KADCYLA 100mg powder for concentrate infusion solution medication leaflet

Kadcyla 100 mg powder for concentrate for solution for infusion

Kadcyla 160 mg powder for concentrate for solution for infusion

Kadcyla 100 mg powder for concentrate for solution for infusion

One vial of powder for concentrate for solution for infusion contains 100 mg of trastuzumabemtansine. After reconstitution one vial of 5 mL solution contains 20 mg/mL of trastuzumabemtansine (see section 6.6).

Kadcyla 160 mg powder for concentrate for solution for infusion

One vial of powder for concentrate for solution for infusion contains 160 mg of trastuzumabemtansine. After reconstitution one vial of 8 mL solution contains 20 mg/mL of trastuzumabemtansine (see section 6.6).

Each 100 mg vial contains 1.38 mg of sodium and 1.1 mg of polysorbate 20.

Each 160 mg vial contains 2.24 mg of sodium and 1.7 mg of polysorbate 20.

For the full list of excipients, see section 6.1.

Trastuzumab emtansine is an antibody-drug conjugate that contains trastuzumab, a humanised IgG1monoclonal antibody produced by mammalian (Chinese hamster ovary) cell suspension culture,covalently linked to DM1, a microtubule inhibitor, via the stable thioether linker MCC(4-[N-maleimidomethyl] cyclohexane-1-carboxylate).

Powder for concentrate for solution for infusion.

White to off-white lyophilised powder.

Early Breast Cancer (EBC)

Kadcyla, as a single agent, is indicated for the adjuvant treatment of adult patients with HER2-positiveearly breast cancer who have residual invasive disease, in the breast and/or lymph nodes, afterneoadjuvant taxane-based and HER2-targeted therapy.

Metastatic Breast Cancer (MBC)

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

* Received prior therapy for locally advanced or metastatic disease, or

* Developed disease recurrence during or within six months of completing adjuvant therapy.

Kadcyla should only be prescribed by a physician and administered as an intravenous infusion underthe supervision of a healthcare professional who is experienced in the treatment of cancer patients (i.e.prepared to manage allergic/anaphylactic infusion reactions and in an environment where fullresuscitation facilities are immediately available (see section 4.4)).

Patients treated with trastuzumab emtansine should have HER2 positive tumour status, defined as ascore of 3 + by immunohistochemistry (IHC) or a ratio of ≥ 2.0 by in situ hybridization (ISH) or byfluorescence in situ hybridization (FISH) assessed by a CE-marked In Vitro Diagnostic (IVD) medicaldevice. If a CE-marked IVD is not available, the HER2-status should be assessed by an alternatevalidated test.

In order to prevent medicinal product errors it is important to check the vial labels to ensure that themedicinal product being prepared and administered is Kadcyla (trastuzumab emtansine) and notanother trastuzumab-containing product (e.g. trastuzumab or trastuzumab deruxtecan).

The recommended dose of trastuzumab emtansine is 3.6 mg/kg bodyweight administered as anintravenous infusion every 3 weeks (21-day cycle).

The initial dose should be administered as a 90 minute intravenous infusion. Patients should beobserved during the infusion and for at least 90 minutes following the initial infusion for fever, chills,or other infusion-related reactions. The infusion site should be closely monitored for possiblesubcutaneous infiltration during administration. Cases of delayed epidermal injury or necrosisfollowing extravasation have been observed in the post-marketing setting (see section 4.4 and 4.8).

If the prior infusion was well tolerated, subsequent doses of trastuzumab emtansine may beadministered as 30 minute infusions. Patients should be observed during the infusion and for at least30 minutes after infusion.

The infusion rate of trastuzumab emtansine should be slowed or interrupted if the patient developsinfusion-related symptoms (see sections 4.4 and 4.8). Trastuzumab emtansine should be discontinuedin case of life-threatening infusion reactions.

Early Breast Cancer (EBC)

Patients should receive treatment for a total of 14 cycles unless there is disease recurrence orunmanageable toxicity.

Metastatic Breast Cancer (MBC)

Patients should receive treatment until disease progression or unmanageable toxicity.

Management of symptomatic adverse reactions may require temporary interruption, dose reduction, ortreatment discontinuation of trastuzumab emtansine as per guidelines provided in text and

Tables 1 and 2.

Trastuzumab emtansine dose should not be re-escalated after a dose reduction is made.

Table 1 Dose reduction schedule

Dose reduction schedule(Starting dose is 3.6 mg/kg) Dose to be administered

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

Dose modifications for patients with EBC

Adverse reaction Severity Treatment modification

Thrombocytopenia Grade 2-3 on day of Do not administer trastuzumab emtansine untilscheduled treatment platelet count recovers to ≤ Grade 1 (≥ 75 000/mm3),(25 000 and then treat at the same dose level. If a patientto < 75 000/mm3) requires 2 delays due to thrombocytopenia, considerreducing dose by one level.

Grade 4 at any time Do not administer trastuzumab emtansine until< 25 000/mm3 platelet count recovers to ≤ Grade 1 (≥ 75 000/mm3),and then reduce one dose level.

Increased Alanine Grade 2-3 Do not administer trastuzumab emtansine until ALT

Transaminase (ALT) (> 3.0 to ≤ 20× ULN on recovers to Grade ≤ 1, and then reduce one doseday of scheduled leveltreatment)

Grade 4 Discontinue trastuzumab emtansine(> 20 × ULN at anytime)

Increased Aspartate Grade 2 Do not administer trastuzumab emtansine until AST

Transaminase (AST) (> 3.0 to ≤ 5× ULN on recovers to Grade ≤ 1, and then treat at the sameday of scheduled dose leveltreatment)

Grade 3 Do not administer trastuzumab emtansine until AST(> 5 to ≤ 20× ULN on recovers to Grade ≤ 1, and then reduce one doseday of scheduled leveltreatment)

Grade 4 Discontinue trastuzumab emtansine(> 20 × ULN at anytime)

Hyperbilirubinaemia TBILI Do not administer trastuzumab emtansine until total> 1.0 to ≤ 2.0× the ULN bilirubin recovers to ≤ 1.0× ULN, and then reduceon day of scheduled one dose leveltreatment

TBILI Discontinue trastuzumab emtansine> 2× ULN at any time

Drug Induced Liver Serum transaminases > Permanently discontinue trastuzumab emtansine in

Injury (DILI) 3 x ULN and the absence of another likely cause for the elevationconcomitant total of liver enzymes and bilirubin, e.g. liver metastasisbilirubin > 2× ULN or concomitant medication

Nodular Regenerative All Grades Permanently discontinue trastuzumab emtansine

Hyperplasia (NRH)

Peripheral Neuropathy Grade 3-4 Do not administer trastuzumab emtansine untilresolution ≤ Grade 2

Left Ventricular LVEF < 45% Do not administer trastuzumab emtansine .

Dysfunction Repeat LVEF assessment within 3 weeks. If LVEF< 45% is confirmed, discontinue trastuzumabemtansine.

LVEF 45% to < 50% Do not administer trastuzumab emtansine.and decrease is ≥ 10% Repeat LVEF assessment within 3 weeks. If thepoints from baseline* LVEF remains < 50% and has not recovered to <10% points from baseline, discontinue trastuzumabemtansine.

LVEF 45% to < 50% Continue treatment with trastuzumab emtansine.and decrease is < 10% Repeat LVEF assessment within 3 weeks.points from baseline*

LVEF ≥ 50% Continue treatment with trastuzumab emtansine

Heart Failure Discontinue trastuzumab emtansine

Symptomatic CHF,

Grade 3-4 LVSD or

Grade 3-4 heart failure,or

Grade 2 heart failureaccompanied by LVEF<45%

Pulmonary Toxicity Interstitial lung disease Permanently discontinue trastuzumab emtansine(ILD) or pneumonitis

Radiotherapy-Related Grade 2 Discontinue trastuzumab emtansine if not resolving

Pneumonitis with standard treatment

Grade 3-4 Discontinue trastuzumab emtansine

Dose modifications for patients with MBC

Adverse reaction Severity Treatment modification

Thrombocytopenia Grade 3 Do not administer trastuzumab emtansine until(25 000 to platelet count recovers to ≤ Grade 1 (≥< 50 000/mm3) 75 000/mm3), and then treat at the same dose level

Grade 4 Do not administer trastuzumab emtansine until(< 25 000/mm3) platelet count recovers to ≤ Grade 1 (≥75 000/mm3), and then reduce one dose level

Increased Transaminase Grade 2 T reat at the same dose level(AST/ALT) (> 2.5 to ≤ 5× the ULN)

Grade 3 Do not administer trastuzumab emtansine until(> 5 to ≤ 20× the ULN) AST/ALT recovers to Grade ≤ 2, and then reduceone dose level

Grade 4 Discontinue trastuzumab emtansine(> 20× the ULN)

Hyperbilirubinaemia Grade 2 Do not administer trastuzumab emtansine until total(> 1.5 to ≤ 3× the ULN) bilirubin recovers to Grade ≤ 1, and then treat at thesame dose level.

Grade 3 Do not administer trastuzumab emtansine until total(> 3 to ≤ 10× the ULN) bilirubin recovers to Grade ≤ 1 and then reduce onedose level.

Grade 4 Discontinue trastuzumab emtansine(> 10× the ULN)

Drug Induced Liver Serum transaminases > Permanently discontinue trastuzumab emtansine in

Injury (DILI) 3 x ULN and the absence of another likely cause for the elevationconcomitant total of liver enzymes and bilirubin, e.g. liver metastasisbilirubin > 2× ULN or concomitant medication

Nodular Regenerative All Grades Permanently discontinue trastuzumab emtansine

Hyperplasia (NRH)

Left Ventricular Symptomatic CHF Discontinue trastuzumab emtansine

Dysfunction

LVEF <40% Do not administer trastuzumab emtansine.

Repeat LVEF assessment within 3 weeks. If LVEF<40% is confirmed, discontinue trastuzumabemtansine

LVEF 40% to ≤ 45% Do not administer trastuzumab emtansine.and decrease is ≥ 10% Repeat LVEF assessment within 3 weeks. If thepoints from baseline LVEF has not recovered to within 10% points frombaseline, discontinue trastuzumab emtansine.

LVEF 40% to ≤ 45% Continue treatment with trastuzumab emtansine.and decrease is < 10% Repeat LVEF assessment within 3 weeks.points from baseline

LVEF > 45% Continue treatment with trastuzumab emtansine.

Peripheral Neuropathy Grade 3-4 Do not administer trastuzumab emtansine untilresolution ≤ Grade 2

Pulmonary Toxicity Interstitial lung disease Permanently discontinue trastuzumab emtansine(ILD) or pneumonitis

ALT = alanine transaminase; AST = aspartate transaminase, CHF = congestive heart failure, LVEF = left ventricular ejectionfraction, LVSD = left ventricular systolic dysfunction, TBILI = Total Bilirubin, ULN = upper limit of normal

* Prior to starting trastuzumab emtansine treatment.

If a planned dose is missed, it should be administered as soon as possible; without waiting until thenext planned cycle. The schedule of administration should be adjusted to maintain a 3-week intervalbetween doses. The next dose should be administered in accordance with the dosing recommendationsabove.

Trastuzumab emtansine should be temporarily discontinued in patients experiencing Grade 3 or 4peripheral neuropathy until resolution to ≤ Grade 2. At retreatment a dose reduction may beconsidered according to the dose reduction schedule (see Table 1).

No dose adjustment is required in patients aged ≥ 65 years. There are insufficient data to establish thesafety and efficacy in patients ≥ 75 years due to limited data in this subgroup. However, for patients≥ 65 years, subgroup analysis of 345 patients from study MO28231 shows a tendency of higherincidences of Grade 3, 4 and 5 AE’s, SAE’s and AE’s leading to treatmentdiscontinuation/interruption, but with a similar incidence of AEs of Grade 3 and above classified astreatment related.

Population pharmacokinetic analysis indicates that age does not have a clinically meaningful effect onthe pharmacokinetics of trastuzumab emtansine (see sections 5.1 and 5.2).

No adjustment to the starting dose is needed in patients with mild or moderate renal impairment (seesection 5.2). The potential need for dose adjustment in patients with severe renal impairment cannot bedetermined due to insufficient data and therefore patients with severe renal impairment should bemonitored carefully.

No adjustment to the starting dose is required for patients with mild or moderate hepatic impairment.

Trastuzumab emtansine has not been studied in patients with severe hepatic impairment. Treatment ofpatients with hepatic impairment should be undertaken with caution due to known hepatotoxicityobserved with trastuzumab emtansine (see section 4.4 and 5.2).

The safety and efficacy in children and adolescents below 18 years of age have not been established asthere is no relevant use in the paediatric population for the indication of breast cancer.

Kadcyla is for intravenous use. Trastuzumab emtansine must be reconstituted and diluted by ahealthcare professional and administered as an intravenous infusion. It must not be administered as anintravenous push or bolus.

For instructions on reconstitution and dilution of the medicinal product before administration, seesection 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve traceability of biological medicinal products, the tradename and the batch numberof the administered product should be clearly recorded (or stated) in the patient file.

In order to prevent medicinal product errors it is important to check the vial labels to ensure that themedicinal product being prepared and administered is Kadcyla (trastuzumab emtansine) and notanother trastuzumab-containing product (e.g. trastuzumab or trastuzumab deruxtecan).

Thrombocytopenia, or decreased platelet counts, was commonly reported with trastuzumab emtansineand was the most common adverse reaction leading to treatment discontinuation, dose reduction, anddose interruption (see section 4.8). In clinical studies, the incidence and severity of thrombocytopeniawere higher in Asian patients (see section 4.8).

It is recommended that platelet counts are monitored prior to each trastuzumab emtansine dose.

Patients with thrombocytopenia (≤ 100 000/mm3) and patients on anticoagulant treatment (e.g.warfarin, heparin, low molecular weight heparins) should be monitored closely while on trastuzumabemtansine treatment. Trastuzumab emtansine 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 orgreater (< 50 000/mm3), do not administer trastuzumab emtansine until platelet counts recover to

Grade 1 (≥ 75 000/mm3) (see section 4.2).

Cases of haemorrhagic events, including central nervous system, respiratory and gastrointestinalhaemorrhage, have been reported with trastuzumab emtansine treatment. Some of these bleedingevents resulted in fatal outcomes. In some of the observed cases the patients had thrombocytopenia, orwere also receiving anti-coagulant therapy or antiplatelet therapy; in others there were no knownadditional risk factors. Use caution with these agents and consider additional monitoring whenconcomitant use is medically necessary.

Hepatotoxicity, predominantly in the form of asymptomatic increases in the concentrations of serumtransaminases (Grade 1-4 transaminitis), has been observed during treatment with trastuzumabemtansine in clinical studies (see section 4.8). Transaminase elevations were generally transient withpeak elevation at day 8 after administration of therapy and subsequent recovery to Grade 1 or lessprior to the next cycle. A cumulative effect on transaminases has also been observed (the proportion ofpatients with Grade 1-2 ALT/AST abnormalities increases with successive cycles).

Patients with elevated transaminases improved to Grade 1 or normal within 30 days of the last dose oftrastuzumab emtansine in the majority of the cases (see section 4.8).

Serious hepatobiliary disorders, including nodular regenerative hyperplasia (NRH) of the liver andsome with a fatal outcome due to drug-induced liver injury have been observed in patients treated withtrastuzumab emtansine. Observed cases may have been confounded by comorbidities and/orconcomitant medicinal products with known hepatotoxic potential.

Liver function should be monitored prior to initiation of treatment and each dose. Patients withbaseline elevation of ALT (e.g. due to liver metastases) may be predisposed to liver injury with ahigher risk of a Grade 3-5 hepatic event or liver function test increase. Dose reductions ordiscontinuation for increased serum transaminases and total bilirubin are specified in section 4.2.

Cases of nodular regenerative hyperplasia (NRH) of the liver have been identified from liver biopsiesin patients treated with trastuzumab emtansine. NRH is a rare liver condition characterised bywidespread benign transformation of hepatic parenchyma into small regenerative nodules; NRH maylead to non-cirrhotic portal hypertension. Diagnosis of NRH can be confirmed only by histopathology.

NRH should be considered in all patients with clinical symptoms of portal hypertension and/orcirrhosis-like pattern seen on the computed tomography (CT) scan of the liver but with normaltransaminases and no other manifestations of cirrhosis. Upon diagnosis of NRH, trastuzumabemtansine treatment must be permanently discontinued.

Trastuzumab emtansine has not been studied in patients with serum transaminases > 2.5 × ULN ortotal bilirubin > 1.5 × ULN prior to initiation of treatment. Treatment in patients with serumtransaminases > 3 × ULN and concomitant total bilirubin > 2 × ULN should be permanentlydiscontinued. Treatment of patients with hepatic impairment should be undertaken with caution (seesections 4.2 and 5.2).

Neurotoxicity

Peripheral neuropathy, mainly Grade 1 and predominantly sensory, has been reported in clinicalstudies with trastuzumab emtansine. MBC patients with Grade ≥ 3 and EBC patients with Grade ≥ 2peripheral neuropathy at baseline were excluded from clinical studies. Treatment with trastuzumabemtansine should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheralneuropathy until symptoms resolve or improve to ≤ Grade 2. Patients should be clinically monitoredon an ongoing basis for signs/symptoms of neurotoxicity.

Patients treated with trastuzumab emtansine are at increased risk of developing left ventriculardysfunction. Left ventricular ejection fraction (LVEF) < 40% has been observed in patients treatedwith trastuzumab emtansine, and therefore symptomatic congestive heart failure (CHF) is a potentialrisk (see section 4.8). General risk factors for a cardiac event and those identified in adjuvant breastcancer studies with trastuzumab therapy include advancing age (> 50 years), low baseline LVEFvalues (< 55%), low LVEF levels prior to or following the use of paclitaxel in the adjuvant setting,prior or concomitant use of antihypertensive medicinal products, previous therapy with ananthracycline and high BMI (> 25 kg/m2).

Standard cardiac function testing (echocardiogram or multigated acquisition (MUGA) scanning)should be performed prior to initiation of treatment and also at regular intervals (e.g. every threemonths) during treatment. The dosing should be delayed, or treatment discontinued as necessary incases of left ventricular dysfunction (see section 4.2). In clinical studies, patients had a LVEF ≥ 50%at baseline. Patients with a history of congestive heart failure (CHF), serious cardiac arrhythmiarequiring treatment, history of myocardial infarction or unstable angina within 6 months ofrandomisation, or current dyspnoea at rest due to advanced malignancy were excluded from clinicalstudies. Events of LVEF drop of > 10% from baseline and/or CHF were observed in an observationalstudy (BO39807) of MBC patients with baseline LVEF of 40-49% in a real world setting. Thedecision to administer trastuzumab emtansine in MBC patients with low LVEF must be made onlyafter careful benefit risk assessment and cardiac function should be closely monitored in these patients(see section 4.8).

Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratorydistress syndrome or a fatal outcome, have been reported in clinical studies with trastuzumabemtansine (see section 4.8). Signs and symptoms include dyspnoea, cough, fatigue, and pulmonaryinfiltrates.

It is recommended that treatment with trastuzumab emtansine be permanently discontinued in patientswho are diagnosed with ILD or pneumonitis, except for radiation pneumonitis in the adjuvant setting,where trastuzumab emtansine should be permanently discontinued for ≥ Grade 3 or for Grade 2 notresponding to standard treatment (see section 4.2).

Patients with dyspnoea at rest due to complications of advanced malignancy, co-morbidities, andreceiving concurrent pulmonary radiation therapy may be at increased risk of pulmonary events.

Trastuzumab emtansine treatment has not been studied in patients who had trastuzumab permanentlydiscontinued due to infusion-related reactions (IRR); treatment is not recommended for these patients.

Patients should be observed closely for infusion-related reactions, especially during the first infusion.

Infusion-related reactions (due to cytokine release), characterised by one or more of the followingsymptoms have been reported: flushing, chills, pyrexia, dyspnoea, hypotension, wheezing,bronchospasm, and tachycardia. In general, these symptoms were not severe (see section 4.8). In mostpatients, these reactions resolved over the course of several hours to a day after the infusion wasterminated. Treatment should be interrupted in patients with a severe IRR until signs and symptomsresolve. Consideration for re-treatment should be based on clinical assessment of the severity of thereaction. Treatment must be permanently discontinued in the event of a life threatening infusion-related reaction (see section 4.2).

Trastuzumab emtansine treatment has not been studied in patients who had trastuzumab permanentlydiscontinued due to hypersensitivity; treatment with trastuzumab emtansine is not recommended forthese patients.

Patients should be observed closely for hypersensitivity/allergic reactions, which may have the sameclinical presentation as an IRR. Serious, anaphylactic reactions have been observed in clinical studieswith trastuzumab emtansine. Medicinal products to treat such reactions, as well as emergencyequipment, should be available for immediate use. In the event of a true hypersensitivity reaction (inwhich severity of reaction increases with subsequent infusions), trastuzumab emtansine treatment mustbe permanently discontinued.

Injection-site reactions

Extravasation of trastuzumab emtansine during intravenous injection may produce local pain.

Exceptionally, cases of severe tissue lesions and epidermal necrosis may occur. If extravasationoccurs, the infusion should be terminated immediately and the patient should be examined regularly asnecrosis may occur within days to weeks after infusion.

This medicine contains 1.1 mg of polysorbate 20 in each 100 mg vial and 1.7 mg of polysorbate 20 ineach 160 mg vial. Polysorbates may cause allergic reactions.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially‘sodium-free’.

No formal interaction studies have been performed.

In vitro metabolism studies in human liver microsomes suggest that DM1, a component oftrastuzumab emtansine, is metabolised mainly by CYP3A4 and, to a lesser extent, by CYP3A5.

Concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin,atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole)with trastuzumab emtansine should be avoided due to the potential for an increase in DM1 exposureand toxicity. Consider an alternate medicinal product with no or minimal potential to inhibit CYP3A4.

If concomitant use of strong CYP3A4 inhibitors is unavoidable, consider delaying trastuzumabemtansine treatment until the strong CYP3A4 inhibitors have cleared from the circulation(approximately 3 elimination half-lives of the inhibitors) when possible. If a strong CYP3A4 inhibitoris co-administered and trastuzumab emtansine treatment cannot be delayed, patients should be closelymonitored for adverse reactions.

Women of childbearing potential should use effective contraception while receiving trastuzumabemtansine and for 7 months following the last dose of trastuzumab emtansine. Male patients or theirfemale partners should also use effective contraception.

There are no data from the use of trastuzumab emtansine in pregnant women. Trastuzumab, acomponent of trastuzumab emtansine, can cause foetal harm or death when administered to a pregnantwoman. In the post-marketing setting, cases of oligohydramnios, some associated with fatalpulmonary hypoplasia, have been reported in pregnant women receiving trastuzumab. Animal studiesof maytansine, a closely related chemical entity of the same maytansinoid class as DM1, suggest that

DM1, the microtubule inhibiting cytotoxic component of trastuzumab emtansine, is expected to beteratogenic and potentially embryotoxic (see section 5.3).

Administration of trastuzumab emtansine to pregnant women is not recommended and women shouldbe informed of the possibility of harm to the foetus before they become pregnant. Women whobecome pregnant must immediately contact their doctor. If a pregnant woman is treated withtrastuzumab emtansine, close monitoring by a multidisciplinary team is recommended.

It is not known whether trastuzumab emtansine is excreted in human milk. Since many medicinalproducts are excreted in human milk and because of the potential for serious adverse reactions inbreast-feeding infants, women should discontinue breast-feeding prior to initiating treatment withtrastuzumab emtansine. Women may begin breast-feeding 7 months after concluding treatment.

No reproductive and developmental toxicology studies have been conducted with trastuzumabemtansine.

Trastuzumab emtansine has minor influence on the ability to drive and use machines.

The significance of reported adverse reactions such as fatigue, headache, dizziness and blurred visionon the ability to drive or use machines is unknown. Patients experiencing infusion-related reactions(flushing, chills, pyrexia, dyspnoea, hypotension, wheezing, bronchospasm, and tachycardia) shouldbe advised not to drive and use machines until symptoms abate.

The safety of trastuzumab emtansine has been evaluated in 2 611 breast cancer patients in clinicalstudies. In this patient population:

* the most common serious adverse drug reactions (ADRs) (> 0.5% of patients) were haemorrhage,pyrexia, thrombocytopenia, dyspnoea, abdominal pain, musculoskeletal pain, and vomiting.

* the most common ADRs (≥ 25%) with trastuzumab emtansine were nausea, fatigue,musculoskeletal pain, haemorrhage, headache, transaminases increased, thrombocytopenia, andperipheral neuropathy. The majority of ADRs reported were of Grade 1 or 2 severity.

* the most common National Cancer Institute - Common Terminology Criteria for Adverse Events(NCI-CTCAE) Grade ≥ 3 ADRs (> 2%) were thrombocytopenia, increased transaminases,anaemia, neutropenia, fatigue and hypokalaemia.

The ADRs in 2 611 patients treated with trastuzumab emtansine are presented in Table 3. The ADRsare listed below by MedDRA system organ class (SOC) and categories of frequency. Frequencycategories are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000) and not known (cannot be estimatedfrom the available data). Within each frequency grouping and SOC, adverse reactions are presented inorder of decreasing seriousness. ADRs were reported using NCI-CTCAE for assessment of toxicity.

Table 3 Tabulated list of ADRs in patients treated with trastuzumab emtansine in clinicalstudies

System Organ Class Frequency Adverse reactions

Infections and infestations Very common Urinary tract infection

Blood and lymphatic system Very common Thrombocytopenia, Anaemiadisorders Common Neutropenia, Leukopoenia

Immune system disorders Common Drug hypersensitivity

Metabolism and nutrition Common Hypokalaemiadisorders

Psychiatric disorders Very common Insomnia

Nervous system disorders Very common Neuropathy peripheral,

Common Dizziness, Dysgeusia, Memoryimpairment

Eye disorders Common Dry eye, Conjunctivitis, Visionblurred, Lacrimation increased

Cardiac disorders Common Left ventricular dysfunction

Vascular disorders Very common Haemorrhage

Common Hypertension

Respiratory, thoracic and Very common Epistaxis, Cough, Dyspnoeamediastinal disorders Uncommon Pneumonitis (ILD)

Gastrointestinal disorders Very common Stomatitis, Diarrhoea,

Vomiting, Nausea,

Constipation, Dry mouth,

Abdominal pain

Common Dyspepsia, Gingival bleeding

Hepatobiliary disorders Very common Transaminases increased

Common Blood alkaline phosphataseincreased, Blood bilirubinincreased

Uncommon Hepatotoxicity, Nodularregenerative hyperplasia, Portalhypertension

Rare Hepatic failure

Skin and subcutaneous tissue Common Rash, Pruritus, Alopecia, Naildisorders disorder, Palmar-plantarerythrodysaesthesia syndrome,

Urticaria

Musculoskeletal and Very common Musculoskeletal pain,connective tissue disorders Arthralgia, Myalgia

General disorders and Very common Fatigue, Pyrexia, Astheniaadministration site conditions Common Peripheral oedema, Chills

Uncommon Injection site extravasation

Injury, poisoning and Common Infusion related reactionsprocedural complications Uncommon Radiation pneumonitis

Table 3 shows pooled data from the overall treatment period in the MBC studies (N = 1871; mediannumber of cycles of trastuzumab emtansine was 10) and in KATHERINE (N = 740; median number ofcycles was 14).

Thrombocytopenia or decreased platelet counts were reported in 24.9% of patients in MBC clinicalstudies with trastuzumab emtansine and was the most common adverse reaction leading to treatmentdiscontinuation (2.6%). Thrombocytopenia was reported in 28.6% of patients in EBC clinical studieswith trastuzumab emtansine and was the most common reported adverse reaction for all grades andgrades ≥ 3, as well as the most common adverse reaction leading to treatment discontinuation (4.2%),dose interruptions, and dose reductions. The majority of the patients had Grade 1 or 2 events(≥ 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 studies, the incidence and severity ofthrombocytopenia were higher in Asian patients. Independent of race, the incidence of Grade 3 or 4events (< 50 000/mm3) was 8.7% in patients with MBC treated with trastuzumab emtansine and 5.7%in patients with EBC. For dose modifications for thrombocytopenia, see sections 4.2 and 4.4.

Haemorrhagic events were reported in 34.8% of patients in MBC clinical studies with trastuzumabemtansine and the incidence of severe haemorrhagic events (Grade ≥ 3) occurred in 2.2%.

Haemorrhagic events were reported in 29.2% of patients with EBC and the incidence of severehaemorrhagic events (Grade ≥ 3) was 0.4%, including one Grade 5 event. In some of the observedcases the patients had thrombocytopenia, or were also receiving anti-coagulant therapy or antiplatelettherapy; in others there were no known additional risk factors. Cases of bleeding events with a fataloutcome have been observed in both MBC and EBC.

Transaminases increased (AST/ALT)

Increase in serum transaminases (Grade 1-4) has been observed during treatment with trastuzumabemtansine in clinical studies (see section 4.4). Transaminase elevations were generally transient. Acumulative effect of trastuzumab emtansine on transaminases has been observed, and generallyrecovered when treatment was discontinued. Increased transaminases were reported in 24.2% ofpatients in MBC clinical studies. Grade 3 or 4 increased AST and ALT were reported in 4.2% and2.7% of patients with MBC respectively and usually occurred in the early treatment cycles (1-6).

Increased transaminases were reported in 32.6% of patients with EBC. Grade 3 and 4 increasedtransaminases were reported in 1.6% of patients with EBC. In general, the Grade ≥ 3 hepatic eventswere not associated with poor clinical outcome; subsequent follow up values tended to showimprovement to ranges allowing the patient to remain on study and continue to receive study treatmentat the same or reduced dose. No relationship was observed between trastuzumab emtansine exposure(AUC), trastuzumab emtansine maximum serum concentration (Cmax), total trastuzumab exposure(AUC), or Cmax of DM1 and increases in transaminase. For dose modifications in the event ofincreased transaminases, see sections 4.2 and 4.4.

Left ventricular dysfunction was reported in 2.2% of patients in MBC clinical studies withtrastuzumab emtansine. The majority of events were asymptomatic Grade 1 or 2 decrease in LVEF.

Grade 3 or 4 events were reported in 0.4% of patients with MBC. In an observational study(BO39807), approximately 22% (7 out of 32) of MBC patients initiating trastuzumab emtansine with

LVEF of 40-49% at baseline, experienced a LVEF drop of > 10% from baseline and/or CHF; most ofthese patients had other cardiovascular risk factors. Left ventricular dysfunction occurred in 3.0% ofpatients with EBC, with Grade 3 in 0.5% of patients, and no events of higher grade. For dosemodifications in the event of LVEF decrease, see Table 2 in section 4.2 and section 4.4.

Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported in clinical studiesof trastuzumab emtansine. In patients with MBC, the overall incidence of peripheral neuropathy was29.0% and 8.6% for Grade ≥ 2. In patients with EBC, the overall incidence was 32.0% and 10.1% for

Grade ≥ 2.

Infusion-related reactions are characterised by one or more of the following symptoms: flushing,chills, pyrexia, dyspnoea, hypotension, wheezing, bronchospasm and tachycardia. Infusion-relatedreactions were reported in 4.0% of patients in MBC clinical studies with trastuzumab emtansine, withsix Grade 3 and no Grade 4 events reported. Infusion-related reactions were reported in 1.6% ofpatients with EBC, with no Grade 3 or 4 events reported. Infusion-related reactions resolved over thecourse of several hours to a day after the infusion was terminated. No dose relationship was observedin clinical studies. For dose modifications in the event of infusion-related reactions, see sections 4.2and 4.4.

Hypersensitivity was reported in 2.6% of patients in MBC clinical studies with trastuzumabemtansine, with one Grade 3 and one Grade 4 events reported. Hypersensitivity was reported in 2.7%of patients with EBC, with Grade 3 in 0.4% of patients and no events of higher grade. Overall, themajority of hypersensitivity reactions were mild or moderate in severity and resolved upon treatment.

For dose modifications in the event of hypersensitivity reactions, see sections 4.2 and 4.4.

As with all therapeutic proteins, there is the potential for an immune response to trastuzumabemtansine. A total of 1 243 patients from seven clinical studies were tested at multiple time points foranti-drug antibody (ADA) responses to trastuzumab emtansine. Following trastuzumab emtansinedosing, 5.1% (64/1 243) of patients tested positive for anti-trastuzumab emtansine antibodies at one ormore post-dose time points. In the Phase I and Phase II studies, 6.4% (24/376) of patients testedpositive for anti-trastuzumab emtansine antibodies. In the EMILIA study (TDM4370g/BO21977),5.2% (24/466) of patients tested positive for anti-trastuzumab emtansine antibodies, of which 13 werealso positive for neutralising antibodies. In the KATHERINE (BO27938) study, 4.0% (16/401) ofpatients tested positive for anti-trastuzumab emtansine antibodies, of which 5 were also positive forneutralizing antibodies. Due to the low occurrence of anti-drug antibodies, the effect of theseantibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of trastuzumabemtansine is unknown.

Reactions secondary to extravasation have been observed in clinical studies with trastuzumabemtansine. These reactions were usually mild or moderate and comprised erythema, tenderness, skinirritation, pain, or swelling at the infusion site. These reactions have been observed more frequentlywithin 24 hours of infusion. In the post-marketing setting, cases of epidermal injury or necrosisfollowing extravasation have been exceptionally observed within days to weeks after infusion.

Specific treatment for trastuzumab emtansine extravasation is unknown at this time (see section 4.4).

Tables 4 and 5 displays laboratory abnormalities observed in patients treated with trastuzumabemtansine in clinical study TDM4370g/BO21977/EMILIA and study BO27938/KATHERINE.

Table 4 Laboratory abnormalities observed in patients treated with trastuzumab emtansinein study TDM4370g/BO21977/EMILIA

Trastuzumab emtansine (N = 490)

All

Parameter Grades (%) Grade 3 (%) Grade 4 (%)

Hepatic

Increased bilirubin 21 < 1 0

Increased AST 98 8 < 1

Increased ALT 82 5 < 1

Haematologic

Decreased platelet count 85 14 3

Decreased haemoglobin 63 5 1

Decreased neutrophils 41 4 < 1

Decreased potassium 35 3 < 1

Table 5 Laboratory abnormalities observed in patients treated with trastuzumab emtansinein study BO27938/KATHERINE

Trastuzumab emtansine (N = 740)

Parameter All Grade % Grade 3 (%) Grade 4 (%)

Hepatic

Increased bilirubin 11 0 0

Increased AST 79 < 1 0

Increased ALT 55 < 1 0

Haematologic

Decreased platelet count 51 4 2

Decreased haemoglobin 31 1 0

Decreased neutrophils 24 1 0

Decreased potassium 26 2 < 1

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no known antidote for trastuzumab emtansine overdose. In case of overdose, the patientshould be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatictreatment instituted. Cases of overdose have been reported with trastuzumab emtansine treatment,most associated with thrombocytopenia, and there was one death. In the fatal case, the patientincorrectly received trastuzumab emtansine 6 mg/kg and died approximately 3 weeks following theoverdose; a causal relationship to trastuzumab emtansine was not established.

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, antineoplastic agents,monoclonal antibodies and antibody drug conjugates, HER2 inhibitors, ATC code: L01FD03

Kadcyla, trastuzumab emtansine, is a HER2-targeted antibody-drug conjugate which contains thehumanised anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitor DM1 (amaytansine derivative) via the stable thioether linker

MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate). Emtansine refers to the MCC-DM1complex. An average of 3.5 DM1 molecules are conjugated to each molecule of trastuzumab.

Conjugation of DM1 to trastuzumab confers selectivity of the cytotoxic agent for

HER2-overexpressing tumour cells, thereby increasing intracellular delivery of DM1 directly tomalignant cells. Upon binding to HER2, trastuzumab emtansine undergoes receptor-mediatedinternalisation and subsequent lysosomal degradation, resulting in release of DM1-containingcytotoxic catabolites (primarily lysine-MCC-DM1).

Trastuzumab emtansine has the mechanisms of action of both trastuzumab and DM1:

* Trastuzumab emtansine, like trastuzumab, binds to domain IV of the HER2 extracellular domain(ECD), as well as to Fcγ receptors and complement C1q. In addition, trastuzumab emtansine, liketrastuzumab, inhibits shedding of the HER2 ECD, inhibits signalling through thephosphatidylinositol 3-kinase (PI3-K) pathway, and mediates antibody-dependent cell-mediatedcytotoxicity (ADCC) in human breast cancer cells that overexpress HER2.

* DM1, the cytotoxic component of trastuzumab emtansine, binds to tubulin. By inhibiting tubulinpolymerisation, both DM1 and trastuzumab emtansine cause cells to arrest in the G2/M phase ofthe cell cycle, ultimately leading to apoptotic cell death. Results from in vitro cytotoxicity assaysshow that DM1 is 20-200 times more potent than taxanes and vinca alkaloids.

* The MCC linker is designed to limit systemic release and increase targeted delivery of DM1, asdemonstrated by detection of very low levels of free DM1 in plasma.

Early Breast Cancer

BO27938 (KATHERINE)

BO27938 (KATHERINE) was a randomised, multicentre, open-label trial of 1486 patients with

HER2-positive, early breast cancer with residual invasive tumour (patients who had not achievedpathological complete response (pCR)) in the breast and/or axillary lymph nodes following completionof preoperative systemic therapy that included chemotherapy and HER2-targeted therapy. Patientsmay have received more than one HER2-targeted therapy. Patients received radiotherapy and/orhormonal therapy concurrent with study treatment as per local guidelines. Breast tumour samples wererequired to show HER2 overexpression defined as 3+ IHC or ISH amplification ratio ≥ 2.0 determinedat a central laboratory. Patients were randomised (1:1) to receive trastuzumab or trastuzumabemtansine. Randomisation was stratified by clinical stage at presentation (operable vs. inoperable),hormone receptor status, preoperative HER2-directed therapy (trastuzumab, trastuzumab plusadditional HER2-directed agent[s]), and pathological nodal status evaluated after preoperative therapy.

Trastuzumab emtansine was given intravenously at 3.6 mg/kg on Day 1 of a 21-day cycle.

Trastuzumab was given intravenously at 6 mg/kg on Day 1 of a 21-day cycle. Patients were treatedwith trastuzumab emtansine or trastuzumab for a total of 14 cycles unless there was recurrence ofdisease, withdrawal of consent, or unacceptable toxicity, whichever occurred first. Patients whodiscontinued trastuzumab emtansine could complete the duration of their intended study treatment upto 14 cycles of HER2-directed therapy with trastuzumab if appropriate based on toxicityconsiderations and investigator discretion.

The primary efficacy endpoint of the study was Invasive Disease-Free Survival (IDFS). IDFS wasdefined as the time from the date of randomisation to first occurrence of ipsilateral invasive breasttumour recurrence, ipsilateral local or regional invasive breast cancer recurrence, distant recurrence,contralateral invasive breast cancer, or death from any cause. Additional endpoints included IDFSincluding second primary non-breast cancer, disease-free survival (DFS), overall survival (OS), anddistant recurrence-free interval (DRFI).

Patient demographics and baseline tumour characteristics were balanced between treatment arms. Themedian age was approximately 49 years (range 23-80 years), 72.8% were White, 8.7% were Asian and2.7% were Black or African American. All but 5 patients were women; 3 men were included in thetrastuzumab arm and 2 in the trastuzumab emtansine arm. 22.5 percent of patients were enrolled in

North America, 54.2% in Europe and 23.3% throughout the rest of the world. Tumour prognosticcharacteristics including hormone receptor status (positive: 72.3%, negative: 27.7%), clinical stage atpresentation (inoperable: 25.3%, operable: 74.8%) and pathological nodal status after preoperativetherapy (node positive: 46.4%, node negative or not evaluated: 53.6%) were similar in the study arms.

The majority of the patients (76.9%) had received an anthracycline-containing neoadjuvantchemotherapy regimen.19.5% percent of patients received another HER2-targeted agent in addition totrastuzumab as a component of neoadjuvant therapy; 93.8% of these patients received pertuzumab. Allof the patients had received taxanes as part of neoadjuvant chemotherapy.

At the time of primary analysis, a statistically significant improvement in IDFS was observed inpatients who received trastuzumab emtansine compared with trastuzumab, see Table 6.

The final descriptive IDFS analysis was conducted when 385 IDFS events had been observed andshowed results which are consistent with the primary analysis (HR = 0.54, 95% CI: 0.44 - 0.66), see

Figure 1. The second interim OS analysis was performed after a median follow-up of 101 months andshowed a statistically significant improvement in OS in patients who received trastuzumab emtansinecompared with trastuzumab (unstratified HR = 0.66, 95% CI: 0.51 - 0.87, p = 0.0027). See Table 6and Figure 2.

Table 6 Summary of efficacy from study BO27938 (KATHERINE)

Trastuzumab

Trastuzumab Emtansine

N = 743 N = 743

Primary Endpoint

Invasive Disease-Free Survival (IDFS) 1,3

Number (%) of patients with event 165 (22.2%) 91 (12.2%)

HR [95% CI] 0.50 [0.39, 0.64]p-value (Log-Rank test, unstratified) < 0.00013 year event-free rate2,% [95% CI] 77.02 [73.78, 80.26] 88.27 [85.81, 90.72]

Secondary Endpoints3

Overall Survival (OS) 4

Number (%) of patients with event 126 (17.0%) 89 (12.0%)

HR [95% CI] 0.66 [0.51, 0.87]p-value (Log-Rank test, unstratified) 0.00277 year survival rate2,% [95% CI] 84.4 [81.58, 87.16] 89.1 [86.71, 91.42]

IDFS including second primary non-breastcancer1,5

Number (%) of patients with event 167 (22.5%) 95 (12.8%)

HR [95% CI] 0.51 [0.40, 0.66]p-value (Log-Rank test, unstratified) < 0.00013 year event-free rate2,% [95% CI] 76.9 [73.65, 80.14] 87.7 [85.18, 90.18]

Disease-Free Survival (DFS)1,5

Number (%) of patients with event 167 (22.5%) 98 (13.2%)

HR [95% CI] 0.53 [0.41, 0.68]p-value (Log-Rank test, unstratified) < 0.00013 year event-free rate2,% [95% CI] 76.9 [73.65, 80.14] 87.41 [84.88, 89.93]

Distant recurrence-free interval (DRFI)1,5

Number (%) of patients with event 121 (16.3%) 78 (10.5%)

HR [95% CI] 0.60 [0.45, 0.79]p-value (Log-Rank test, unstratified) 0.00033 year event-free rate2,% [95% CI] 83.0 [80.10, 85.92] 89.7 [87.37, 92.01]

Key to abbreviations (Table6): HR: Hazard Ratio; CI: Confidence Intervals,1. Data from primary analysis2. 3 year event-free rate and 7 year survival rate derived from Kaplan-Meier estimates3. Hierarchical testing applied for IDFS and OS4. Data from second interim OS analysis5. These secondary endpoints were not adjusted for multiplicity

Figure 1 Kaplan-Meier Curve of Invasive Disease-Free Survival in KATHERINE (Updated

Analysis)1.00.80.60.40.2

Trastuzumab Trastuzumab Emtansine

Trastuzumab (N=743) (N = 743) (N=743)

Trastuzumab Emtansine (N=743) 7-Year IDFS

Censored0.0 Event Free Rate 67.1% 80.8%0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120

No. of pa�ents atrisk Time (months)

Trastuzumab 743 677 636 595 556 540 511 495 485 475 460 444 431 421 397 368 238 187 74 42 2

Pa�ents with IDFS event 0 22 54 84 115 131 156 169 175 182 188 200 204 210 220 229 235 239 239 239 239

Pa�ents censored 0 44 53 64 72 72 76 79 83 86 95 99 108 112 126 146 270 317 430 462 502

Trastuzumab Emtansine 743 708 682 658 637 620 605 591 574 561 548 537 521 516 481 443 281 236 89 50 3

Pa�ents with IDFS event 0 7 23 44 57 70 81 88 98 104 108 116 124 126 131 137 141 142 145 146 146

Pa�ents censored 0 28 38 41 49 53 57 64 71 78 87 90 98 101 131 163 321 365 509 547 594

Figure 2 Kaplan-Meier Curve of Overall Survival in KATHERINE (Updated Analysis)1.00.80.60.40.2

Trastuzumab (N=743)

Trastuzumab Emtansine (N=743)0.0 Censored0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120

No. of pa�ents at risk Time (months)

Trastuzumab 743 696 677 661 643 625 616 600 586 576 558 549 543 532 511 490 374 280 146 72 9

Pa�ents with OS event 0 1 7 16 22 36 43 53 62 68 81 90 92 95 102 110 117 125 126 126 126

Pa�ents censored 0 46 59 66 78 82 84 90 96 99 104 104 108 116 130 143 252 338 471 545 608

Trastuzumab Emtansine 743 719 702 695 675 662 649 642 626 614 604 597 585 576 554 530 394 312 158 93 14

Pa�ents with OS event 0 1 3 8 21 26 34 39 46 53 59 59 64 69 74 83 86 88 89 89 89

Pa�ents censored 0 23 38 40 47 55 60 62 71 76 80 87 94 98 115 130 263 343 496 561 640

In KATHERINE, consistent treatment benefit of trastuzumab emtansine for IDFS was seen in all thepre-specified subgroups evaluated, supporting the overall result.

Propor�on event free Propor�on event free

Metastatic Breast Cancer

TDM4370g/BO21977(EMILIA)

A Phase III, randomised, multicentre, international, open-label clinical study was conducted in patientswith HER2-positive unresectable locally advanced breast cancer (LABC) or MBC who had receivedprior taxane and trastuzumab-based therapy, including patients who received prior therapy withtrastuzumab and a taxane in the adjuvant setting and who relapsed during or within six months ofcompleting adjuvant therapy. Only patients with Eastern Cooperative Oncology Group (ECOG)

Performance Status 0 or 1 were eligible. Prior to enrolment, breast tumour samples were required to becentrally confirmed for HER2-positive status defined as a score of 3 + by IHC or gene amplificationby ISH. Baseline patient and tumour characteristics were well balanced between treatment groups.

Patients with treated brain metastases were eligible for enrollment if they did not require therapy tocontrol symptoms. For patients randomised to trastuzumab emtansine, the median age was 53 years,most patients were female (99.8%), the majority were Caucasian (72%), and 57% hadoestrogen-receptor and/or progesterone-receptor positive disease. The study compared the safety andefficacy of trastuzumab emtansine with that of lapatinib plus capecitabine. A total of 991 patients wererandomised to trastuzumab emtansine or lapatinib plus capecitabine as follows:

* Trastuzumab emtansine arm: trastuzumab emtansine 3.6 mg/kg intravenously over 30-90 minuteson Day 1 of a 21-day cycle

* Control arm (lapatinib plus capecitabine): lapatinib 1250 mg/day orally once per day of a 21-daycycle plus capecitabine 1000 mg/m2 orally twice daily on Days 1-14 of a 21-day cycle

The co-primary efficacy endpoints of the study were progression-free survival (PFS) as assessed by anindependent review committee (IRC) and overall survival (OS) (see Table 7 and Figures 3 to 4).

Time to symptom progression, as defined by a 5-point decrease in the score derived from the Trials

Outcome Index-Breast (TOI-B) subscale of the Functional Assessment of Cancer Therapy-Breast

Quality of Life (FACT-B QoL) questionnaire was also assessed during the clinical study. A change of5 points in the TOI-B is considered clinically significant. Kadcyla delayed patient-reported time tosymptom progression for 7.1 months compared with 4.6 months for the control arm (Hazard Ratio0.796 (0.667, 0.951); p-value 0.0121). The data are from an open-label study and no firm conclusionscan be drawn.

Table 7 Summary of efficacy from study TDM4370g/BO21977 (EMILIA)

Trastuzumab

Lapatinib + Capecitabine emtansinen = 496 n = 495

Primary endpoints

IRC-assessed progression-free survival(PFS)

Number (%) of patients with event 304 (61.3%) 265 (53.5%)

Median duration of PFS (months) 6.4 9.6

Hazard ratio (stratified*) 0.65095% CI for Hazard ratio (0.549, 0.771)p-value (Log-rank test, stratified*) < 0.0001

Overall Survival (OS)**

Number (%) of patients who died 182 (36.7%) 149 (30.1%)

Median duration of survival (months) 25.1 30.9

Hazard ratio (stratified*) 0.68295% CI for Hazard ratio (0.548, 0.849)p-value (Log-rank test*) 0.0006

Key secondary endpoints

Investigator-assessed PFS

Number (%) of patients with event 335 (67.5%) 287 (58.0%)

Median duration of PFS (months) 5.8 9.4

Hazard ratio (95% CI) 0.658 (0.560, 0.774)p-value (Log-rank test*) < 0.0001

Objective response rate (ORR)

Patients with measurable disease 389 397

Number of patients with OR (%) 120 (30.8%) 173 (43.6%)

Difference (95% CI) 12.7% (6.0, 19.4)p-value (Mantel-Haenszel chi-squared 0.0002test*)

Duration of objective response(months)

Number of patients with OR 120 173

Median 95% CI 6.5 (5.5, 7.2) 12.6 (8.4, 20.8)

OS: overall survival; PFS: progression-free survival; ORR: objective response rate; OR: objectiveresponse; IRC: independent review committee; HR: hazard ratios; CI: confidence interval

* Stratified by: world region (United States, Western Europe, other), number of priorchemotherapeutic regimens for locally advanced or metastatic disease (0-1 vs. > 1), and visceral vs.non-visceral disease.

** The interim analysis for OS was conducted when 331 events were observed. Since the efficacyboundary was crossed at this analysis, this is considered the definitive analysis.

A treatment benefit was seen in the subgroup of patients who had relapsed within 6 months ofcompleting adjuvant treatment and had not received any prior systemic anti-cancer therapy in themetastatic setting (n = 118); hazard ratios for PFS and OS were 0.51 (95% CI: 0.30, 0.85) and 0.61(95% CI: 0.32, 1.16), respectively. The median PFS and OS for the trastuzumab emtansine group were10.8 months and not reached, respectively, compared with 5.7 months and 27.9 months, respectively,for the lapatinib plus capecitabine group.

Figure 3 Kaplan-Meier curve of IRC-assessed progression-free survival

Figure 4 Kaplan-Meier curve of overall survival

In study TDM4370g/BO21977, consistent treatment benefit of trastuzumab emtansine was seen in themajority of pre-specified subgroups evaluated, supporting the robustness of the overall result. In thesubgroup of patients with hormone receptor-negative disease (n = 426), the hazard ratios for PFS and

OS were 0.56 (95% CI: 0.44, 0.72) and 0.75 (95% CI: 0.54, 1.03), respectively. In the subgroup ofpatients with hormone receptor-positive disease (n = 545), the hazard ratios for PFS and OS were 0.72(95% CI: 0.58, 0.91) and 0.62 (95% CI: 0.46, 0.85), respectively.

In the subgroup of patients with non-measurable disease (n = 205), based on IRC assessments, thehazard ratios for PFS and OS were 0.91 (95% CI: 0.59, 1.42) and 0.96 (95% CI: 0.54, 1.68),respectively. In patients ≥ 65 years old (n = 138 across both treatment arms) the hazard ratios forprogression-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. In patients 65 to 74 years old (n = 113), based on IRC assessments,the hazard ratios for PFS and OS were 0.88 (95% CI: 0.53, 1.45) and 0.74 (95% CI: 0.37, 1.47),respectively. For patients 75 years or above, based on IRC assessments, the hazard ratios for PFS and

OS were 3.51 (95% CI: 1.22, 10.13) and 3.45 (95% CI: 0.94, 12.65), respectively. The subgroup ofpatients 75 years or above did not demonstrate a benefit for PFS or OS, but was too small (n = 25) todraw any definitive conclusions.

In the descriptive follow-up overall survival analysis, the hazard ratio was 0.75 (95% CI 0.64, 0.88).

The median duration of overall survival was 29.9 months in the trastuzumab emtansine arm comparedwith 25.9 months in the lapatinib plus capecitabine arm. At the time of the descriptive follow-upoverall survival analysis, a total of 27.4% of the patients had crossed over from the lapatinib pluscapecitabine arm to the trastuzumab emtansine arm. In a sensitivity analysis censoring patients at thetime of cross-over, the hazard ratio was 0.69 (95% CI 0.59, 0.82). The results of this descriptivefollow-up analysis are consistent with the confirmatory OS analysis.

TDM4450g

A randomised, multicentre, open-label phase II study evaluated the effects of trastuzumab emtansineversus trastuzumab plus docetaxel in patients with HER2-positive MBC who had not received priorchemotherapy for metastatic disease. Patients were randomised to receive trastuzumab emtansine3.6 mg/kg intravenously every 3 weeks (n = 67) or trastuzumab 8 mg/kg intravenous loading dosefollowed by 6 mg/kg intravenously every 3 weeks plus docetaxel 75-100 mg/m2 intravenously every3 weeks (n = 70).

The primary endpoint was investigator assessed Progression-Free Survival (PFS). The median PFSwas 9.2 months in the trastuzumab plus docetaxel arm and 14.2 months in the trastuzumab emtansinearm (hazard ratio, 0.59; p = 0.035), with a median follow-up of approximately 14 months in both arms.

The objective response rate (ORR) was 58.0% with trastuzumab plus docetaxel and 64.2% withtrastuzumab emtansine. The median duration of response was not reached with trastuzumab emtansinevs. 9.5 months in the control arm.

TDM4374g

A Phase II, single-arm, open-label study evaluated the effects of trastuzumab emtansine in patientswith HER2-positive incurable, LABC or MBC. All patients were previously treated with

HER2-directed therapies (trastuzumab and lapatinib), and chemotherapy (anthracycline, taxane, andcapecitabine) in the neoadjuvant, adjuvant, locally advanced, or metastatic setting. The mediannumber of anti-cancer agents that patients had received in any setting was 8.5 (range, 5-19) and in themetastatic setting was 7.0 (range, 3-17), including all agents intended for the treatment of breastcancer.

Patients (n = 110) received 3.6 mg/kg of trastuzumab emtansine intravenously every 3 weeks untildisease progression or unacceptable toxicity.

The key efficacy analyses were ORR based on independent radiologic review and duration ofobjective response. The ORR was 32.7% (95% CI: 24.1, 42.1), n = 36 responders, by both IRC andinvestigator review. The median duration of response by IRC was not reached (95% CI, pct. 4.6 months tonot estimable).

The European Medicines Agency has waived the obligation to submit the results of studies withtrastuzumab emtansine in all subsets of the paediatric population in breast cancer (see section 4.2 forinformation on paediatric use).

The population pharmacokinetic analysis suggested no difference in trastuzumab emtansine exposurebased on disease status (adjuvant vs. metastatic setting).

Trastuzumab emtansine is administered intravenously. There have been no studies performed withother routes of administration.

Patients in Study TDM4370g/BO21977 and Study BO29738 who received 3.6 mg/kg of trastuzumabemtansine intravenously every 3 weeks had a mean Cycle 1 maximum serum concentration (Cmax) oftrastuzumab emtansine of 83.4 (± 16.5) µg/mL and 72.6 (± 24.3) µg/mL, respectively. Based onpopulation PK analysis, following intravenous administration, the central volume of distribution oftrastuzumab emtansine was (3.13 L) and approximated that of plasma volume.

Biotransformation (trastuzumab emtansine and DM1)

Trastuzumab emtansine is expected to undergo deconjugation and catabolism by means of proteolysisin cellular lysosomes.

In vitro metabolism studies in human liver microsomes suggest that DM1, a small moleculecomponent of trastuzumab emtansine, is metabolised mainly by CYP3A4 and to a lesser extent by

CYP3A5. DM1 did not inhibit major CYP450 enzymes in vitro. In human plasma, trastuzumabemtansine catabolites MCC-DM1, Lys-MCC-DM1, and DM1 were detected at low levels. In vitro,

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

Based on population pharmacokinetic (PK) analysis, following intravenous administration oftrastuzumab emtansine in patients with HER2-positive metastatic breast cancer, the clearance oftrastuzumab emtansine was 0.68 L/day and the elimination half-life (t1/2) was approximately 4 days.

No accumulation of trastuzumab emtansine was observed after repeated dosing of intravenous infusionevery 3 weeks.

Based on population PK analysis, body weight, albumin, sum of longest diameter of target lesions by

Response Evaluation Criteria In Solid Tumours (RECIST), HER2 shed extracellular domain (ECD),baseline trastuzumab concentrations, and aspartate aminotransferase (AST) were identified asstatistically significant covariates for trastuzumab emtansine PK parameters. However, the magnitudeof effect of these covariates on trastuzumab emtansine exposure suggests that these covariates areunlikely to have any clinically meaningful effect on trastuzumab emtansine exposure. In addition,exploratory analysis showed that the impact of covariates (i.e., renal function, race and age) on thepharmacokinetics of total trastuzumab and DM1 was limited and was not clinically relevant. Innon-clinical studies, trastuzumab emtansine catabolites including DM1, Lys-MCC-DM1, and

MCC-DM1 are mainly excreted in the bile with minimal elimination in urine.

Linearity/non linearity

Trastuzumab emtansine when administered intravenously every 3 weeks exhibited linear PK acrossdoses ranging from 2.4 to 4.8 mg/kg; patients who received doses less than or equal to 1.2 mg/kg hadfaster clearance.

The population PK analysis showed that age did not affect the PK of trastuzumab emtansine. Nosignificant difference was observed in the PK of trastuzumab emtansine among patients < 65 years(n = 577), patients between 65-75 years (n = 78) and patients > 75 years (n = 16).

No formal PK study has been conducted in patients with renal impairment. The population PKanalysis showed that creatinine clearance does not affect the PK of trastuzumab emtansine.

Pharmacokinetics of trastuzumab emtansine in patients with mild (creatinine clearance CLcr 60 to89 mL/min, n = 254) or moderate (CLcr 30 to 59 mL/min, n = 53) renal impairment were similar tothose in patients with normal renal function (CLcr ≥ 90 mL/min, n = 361). Pharmacokinetic data inpatients with severe renal impairment (CLcr 15 to 29 mL/min) are limited (n = 1), therefore noposology recommendations can be made.

The liver is a primary organ for eliminating DM1 and DM1-containing catabolites. Thepharmacokinetics of trastuzumab emtansine and DM1-containing catabolites were evaluated after theadministration of 3.6 mg/kg of trastuzumab emtansine to metastatic HER2+ breast cancer patients withnormal 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 trastuzumab emtansine at Cycle 1 in patients with mild and moderatehepatic impairment were approximately 38% and 67% lower than that of patients with normal hepaticfunction, respectively. Trastuzumab emtansine exposure (AUC) at Cycle 3 after repeated dosing inpatients with mild or moderate hepatic dysfunction was within the range observed in patients withnormal hepatic function.

No formal pharmacokinetic study has been conducted and no population PK data was collected inpatients with severe hepatic impairment (Child-Pugh class C).

The population PK analysis showed that race did not appear to influence the PK of trastuzumabemtansine. Because most of the patients in trastuzumab emtansine clinical studies were females, theeffect of gender on the PK of trastuzumab emtansine was not formally evaluated.

Administration of trastuzumab emtansine was well tolerated in rats and monkeys at doses up to 20 and10 mg/kg, respectively, corresponding to 2040 µg DM1/m2 in both species, which is approximatelyequivalent to the clinical dose of trastuzumab emtansine in patients. In the GLP toxicity studies, withthe exception of irreversible peripheral axonal toxicity (observed only in monkeys at ≥ 10 mg/kg) andreproductive organ toxicity (observed only in rats at 60 mg/kg), partially or completely reversible dosedependent toxicities were identified in both animal models. Principal toxicities included liver (liverenzyme elevations) at ≥ 20 mg/kg and ≥ 10 mg/kg, bone marrow (reduced platelet and white bloodcell count)/haematologic at ≥ 20 mg/kg and ≥ 10 mg/kg, and lymphoid organs at ≥ 20 mg/kgand ≥ 3 mg/kg, in rat and monkey, respectively.

DM1 was aneugenic or clastogenic in an in vivo single-dose rat bone marrow micronucleus assay atexposures that were comparable to mean maximum concentrations of DM1 measured in humansadministered trastuzumab emtansine. DM1 was not mutagenic in an in vitro bacterial reverse mutation(Ames) assay.

Impairment of fertility and teratogenicity

No fertility studies in animals have been performed to evaluate the effect of trastuzumab emtansine.

However, based on results from general animal toxicity studies, adverse effects on fertility can beexpected.

Dedicated embryo-foetal development studies have not been conducted in animals with trastuzumabemtansine. Developmental toxicity of trastuzumab has been identified in the clinical setting although itwas not predicted in the non-clinical program. In addition, developmental toxicity of maytansine hasbeen identified in non-clinical studies which suggests that DM1, the microtubule-inhibiting cytotoxicmaytansinoid component of trastuzumab emtansine, will be similarly teratogenic and potentiallyembryotoxic.

Succinic acid

Sodium hydroxide

Sucrose

Polysorbate 20

This medicinal product must not be mixed or diluted with other medicinal products except thosementioned in section 6.6.

Glucose (5%) solution should not be used for reconstitution or dilution since it causes aggregation ofthe protein.

Unopened vial4 years.

Chemical and physical in-use stability of the reconstituted solution has been demonstrated for up to24 hours at 2 °C to 8 °C. From a microbiological point of view, the product should be usedimmediately. If not used immediately, the reconstituted vials can be stored for up to 24 hours at2 °C to 8 °C, provided it was reconstituted under controlled and validated aseptic conditions, and mustbe discarded thereafter.

The reconstituted Kadcyla solution diluted in infusion bags containing sodium chloride 9 mg/mL(0.9%) solution for infusion, or sodium chloride 4.5 mg/mL (0.45%) solution for infusion, is stable forup to 24 hours at 2 °C to 8 °C, provided it was prepared under controlled and validated asepticconditions. Particulates may be observed on storage if diluted in 0.9% sodium chloride(see section 6.6).

Store in a refrigerator (2°C - 8°C).

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

Kadcyla 100 mg powder for concentrate for solution for infusion

Kadcyla is provided in 15 mL (100 mg) Type 1 glass vial closed with a grey-butyl rubber stoppercoated with fluoro-resin laminate, and sealed with an aluminium seal with a white plastic flip-off cap.

Pack of 1 vial.

Kadcyla 160 mg powder for concentrate for solution for infusion

Kadcyla is provided in 20 mL (160 mg) Type 1 glass vial closed with a grey-butyl rubber stoppercoated with fluoro resin laminate, and sealed with an aluminium seal with a purple plastic flip-off cap.

Pack of 1 vial.

Appropriate aseptic technique should be used. Appropriate procedures for the preparation ofchemotherapeutic medicinal products should be used.

The reconstituted Kadcyla solution should be diluted in polyvinyl chloride (PVC) or latex-free

PVC-free polyolefin infusion bags.

The use of 0.20 or 0.22 micron in-line polyethersulfone (PES) filter is required for the infusion whenthe concentrate for infusion is diluted with sodium chloride 9 mg/mL (0.9%) solution for infusion.

In order to prevent medicinal product errors it is important to check the vial labels to ensure that themedicinal product being prepared is Kadcyla (trastuzumab emtansine) and not another trastuzumab-containing product (e.g. trastuzumab or trastuzumab deruxtecan).

* 100 mg trastuzumab emtansine vial: Using a sterile syringe, slowly inject 5 mL of sterile water forinjection into the vial.

* 160 mg trastuzumab emtansine vial: Using a sterile syringe, slowly inject 8 mL of sterile water forinjection into the vial.

* Swirl the vial gently until completely dissolved. Do not shake.

Reconstituted solution should be inspected visually for particulate matter and discolouration prior toadministration. The reconstituted solution should be free of visible particulates, clear to slightlyopalescent. The colour of the reconstituted solution should be colourless to pale brown. Do not use ifthe reconstituted solution contains visible particulates, or is cloudy or discoloured.

Determine the volume of the reconstituted solution required based on a dose of 3.6 mg trastuzumabemtansine/kg body weight (see section 4.2):

Volume (mL) = Total dose to be administered (body weight (kg) x dose (mg/kg))20 (mg/mL, concentration of reconstituted solution)

The appropriate amount of solution should be withdrawn from the vial and added to an infusion bagcontaining 250 mL of sodium chloride 4.5 mg/mL (0.45%) solution for infusion or sodium chloride9 mg/mL (0.9%) solution for infusion. Glucose (5%) solution should not be used (see section 6.2).

Sodium chloride 4.5 mg/mL (0.45%) solution for infusion may be used without a polyethersulfone(PES) 0.20 or 0.22-μm in-line filter. If sodium chloride 9 mg/mL (0.9%) solution for infusion is usedfor infusion, a 0.20 or 0.22 micron in-line polyethersulfone (PES) filter is required. Once the infusionis prepared it should be administered immediately. Do not freeze or shake the infusion during storage.

The reconstituted product contains no preservative and is intended for single use only. Discard anyunused portion.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/13/885/001

EU/1/13/885/002

Date of first authorisation: 15 November 2013

Date of latest renewal: 17 September 2018

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.