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`EXHIBIT 42
`REDACTED IN
`ITS ENTIRETY
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`EXHIBIT 43
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`interruption, dose reduction, or treatment discontinuation of
`KADCYLA. (2.3)
`
` DOSAGE FORMS AND STRENGTHS
`Lyophilized powder in single-dose vials containing 100 mg per vial or 160 mg
`per vial. (3)
`
`None. (4)
`
` CONTRAINDICATIONS
`
` WARNINGS AND PRECAUTIONS
`• Pulmonary Toxicity: Permanently discontinue KADCYLA in patients
`diagnosed with interstitial lung disease or pneumonitis. For patients with
`radiation pneumonitis in the adjuvant setting, permanently discontinue
`KADCYLA for Grade 3 or for Grade 2 not responding to standard
`treatment. (2.2, 5.4)
`• Infusion-Related Reactions, Hypersensitivity Reactions: Monitor for
`signs and symptoms during and after infusion. If significant infusion-
`related reactions or hypersensitivity reactions occur, slow or interrupt
`the infusion and administer appropriate medical therapies. Permanently
`discontinue KADCYLA for life threatening infusion-related reaction.
`(2.1, 2.2, 5.5)
`• Hemorrhage: Fatal cases of hemorrhage occurred in clinical trials among
`patients with no known identified risk factors, as well as among patients
`with thrombocytopenia and those receiving anti-coagulation and
`antiplatelet therapy. Use caution with these agents and consider
`additional monitoring when concomitant use is medically necessary.
`(5.6)
`• Thrombocytopenia: Monitor platelet counts prior to each KADCYLA
`dose. Institute dose modifications as appropriate. (2.2, 5.7)
`• Neurotoxicity: Monitor for signs or symptoms. Withhold dosing
`temporarily for patients experiencing Grade 3 or 4 peripheral
`neuropathy. (2.2, 5.8, 13.2)
`
` ADVERSE REACTIONS
`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 ww.fda.ecov/medwatch.
`
` USE IN SPECIFIC POPULATIONS
`• Lactation: Advise not to breastfeed. (8.2)
`• Females and Males of Reproductive Potential: Verify pregnancy status
`of females prior to initiation of KADCYLA. (8.3)
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Revised: 05/2019
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`KADCYLA safely and effectively. See full prescribing information for
`KADCYLA.
`
`KADCYLA® (ado-trastuzumab emtansine) for injection, for intravenous
`use
`Initial U.S. Approval: 2013
`
`WARNING: HEPATOTOXICITY, CARDIAC TOXICITY,
`EMBRYO-FETAL TOXICITY
`See full prescribing information for complete boxed warning
`• Hepatotoxicity, liver failure and death have occurred in
`KADCYLA-treated patients. Monitor hepatic function
`prior to initiation and prior to each dose. Institute dose
`modifications or permanently discontinue as appropriate.
`(2.3, 5.1)
`KADCYLA may lead to reductions in left ventricular
`ejection fraction (LVEF). Assess LVEF prior to
`initiation. Monitor and withhold dosing or discontinue as
`appropriate. (2.3, 5.2)
`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, 8.1, 8.3)
`
`RECENT MAJOR CHANGES
`Indications and Usage (1.2)
`Dosage and Administration (2.1, 2.2, 2.3)
`Warnings and Precautions (5.1, 5.2, 5.4, 5.8)
`
`05/2019
`05/2019
`05/2019
`
` INDICATIONS AND USAGE
`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)]
`
` DOSAGE AND ADMINISTRATION
`• 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
`m,Q/k,Q. (2.2)
`• Management of adverse reactions (infusion-related reactions,
`hepatotoxicity, left ventricular cardiac dysfunction, thrombocytopenia,
`pulmonary toxicity or peripheral neuropathy) may require temporary
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`FULL PRESCRIBING INFORMATION: CONTENTS"
`1 INDICATIONS AND USAGE
`1.1 Metastatic Breast Cancer (MBC)
`1.2 Early Breast Cancer (EBC)
`2 DOSAGE AND ADMINISTRATION
`2.1 Patient Selection
`2.2 Recommended Doses and Schedules
`2.3 Dose Modifications
`2.4 Preparation for Administration
`3 Dosage Forms and Strengths
`4 Contraindications
`5 Warnings and Precautions
`5.1 Hepatotoxicity
`5.2 Left Ventricular Dysfunction
`5.3 Embryo-Fetal Toxicity
`5.4 Pulmonary Toxicity
`5.5 Infusion-Related Reactions, Hypersensitivity Reactions
`5.6 Hemorrhage
`5.7 Thrombocytopema
`5.8 Neurotoxicity
`5.9 Extravasation
`6 Adverse Reactions
`6.1 Clinical Trials Experience
`6.2 Immunogenicity
`7 Drug Interactions
`
`8
`
`10
`11
`
`Use in Specific Populations
`8.1 Pregnancy
`8.2 Lactation
`8.3 Females and Males of Reproductive Potential
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`Overdosage
`Description
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 Nonclinical Toxicology
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 Clinical Studies
`14.1 Metastatic Breast Cancer
`14.2 Early Breast Cancer
`15 REFERENCES
`16 How Supplied/Storage and Handling
`16.1 How Supplied/Storage
`16.2 Special Handling
`17 Patient Counseling Information
`
`" Sections or subsections omitted from the Full Prescribing Information
`are not listed.
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`FULL PRESCRIBING INFORMATION
`
`WARNING: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL
`TOXICITY
`
`• 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, 5.1)
`• 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, 5.2)
`• 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, 8.1, 8.3)
`
`1 INDICATIONS AND USAGE
`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)].
`
`2 DOSAGE AND ADMINISTRATION
`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
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`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
`3.6 mg/kg
`Starting dose
`3 mg/kg
`First dose reduction
`2.4 mg/kg
`Second dose reduction
`Requirement for further dose reduction
`Discontinue treatment
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`Table 2 Dose Modification Guidelines for KADCYLA
`
`Dose Modifications for Patients with MBC
`Treatment modification
`
`Left Ventricular
`Dysfunction
`
`Symptomatic CHF
`
`LVEF <40%
`
`LVEF 40% to <45%
`and decrease is > 10%
`points from baseline
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`Adverse reaction
`Increased
`Transaminase
`(AST/ALT)
`
`Hyperbilirubinemia
`
`Drug Induced Liver
`Injury (DILI)
`
`Nodular Regenerative
`Hyperplasia (NRH)
`Thrombocytopenia
`
`Severity
`Grade 2
`(>2.5 to < 5x the
`ULN)
`Grade 3
`(>5 to < 20x the ULN)
`
`Grade 4
`(>20x the ULN)
`Grade 2
`(> 1.5 to < 3x the
`ULN)
`Grade 3
`(>3 to < 10x the ULN)
`
`Grade 4
`(>10x the ULN)
`Serum transaminases >
`3 x ULN and
`concomitant total
`bilirubin > 2 x ULN
`All Grades
`
`Grade 3
`(25,000 to
`< 50,000/mm3)
`
`Grade 4
`(< 25,000/mm3)
`
`Treat at the same dose level.
`
`Do not administer KADCYLA until
`AST/ALT recovers to Grade < 2, and then
`reduce one dose level
`Discontinue KADCYLA
`
`Do not administer KADCYLA until total
`bilirubin recovers to Grade < 1, and then
`treat at the same dose level.
`
`Do not administer KADCYLA until total
`bilirubin recovers to Grade < 1 and then
`reduce one dose level.
`Discontinue KADCYLA
`
`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
`Permanently discontinue KADCYLA
`
`Do not administer KADCYLA until platelet
`count recovers to Grade 1 (>
`75,000/mm3), and then treat at the same
`dose level
`Do not administer KADCYLA until platelet
`count recovers to Grade 1 (>
`75,000/mm3), and then reduce one dose
`level
`Discontinue KADCYLA
`
`Do not administer KADCYLA
`Repeat LVEF assessment within 3 weeks. If
`LVEF <40% is confirmed, discontinue
`KADCYLA
`Do not administer KADCYLA
`Repeat LVEF assessment within 3 weeks. If
`the LVEF has not recovered to within 10%
`points from baseline, discontinue
`KADCYLA
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`LVEF 40% to <45%
`Continue treatment with KADCYLA.
`and decrease is < 10%
`Repeat LVEF assessment within 3 weeks.
`points from baseline
`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
`Severity
`Treatment modification
`Grade 2-3
`Do not administer KADCYLA until ALT
`recovers to Grade < 1, and then reduce one
`(>3.0 to < 20 x ULN
`dose level
`on day of scheduled
`treatment)
`Grade 4
`(>20 x ULN at any
`time)
`Grade 2
`(>3.0 to < 5 x ULN on
`day of scheduled
`treatment)
`Grade 3
`(>5 to < 20 x ULN on
`day of scheduled
`treatment)
`Grade 4
`(>20 x ULN at any
`time)
`TBILI
`> 1.0 to < 2.0 x the
`ULN on day of
`scheduled treatment
`TBILI
`> 2 x ULN at any time
`All Grades
`
`Discontinue KADCYLA
`
`Do not administer KADCYLA until AST
`recovers to Grade 1, and then treat at the
`same dose level
`
`Do not administer KADCYLA until AST
`recovers to Grade < 1, and then reduce one
`dose level
`
`Discontinue KADCYLA
`
`Do not administer KADCYLA until total
`bilirubin recovers to < 1.0 x ULN, and then
`reduce one dose level
`
`Discontinue KADCYLA
`
`Permanently discontinue KADCYLA
`
`Adverse reaction
`Increased Alanine
`Transaminase (ALT)
`
`Increased Aspartate
`Transaminase (AST)
`
`Hyperbilirubinemia
`
`Nodular Regenerative
`Hyperplasia (NRH)
`Thrombocytopenia
`
`Grade 2-3 on day of
`scheduled treatment
`(25,000 to <
`75,000/mm3)
`
`Grade 4 at any time
`< 25,000/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.
`Do not administer KADCYLA until platelet
`count recovers to Grade 1 (> 75,000/mm3),
`and then reduce one dose level.
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`Do not administer KADCYLA
`Repeat LVEF assessment within 3 weeks. If
`LVEF <45% is confirmed, discontinue
`KADCYLA.
`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.
`Continue treatment with KADCYLA.
`Repeat LVEF assessment within 3 weeks.
`
`Left Ventricular
`Dysfunction
`
`LVEF <45%
`
`LVEF 45% to < 50%
`and decrease is > 10%
`points from baseline*
`
`LVEF 45% to < 50%
`and decrease is < 10%
`points from baseline*
`LVEF > 50%
`
`Heart Failure
`
`Symptomatic CHF,
`Grade 3-4 LVSD or
`Grade 3-4 heart failure,
`or
`Grade 2 heart failure
`accompanied by LVEF
`< 45%
`Peripheral Neuropathy Grade 3-4
`
`Pulmonary Toxicity
`
`Radiotherapy-Related
`Pneumonitis
`
`Interstitial lung disease
`(ILD) or pneumonitis
`Grade 2
`
`Grade 3-4
`
`Continue treatment with KADCYLA.
`Discontinue KADCYLA
`
`Do not administer KADCYLA until
`resolution Grade 2
`
`Permanently discontinue KADCYLA
`
`Discontinue KADCYLA if not resolving
`with standard treatment
`Discontinue 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
`*Prior to starting KADCYLA treatment
`
`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.
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`• Using a sterile syringe, slowly inject 5 mL of Sterile Water for Injection into the 100 mg
`KADCYLA vial, or 8 mL of Sterile Water for 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. If not used immediately, the reconstituted KADCYLA vials can
`be stored for up to 24 hours in a refrigerator at 2°C to 8°C (36°F to 46°F); discard unused
`KADCYLA after 24 hours. 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.
`
`3 DOSAGE FORMS AND STRENGTHS
`Lyophilized powder in single-dose vials: 100 mg per vial or 160 mg per vial of ado-trastuzumab
`emtansine.
`
`4 CONTRAINDICATIONS
`None.
`
`5 WARNINGS AND PRECAUTIONS
`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 x ULN and
`concomitant total bilirubin > 2 x ULN. KADCYLA has not been studied in patients with serum
`transaminases > 2.5 x ULN or bilirubin > 1.5 x ULN prior to the initiation of treatment.
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`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.
`
`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)].
`
`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. Treatment with
`KADCYLA has not been studied in patients with LVEF < 50% prior to initiation of treatment.
`
`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 congestive heart failure (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)] .
`
`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)].
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`
`5.4 Pulmonary Toxicity
`Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratory
`distress syndrome or fatal outcome have been reported in clinical trials with KADCYLA. Signs
`and symptoms include dyspnea, cough, fatigue, and pulmonary infiltrates.
`
`In patients with MBC, pneumonitis was reported at an incidence of 0.8% (7 out of 884 treated
`patients), with one case of Grade 3 pneumonitis. The overall incidence of pneumonitis was 1.2%
`in EMILIA. In KATHERINE, pneumonitis was reported at an incidence of 1.1% (8 out of 740
`patients treated with KADCYLA), with one case of Grade 3 pneumonitis.
`
`Radiation pneumonitis was reported at an incidence of 1.8% (11 out of 623 patients treated with
`adjuvant radiotherapy and KADCYLA), with 2 cases of Grade 3 radiation pneumonitis [see
`Adverse Reactions (6.1)].
`
`Permanently discontinue treatment with KADCYLA in patients diagnosed with ILD or
`pneumonitis. For patients with radiation pneumonitis in the adjuvant setting, KADCYLA should
`be permanently discontinued for Grade 3 or for Grade 2 not responding to standard treatment
`[see Dose Modifications (2.2)].
`
`Patients with dyspnea at rest due to complications of advanced malignancy, co-morbidities, and
`receiving concurrent pulmonary radiation therapy may be at increased risk of pulmonary toxicity.
`
`5.5 Infusion-Related Reactions, Hypersensitivity Reactions
`Treatment with KADCYLA has not been studied in patients who had trastuzumab permanently
`discontinued due to infusion-related react