information on the FDA-authorized tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at: 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.

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

KADCYLA at doses greater than 3.6 mg/kg.

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

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.

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.

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

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.

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 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.

LVEF assessment within 3 weeks.

LVEF > 45% Continue treatment with KADCYLA.

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 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.

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.

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.

LVEF ≥ 50% Continue treatment with KADCYLA.

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.

Administer KADCYLA as an intravenous infusion only with a 0.2 or 0.22 micron in-line polyethersulfone (PES) filter.

Do not mix

KADCYLA, or administer as an infusion, with other medicinal products.

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 Injection into the 100 mg KADCYLA vial, or 8 mL of Sterile Water for Injection or 0.45% Sodium Chloride Injection 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 Injection.

If not used immediately, the reconstituted KADCYLA vials can be stored for up to 120 hours (5 days) in a refrigerator at 2°C to 8°C (36°F to 46°F); discard unused KADCYLA after 120 hours (5 days) if stored at 2°C to 8°C (36°F to 46°F).

Do not freeze.

The reconstituted product contains no preservative and is intended for single-dose only.

Determine the correct dose (mg) of KADCYLA.

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.

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.

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. 16.2 Special Handling Follow procedures for proper handling and disposal of anticancer drugs.

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.

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.

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.

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

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.

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.

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.

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 to 50) and late (Gestation Days 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.

Safety and effectiveness of

KADCYLA have not been established in pediatric patients.

Of the 495 patients who were randomized to KADCYLA in EMILIA, 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.

Of the 743 patients who were randomized to KADCYLA in KATHERINE, 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.

Population pharmacokinetic analysis indicates that age does not have a clinically meaningful effect on the pharmacokinetics of ado-trastuzumab emtansine.