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
`Do not substitute KADCYLA for or with trastuzumab.
`(2.1)
`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.
`(2.2, 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. (2.2, 5.2)
`Can cause fetal harm. Advise women of potential risk to
`the fetus. (5.3, 8.1, 8.6)
`
`
`!!!!!!!!!RECENT MAJOR CHANGES!!!!!!!!!
`Dosage and Administration (2.3) 05/2013
`
`!!!!!!!!!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)
`
`∀
`
`∀
`
`!!!!!!!DOSAGE AND ADMINISTRATION!!!!!!!
`For intravenous infusion only. Do not administer as an intravenous push
`or bolus. Do not use Dextrose (5%) solution. (2.3)
`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. Do not administer KADCYLA at
`doses greater than 3.6 mg/kg. Do not substitute KADCYLA for or with
`trastuzumab. (2.1)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1
`Recommended Doses and Schedules
`2.2 Dose Modifications
`2.3
`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
`Thrombocytopenia
`5.7 Neurotoxicity
`5.8 HER2 Testing
`5.9 Extravasation
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2
`Immunogenicity
`7 DRUG INTERACTIONS
`* Sections or subsections omitted from the Full Prescribing Information are
`not listed.
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`
`∀
`
`Management of adverse events (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. (2.2)
`
`!!!!!!!DOSAGE FORMS AND STRENGTHS!!!!!!!
`Lyophilized powder in single-use vials containing 100 mg per vial or 160 mg
`per vial. (3)
`
`!!!!!!!!!!CONTRAINDICATIONS!!!!!!!!!!
`None. (4)
`
`∀
`
`∀
`
`∀
`
`∀
`
`∀
`
`!!!!!!!!WARNINGS AND PRECAUTIONS!!!!!!!
`Pulmonary Toxicity: Permanently discontinue KADCYLA in patients
`diagnosed with interstitial lung disease or pneumonitis. (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)
`Thrombocytopenia: Monitor platelet counts prior to each KADCYLA
`dose. Institute dose modifications as appropriate. (2.2, 5.6)
`Neurotoxicity: Monitor for signs or symptoms. Withhold dosing
`temporarily for patients experiencing Grade 3 or 4 peripheral
`neuropathy. (2.2, 5.7, 13.2)
`HER2 Testing: Perform using FDA-approved tests by laboratories with
`demonstrated proficiency. (5.8)
`
`!!!!!!!!!!!ADVERSE REACTIONS!!!!!!!!!
`The most common adverse drug reactions (frequency > 25%) with
`KADCYLA (n=884 treated patients) were fatigue, nausea, musculoskeletal
`pain, thrombocytopenia, headache, increased transaminases, and constipation.
`(6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Genentech at
`1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`!!!!!!!USE IN SPECIFIC POPULATIONS!!!!!!!!
`Nursing Mothers: Discontinue nursing or discontinue KADCYLA taking
`∀
`into consideration the importance of the drug to the mother. (8.3)
`Females of Reproductive Potential: Counsel females on pregnancy
`prevention and planning. Encourage patient participation in the
`MotHER Pregnancy Registry by contacting 1-800-690-6720). (5.3, 8.1,
`8.6)
`
`∀
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Revised: 05/2013
`
`8 USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3 Nursing Mothers
`8.4
`Pediatric Use
`8.5 Geriatric Use
`8.6 Females of Reproductive Potential
`8.7 Renal Impairment
`8.8 Hepatic Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`12.6 Cardiac Electrophysiology
`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
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied/Storage
`16.2 Special Handling
`17 PATIENT COUNSELING INFORMATION
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`FULL PRESCRIBING INFORMATION
`
`Do Not Substitute KADCYLA for or with Trastuzumab
`
`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. (2.2, 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. (2.2, 5.2)
`∀ Embryo-Fetal Toxicity: Exposure to KADCYLA can result in embryo-fetal death or
`birth defects. Advise patients of these risks and the need for effective contraception.
`(5.3, 8.1, 8.6)
`
`INDICATIONS AND USAGE
`1
`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.
`DOSAGE AND ADMINISTRATION
`2
`2.1 Recommended Doses and Schedules
`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. Do not
`administer KADCYLA at doses greater than 3.6 mg/kg. Do not substitute KADCYLA for or with
`trastuzumab.
`infusion site for possible subcutaneous
`the
`Closely monitor
`administration [see Warnings and Precautions (5.9)].
`First infusion: Administer infusion over 90 minutes. Patients should be observed 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.
`Patients should be observed during the infusion and for at least 30 minutes after infusion.
`2.2 Dose Modifications
`KADCYLA dose should not be re-escalated after a dose reduction is made.
`If a planned dose is delayed or missed, it should be administered as soon as possible; do not wait
`until the next planned cycle. The schedule of administration should be adjusted to maintain a 3-
`
`infiltration during drug
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`week interval between doses. The infusion may be administered at the dose and rate the patient
`tolerated in the most recent infusion.
`The infusion rate of KADCYLA should be slowed or interrupted 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 to 5.
`Table 1 Recommended Dose Reduction Schedule for Adverse Events
`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
`
`Hepatotoxicity [see Warnings and Precautions (5.1)]
`A reduction in the dose of KADCYLA is recommended in the case of hepatotoxicity exhibited as
`increases in serum transaminases and/or hyperbilirubinemia (see Tables 2 and 3).
`Table 2 Dose Modification Guidelines for Increased Serum Transaminases (AST/ALT)
`Grade 2
`Grade 3
`Grade 4
`(## 2.5 to ≤ 5 ∃ ULN)
`(# 5 to ≤ 20 ∃ ULN)
`(# 20 ∃ ULN)
`Treat at same dose level.
`Do not administer
`Permanently discontinue
`KADCYLA until AST/ALT
`KADCYLA.
`recovers to Grade ≤ 2, and
`then reduce one dose level.
`ALT % alanine transaminase; AST % aspartate transaminase; ULN % upper limit of normal.
`
`Table 3 Dose Modification Guidelines for Hyperbilirubinemia
`Grade 2
`Grade 3
`(# 1.5 to ≤ 3 ∃ ULN)
`(# 3 to ≤ 10 ∃ ULN)
`Do not administer
`Do not administer
`KADCYLA until total
`KADCYLA until total
`bilirubin recovers to
`bilirubin recovers to
`Grade ≤ 1, and then reduce
`Grade & 1, and then treat at
`one dose level.
`same dose level.
`
`Grade 4
`(# 10 ∃ ULN)
`Permanently discontinue
`KADCYLA.
`
`Permanently discontinue KADCYLA treatment in patients with serum transaminases > 3 x ULN
`and concomitant total bilirubin > 2 x ULN.
`Permanently discontinue KADCYLA
`in patients diagnosed with nodular regenerative
`hyperplasia (NRH).
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`Symptomatic
`CHF
`
`LVEF < 40%
`
`Left Ventricular Dysfunction [see Warnings and Precautions (5.2)]
`Table 4 Dose Modifications for Left Ventricular Dysfunction
`LVEF 40% to
`LVEF 40% to
`≤45% and
`≤45% and
`decrease is
`decrease is
`≥10% points
`< 10% points
`from baseline
`from baseline
`Do not
`Continue
`administer
`treatment with
`KADCYLA.
`KADCYLA.
`
`Discontinue
`KADCYLA
`
`Do not
`administer
`KADCYLA.
`
`LVEF > 45%
`
`Continue
`treatment with
`KADCYLA.
`
`Repeat LVEF
`assessment
`within 3 weeks.
`
`Repeat LVEF
`assessment
`within 3 weeks.
`If LVEF < 40%
`is confirmed,
`discontinue
`KADCYLA.
`
`Repeat LVEF
`assessment
`within 3 weeks.
`If the LVEF has
`not recovered to
`within 10%
`points from
`baseline,
`discontinue
`KADCYLA.
`CHF = Congestive Heart Failure; LVEF = Left Ventricular Ejection Fraction
`
`Thrombocytopenia [see Warnings and Precautions (5.6)]
`A reduction
`in dose
`is recommended
`in
`the case of Grade 4 thrombocytopenia
`(platelets < 25,000/mm3) (see Table 5).
`Table 5 Dose Modification Guidelines for Thrombocytopenia
`Grade 3
`PLT 25,000/mm3 to ∋∋ 50,000/mm3
`Do not administer KADCYLA until platelet
`count recovers to ≤ Grade 1 (≥ 75,000/mm3),
`and then treat at same dose level.
`PLT % Platelets
`
`Grade 4
`PLT ∋ 25,000/mm3
`Do not administer KADCYLA until platelet
`count recovers to ≤ Grade 1 (≥ 75,000/mm3),
`and then reduce one dose level.
`
`Pulmonary Toxicity [see Warnings and Precautions (5.4)]
`KADCYLA should be permanently discontinued in patients diagnosed with interstitial lung
`disease (ILD) or pneumonitis.
`Peripheral Neuropathy [see Warnings and Precautions (5.7)]
`KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral
`neuropathy until resolution to ≤ Grade 2.
`2.3 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.
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`Administration:
`∀ Administer KADCYLA as an intravenous infusion only with a 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.
`In order to improve traceability of biological medicinal products, the tradename of the
`∀
`administered product should be clearly recorded (or stated) in the patient file.
`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 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 2ºC to 8ºC (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-use 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.
`DOSAGE FORMS AND STRENGTHS
`3
`Lyophilized powder in single-use vials: 100 mg per vial or 160 mg per vial of ado-trastuzumab
`emtansine.
`4
`CONTRAINDICATIONS
`None.
`5 WARNINGS AND PRECAUTIONS
`5.1 Hepatotoxicity
`increases in the
`Hepatotoxicity, predominantly in the form of asymptomatic, transient
`concentrations of serum transaminases, has been observed in clinical trials with KADCYLA [see
`Adverse Reactions (6.1)]. Serious hepatobiliary disorders, including at least two fatal cases of
`severe drug-induced liver injury and associated hepatic encephalopathy, have been reported in
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`clinical trials with KADCYLA. Some of the observed cases may have been confounded by
`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 hepatitis B virus or hepatitis C virus were
`excluded from Study 1 [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.
`In clinical trials of KADCYLA, cases of nodular regenerative hyperplasia (NRH) of the liver
`have been identified from liver biopsies (3 cases out of 884 treated patients). Two of these three
`cases of NRH were observed in the randomized trial (Study 1) [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 but with normal transaminases and no
`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. In the
`randomized trial (Study 1), 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
`[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.
`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 [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 Study 1 [see
`Clinical Studies (14.1)].
`5.3 Embryo-Fetal Toxicity
`KADCYLA can cause fetal harm when administered to a pregnant woman. There are no
`adequate and well-controlled studies of KADCYLA in pregnant women and no reproductive and
`developmental toxicology studies have been conducted with ado-trastuzumab emtansine.
`Nevertheless, treatment with trastuzumab,
`the antibody component of KADCYLA, during
`pregnancy in the postmarketing setting has resulted in oligohydramnios, some associated with
`fatal pulmonary hypoplasia, skeletal abnormalities and neonatal death. DM1, the cytotoxic
`component of KADCYLA, can be expected to cause embryo-fetal toxicity based on its
`mechanism of action.
`If KADCYLA is used during pregnancy, or if the patient becomes pregnant while receiving
`KADCYLA, apprise the patient of the potential hazard to the fetus [see Use in Specific
`Populations (8.1)].
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`Verify pregnancy status prior to the initiation of KADCYLA. Advise patients of the risks of
`embryo-fetal death and birth defects and the need for contraception during and after treatment.
`Advise patients to contact their healthcare provider immediately if they suspect they may be
`pregnant. If KADCYLA is administered during pregnancy or if a patient becomes pregnant
`while receiving KADCYLA, immediately report exposure to the Genentech Adverse Event Line
`at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the
`MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling
`Information (17)].
`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.
`Pneumonitis at an incidence of 0.8% (7 out of 884 treated patients) has been reported, with one
`case of grade 3 pneumonitis. Signs and symptoms include dyspnea, cough, fatigue, and
`pulmonary infiltrates. These events may or may not occur as sequelae of infusion reactions. In
`the randomized trial (Study 1), the overall frequency of pneumonitis was 1.2% [see Adverse
`Reactions (6.1)].
`Permanently discontinue treatment with KADCYLA in patients diagnosed with ILD or
`pneumonitis.
`Patients with dyspnea at rest due to complications of advanced malignancy and co-morbidities
`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 reactions (IRR) and/or hypersensitivity; treatment with
`KADCYLA is not recommended for these patients.
`Infusion-related reactions, characterized by one or more of the following symptoms − flushing,
`chills, pyrexia, dyspnea, hypotension, wheezing, bronchospasm, and tachycardia have been
`reported in clinical trials of KADCYLA. In the randomized trial (Study 1), the overall frequency
`of IRRs in patients treated with KADCYLA was 1.4% [see Adverse Reactions (6.1)]. In most
`patients, these reactions resolved over the course of several hours to a day after the infusion was
`terminated. KADCYLA treatment should be interrupted in patients with severe IRR.
`KADCYLA treatment should be permanently discontinued in the event of a life-threatening IRR
`[see Dosage and Administration (2.2)]. Patients should be observed closely for IRR reactions,
`especially during the first infusion.
`One case of a serious, allergic/anaphylactic-like reaction has been observed in clinical trials of
`single-agent KADCYLA. Medications to treat such reactions, as well as emergency equipment,
`should be available for immediate use.
`5.6 Thrombocytopenia
`Thrombocytopenia, or decreased platelet count, was reported in clinical trials of KADCYLA
`(103 of 884 treated patients with ≥ Grade 3; 283 of 884 treated patients with any Grade). The
`majority of these patients had Grade 1 or 2 events (< LLN to ≥ 50,000/mm3) with the nadir
`occurring by day 8 and generally improving to Grade 0 or 1 (≥ 75,000 /mm3) by the next
`scheduled dose. In clinical trials of KADCYLA, the incidence and severity of thrombocytopenia
`were higher in Asian patients. Independent of race, the incidence of severe hemorrhagic events
`in patients treated with KADCYLA was low.
`In the randomized trial (Study 1), the overall frequency of thrombocytopenia was 31.2% in the
`KADCYLA-treated group and 3.3% in the lapatinib plus capecitabine-treated group [see Adverse
`
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`Reactions (6.1)]. The incidence of ≥ Grade 3 thrombocytopenia was 14.5% in the KADCYLA-
`treated group and 0.4% in the lapatinib plus capecitabine-treated group. In Asian patients, the
`incidence of > Grade 3 thrombocytopenia was 45.1% in the KADCYLA-treated group and 1.3%
`in the lapatinib plus capecitabine-treated group.
`Monitor platelet counts prior to initiation of KADCYLA and prior to each KADCYLA dose [see
`Dosage and Administration (2.2)]. KADCYLA has not been studied in patients with platelet
`counts <100,000/mm3 prior to initiation of treatment. In the event of decreased platelet count to
`Grade 3 or greater (< 50,000/mm3) do not administer KADCYLA until platelet counts recover to
`Grade 1 (≥ 75,000/mm3)
`[see Dosage and Administration
`(2.2)].
` Patients with
`thrombocytopenia (< 100,000/mm3) and patients on anti-coagulant treatment should be closely
`monitored during treatment with KADCYLA.
`5.7 Neurotoxicity
`Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported in clinical
`trials of KADCYLA (14 of 884 treated patients with ≥ Grade 3; 196 of 884 treated patients with
`any Grade). In the randomized trial (Study 1), the overall frequency of peripheral neuropathy
`was 21.2% in the KADCYLA-treated group and 13.5% in the lapatinib plus capecitabine-treated
`group [see Adverse Reactions (6.1)]. The incidence of ≥ Grade 3 peripheral neuropathy was
`2.2% in the KADCYLA-treated group and 0.2% in the lapatinib plus capecitabine-treated group.
`KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral
`neuropathy until resolution to ≤ Grade 2. Patients should be clinically monitored on an ongoing
`basis for signs or symptoms of neurotoxicity [see Nonclinical Toxicology (13.2)].
`5.8 HER2 Testing
`Detection of HER2 protein overexpression or gene amplification is necessary for selection of
`patients appropriate for KADCYLA therapy because these are the only patients studied for
`whom benefit has been shown [see Indications and Usage (1), Clinical Studies (14.1)]. In the
`randomized study (Study 1), patients with breast cancer were required to have evidence of HER2
`overexpression defined as 3+ IHC by Dako Herceptest™ or evidence of overexpression defined
`as FISH amplification ratio ≥ 2.0 by Dako HER2 FISH PharmDx™ test kit. Only limited data
`were available for patients whose breast cancer was positive by FISH and 0 or 1+ by IHC.
`Assessment of HER2 status should be performed by laboratories with demonstrated proficiency
`in the specific technology being utilized. 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.
`5.9 Extravasation
`In KADCYLA clinical studies, reactions secondary to extravasation have been observed. These
`reactions, observed more frequently within 24 hours of infusion, were usually mild and
`comprised erythema, tenderness, skin irritation, pain, or swelling at the infusion site. Specific
`treatment for KADCYLA extravasation is unknown. The infusion site should be closely
`monitored for possible subcutaneous infiltration during drug administration.
`6
`ADVERSE REACTIONS
`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)]
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`∀ Pulmonary Toxicity [See Warnings and Precautions (5.4)]
`Infusion-Related Reactions, Hypersensitivity Reactions [See Warnings and Precautions
`∀
`(5.5)]
`∀ Thrombocytopenia [See Warnings and Precautions (5.6)]
`∀ Neurotoxicity [See Warnings and Precautions (5.7)]
`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.
`In clinical trials, KADCYLA has been evaluated as single-agent in 884 patients with HER2-
`positive metastatic breast cancer. The most common (frequency ≥ 25%) adverse drug reactions
`(ADRs) seen in 884 patients treated with KADCYLA were fatigue, nausea, musculoskeletal
`pain, thrombocytopenia, headache, increased transaminases, and constipation.
`The ADRs described in Table 6 were identified in patients with HER2-positive metastatic breast
`cancer treated in a randomized trial (Study 1) [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. Two hundred and
`eleven (43.1%) patients experienced ≥ Grade 3 adverse events in the KADCYLA-treated group
`compared with 289 (59.2%) patients in the lapatinib plus capecitabine-treated group. Dose
`adjustments for KADCYLA were permitted [see Dosage and Administration (2.2)]. Thirty-two
`patients (6.5%) discontinued KADCYLA due to an adverse event, compared with 41 patients
`(8.4%) who discontinued lapatinib, and 51 patients (10.5%) who discontinued capecitabine due
`to an adverse event. The most common adverse events leading to KADCYLA withdrawal were
`thrombocytopenia and increased transaminases.
` Eighty patients
`(16.3%)
`treated with
`KADCYLA had adverse events leading to dose reductions. The most frequent adverse events
`leading to dose reduction of KADCYLA (in ( 1% of patients) included thrombocytopenia,
`increased transaminases, and peripheral neuropathy. Adverse events that led to dose delays
`occurred in 116 (23.7%) of KADCYLA treated patients. The most frequent adverse events
`leading to a dose delay of KADCYLA (in ≥
`1% of patients) were neutropenia,
`thrombocytopenia, leukopenia, fatigue, increased transaminases and pyrexia.
`Table 6 reports the ADRs that occurred in patients in the KADCYLA-treated group (n=490) of
`the randomized trial (Study 1). Selected laboratory abnormalities are shown in Table 7. The
`most common ADRs seen with KADCYLA in the randomized trial (frequency > 25%) were
`nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, and
`constipation. The most common NCI–CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%)
`were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy
`and fatigue.
`
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`Table 6
`
`Adverse Drug Reactions
`(MedDRA)
`System Organ Class
`
`Summary of Adverse Drug Reactions Occurring in Patients on the KADCYLA
`Treatment Arm in the Randomized Trial (Study 1)
`KADCYLA
`(3.6 mg/kg)
`n=490
`Frequency rate %
`All grades
`Grade 3 – 4
`(%)
`(%)
`
`Lapatinib (1250 mg) +
`Capecitabine (2000
`mg/m2)
`n=488
`Frequency rate %
`Grade 3 – 4
`All grades
`(%)
`(%)
`
`Blood and Lymphatic System
`Disorders
`Neutropenia
`Anemia
`Thrombocytopenia
`Cardiac Disorders
`Left ventricular dysfunction
`Eye Disorders
`Lacrimation increased
`Dry eye
`Vision blurred
`Conjunctivitis
`Gastrointestinal Disorders
`Dyspepsia
`Stomatitis
`Dry Mouth
`Abdominal pain
`Vomiting
`Diarrhea
`Constipation
`Nausea
`General Disorders and
`Administration
`Peripheral edema
`Chills
`Pyrexia
`Asthenia
`Fatigue
`Hepatobiliary Disorders
`Nodular regenerative hyperplasia*
`Portal hypertension*
`Immune System Disorders
`Drug hypersensitivity
`Injury, Poisoning, and
`Procedural
`Infusion-related reaction
`Infections and Infestations
`Urinary tract infection
`Investigations
`Blood alkaline phosphatase
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`
`6.7
`14.3
`31.2
`
`1.8
`
`3.3
`3.9
`4.5
`3.9
`
`9.2
`14.1
`16.7
`18.6
`19.2
`24.1
`26.5
`39.8
`
`7.1
`7.6
`18.6
`17.8
`36.3
`
`0.4
`0.4
`
`2.2
`
`1.4
`
`9.4
`
`4.7
`
`2.0
`4.1
`14.5
`
`0.2
`
`0
`0
`0
`0
`
`0
`0.2
`0
`0.8
`0.8
`1.6
`0.4
`0.8
`
`0
`0
`0.2
`0.4
`2.5
`
`ND
`0.2
`
`0
`
`0
`
`0.6
`
`0.4
`
`9.0
`10.5
`3.3
`
`3.3
`
`2.5
`3.1
`0.8
`2.3
`
`11.5
`32.6
`4.9
`17.6
`29.9
`79.7
`11.1
`45.1
`
`8.2
`3.1
`8.4
`17.6
`28.3
`
`0
`0
`
`0.8
`
`0.2
`
`3.9
`
`3.7
`
`4.3
`2.5
`0.4
`
`0.4
`
`0
`0
`0
`0
`
`0.4
`2.5
`0.2
`1.6
`4.5
`20.7
`0
`2.5
`
`0.2
`0
`0.4
`1.6
`3.5
`
`0
`0
`
`0
`
`0
`
`0
`
`0.4
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`

`

`Adverse Drug Reactions
`(MedDRA)
`System Organ Class
`
`KADCYLA
`(3.6 mg/kg)
`n=490
`Frequency rate %
`All grades
`Grade 3 – 4
`(%)
`(%)
`
`Lapatinib (1250 mg) +
`Capecitabine (2000
`mg/m2)
`n=488
`Frequency rate %
`Grade 3 – 4
`All grades
`(%)
`(%)
`
`2.5
`
`4.7
`
`0
`0
`1.4
`
`0.2
`0.2
`0.2
`0.8
`
`0.2
`
`0
`0.4
`0.2
`0
`
`0
`1.8
`
`0.4
`
`increased
`Increased transaminases
`Metabolism and Nutrition
`Disorders
`Hypokalemia
`Musculoskeletal and Connective
`Tissue Disorders
`Myalgia
`Arthralgia
`Musculoskeletal pain
`Nervous System Disorders
`Dysgeusia
`Dizziness
`Peripheral neuropathy
`Headache
`Psychiatric Disorders
`Insomnia
`Respiratory, Thoracic, and
`Mediastinal Disorders
`Pneumonitis
`Dyspnea
`Cough
`Epistaxis
`Skin and Subcutaneous Tissue
`Disorders
`Pruritus
`Rash
`Vascular Disorders
`2.3
`1.2
`5.1
`Hypertension
`* Nodular Regenerative Hyperplasia and Portal Hypertension occurred in the same patient.
`ND = Not determined
`
`14.3
`
`9.4
`
`3.7
`8.4
`30.5
`
`4.1
`10.7
`13.5
`14.5
`
`8.6
`
`0
`8.0
`13.1
`8.4
`
`9.2
`27.5
`
`28.8
`
`10.2
`
`14.1
`19.2
`36.1
`
`8.0
`10.2
`21.2
`28.2
`
`12.0
`
`1.2
`12.0
`18.2
`22.5
`
`5.5
`11.6
`
`8.0
`
`2.7
`
`0.6
`0.6
`1.8
`
`0
`0.4
`2.2
`0.8
`
`0.4
`
`0
`0.8
`0.2
`0.2
`
`0.2
`0
`
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