Kadcyla

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Kadcyla 100 mg powder for concentrate for solution for infusion. 
Kadcyla 160 mg powder for concentrate for solution for infusion. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Kadcyla 100 mg powder for concentrate for solution for infusion 
One vial of powder for concentrate for solution for infusion contains 100 mg of trastuzumab 
emtansine. After reconstitution one vial of 5 mL solution contains 20 mg/mL of trastuzumab 
emtansine (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 trastuzumab 
emtansine. After reconstitution one vial of 8 mL solution contains 20 mg/mL of trastuzumab 
emtansine (see section 6.6). 
 
Trastuzumab emtansine is an antibody-drug conjugate that contains trastuzumab, a humanised IgG1 
monoclonal 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). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for concentrate for solution for infusion. 
 
White to off-white lyophilised powder. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Early Breast Cancer (EBC) 
Kadcyla, as a single agent, is indicated for the adjuvant treatment of adult patients with HER2-positive 
early breast cancer who have residual invasive disease, in the breast and/or lymph nodes, after 
neoadjuvant 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 a 
taxane, 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. 

 
4.2 Posology and method of administration 
 
Kadcyla should only be prescribed by a physician and administered as an intravenous infusion under 
the 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 full 
resuscitation facilities are immediately available (see section 4.4)). 
 



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Patients treated with trastuzumab emtansine should have HER2 positive tumour status, defined as a 
score of 3 + by immunohistochemistry (IHC) or a ratio of ≥ 2.0 by in situ hybridization (ISH) or by 
fluorescence in situ hybridization (FISH) assessed by a CE-marked In Vitro Diagnostic (IVD) medical 
device. If a CE-marked IVD is not available, the HER2-status should be assessed by an alternate 
validated test.  
 
In order to prevent medicinal product errors it is important to check the vial labels to ensure that the 
medicinal product being prepared and administered is Kadcyla (trastuzumab emtansine) and not 
Herceptin (trastuzumab). 
 
Posology 
 
The recommended dose of trastuzumab emtansine is 3.6 mg/kg bodyweight administered as an 
intravenous infusion every 3 weeks (21-day cycle).  
 
The initial dose should be administered as a 90 minute intravenous infusion. Patients should be 
observed 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 possible 
subcutaneous infiltration during administration (see section 4.8). 
 
If the prior infusion was well tolerated, subsequent doses of trastuzumab emtansine may be 
administered as 30 minute infusions. Patients should be observed during the infusion and for at least 
30 minutes after infusion. 
 
The infusion rate of trastuzumab emtansine should be slowed or interrupted if the patient develops 
infusion-related symptoms (see sections 4.4 and 4.8). Trastuzumab emtansine should be discontinued 
in case of life-threatening infusion reactions. 
 
Duration of treatment 
 
Early Breast Cancer (EBC) 
Patients should receive treatment for a total of 14 cycles unless there is disease recurrence or 
unmanageable toxicity. 
 
Metastatic Breast Cancer (MBC) 
Patients should receive treatment until disease progression or unmanageable toxicity. 
Dose modification 
Management of symptomatic adverse reactions may require temporary interruption, dose reduction, or 
treatment 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 
 



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Table 2 Dose Modification Guidelines 
  

Dose Modifications for Patients with EBC 
Adverse reaction Severity Treatment modification 
Thrombocytopenia Grade 2-3 on day of 

scheduled treatment 
(25,000 to < 
75,000/mm3) 

Do not administer trastuzumab emtansine until 
platelet count recovers to £ Grade 1 (≥ 
75,000/mm3), and then treat at the same dose level. 
If a patient requires 2 delays due to 
thrombocytopenia, consider reducing dose by one 
level. 

Grade 4 at any time 
< 25,000/mm3 

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

Increased Alanine 
Transaminase (ALT) 

Grade 2-3 
(> 3.0 to ≤ 20¥ ULN on 
day of scheduled 
treatment) 

Do not administer trastuzumab emtansine until 
ALT recovers to Grade ≤ 1, and then reduce one 
dose level 

Grade 4 
(> 20 ¥ ULN at any 
time) 

Discontinue trastuzumab emtansine 

Increased Aspartate 
Transaminase (AST) 

Grade 2  
(> 3.0 to ≤ 5¥ ULN on 
day of scheduled 
treatment)  

Do not administer trastuzumab emtansine until 
AST recovers to Grade £ 1, and then treat at the 
same dose level 

Grade 3  
(> 5 to ≤ 20¥ ULN on 
day of scheduled 
treatment)  

Do not administer trastuzumab emtansine until 
AST recovers to Grade ≤ 1, and then reduce one 
dose level 

Grade 4  
(> 20 ¥ ULN at any 
time)  

Discontinue trastuzumab emtansine 

Hyperbilirubinemia TBILI  
> 1.0 to ≤ 2.0¥ the ULN 
on day of scheduled 
treatment  

Do not administer trastuzumab emtansine until total 
bilirubin recovers to ≤ 1.0× ULN, and then reduce 
one dose level 

TBILI  
> 2¥ ULN at any time  

Discontinue trastuzumab emtansine 

Drug Induced Liver 
Injury (DILI) 

Serum transaminases > 3 
x ULN and concomitant 
total bilirubin > 2¥ ULN 

Permanently discontinue trastuzumab emtansine in 
the absence of another likely cause for the elevation 
of liver enzymes and bilirubin, e.g. liver metastasis 
or concomitant medication 

Nodular Regenerative 
Hyperplasia (NRH) 

All Grades Permanently discontinue trastuzumab emtansine 

Peripheral Neuropathy Grade 3-4 Do not administer trastuzumab emtansine until 
resolution £ Grade 2 



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Left Ventricular 
Dysfunction  

LVEF < 45% Do not administer trastuzumab emtansine . 
Repeat LVEF assessment within 3 weeks. If LVEF 
< 45% is confirmed, discontinue trastuzumab 
emtansine. 

LVEF 45% to < 50% 
and decrease is ≥ 10% 
points from baseline* 

Do not administer trastuzumab emtansine. 
Repeat LVEF assessment within 3 weeks. If the 
LVEF remains < 50% and has not recovered to < 
10% points from baseline, discontinue trastuzumab 
emtansine. 

LVEF 45% to < 50% 
and decrease is < 10% 
points from baseline* 

Continue treatment with trastuzumab emtansine.  
Repeat LVEF assessment within 3 weeks.  

LVEF ≥ 50% Continue treatment with trastuzumab emtansine 
Heart Failure 

Symptomatic CHF, 
Grade 3-4 LVSD or 
Grade 3-4 heart failure, 
or 
Grade 2 heart failure  
accompanied by LVEF 
<45%  

Discontinue trastuzumab emtansine 

Pulmonary Toxicity Interstitial lung disease 
(ILD) or pneumonitis 

Permanently discontinue trastuzumab emtansine 

Radiotherapy-Related 
Pneumonitis 

Grade 2 Discontinue trastuzumab emtansine if not resolving 
with standard treatment 

Grade 3-4 Discontinue trastuzumab emtansine 

Dose Modifications for Patients with MBC 

Adverse reaction Severity Treatment modification 

Thrombocytopenia Grade 3  
(25,000 to 
< 50,000/mm3) 

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

Grade 4 
(< 25,000/mm3) 

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

Increased Transaminase 
(AST/ALT) 

Grade 2 
(> 2.5 to ≤ 5¥ the ULN) 

Treat at the same dose level 
 

Grade 3 
(> 5 to ≤ 20¥ the ULN) 

Do not administer trastuzumab emtansine until 
AST/ALT recovers to Grade ≤ 2, and then reduce 
one dose level 

Grade 4 
(> 20¥ the ULN) 

Discontinue trastuzumab emtansine 



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Hyperbilirubinemia Grade 2 
(> 1.5 to ≤ 3¥ the ULN) 

Do not administer trastuzumab emtansine until 
total bilirubin recovers to Grade ≤ 1, and then treat 
at the same dose level. 

Grade 3 
(> 3 to ≤ 10¥ the ULN) 

Do not administer trastuzumab emtansine until 
total bilirubin recovers to Grade ≤ 1 and then 
reduce one dose level. 

Grade 4 
(> 10¥ the ULN) 

Discontinue trastuzumab emtansine 

Drug Induced Liver 
Injury (DILI) 

Serum transaminases > 3 
x ULN and concomitant 
total bilirubin > 2¥ ULN 

Permanently discontinue trastuzumab emtansine in 
the absence of another likely cause for the 
elevation of liver enzymes and bilirubin, e.g. liver 
metastasis or concomitant medication 

Left Ventricular 
Dysfunction  

Symptomatic CHF Discontinue trastuzumab emtansine 
LVEF <40% Do not administer trastuzumab emtansine. 

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

LVEF 40% to ≤ 45% 
and decrease is ≥ 10% 
points from baseline 

Do not administer trastuzumab emtansine. 
Repeat LVEF assessment within 3 weeks. If the 
LVEF has not recovered to within 10% points 
from baseline, discontinue trastuzumab emtansine. 

LVEF 40% to ≤ 45% 
and decrease is < 10% 
points from baseline 

Continue treatment with trastuzumab emtansine. 
Repeat LVEF assessment within 3 weeks. 

LVEF > 45% Continue treatment with trastuzumab emtansine. 

ALT = alanine transaminase; AST = aspartate transaminase, CHF = congestive heart failure, LVEF = left ventricular ejection 
fraction, LVSD = left ventricular systolic dysfunction, TBILI = Total Bilirubin, ULN = upper limit of normal 
* Prior to starting trastuzumab emtansine treatment.  
 
Delayed or missed dose 
If a planned dose is missed, it should be administered as soon as possible; without waiting until the 
next planned cycle. The schedule of administration should be adjusted to maintain a 3-week interval 
between doses. The next dose should be administered in accordance with the dosing recommendations 
above. 
 
Peripheral neuropathy 
Trastuzumab emtansine should be temporarily discontinued in patients experiencing Grade 3 or 4 
peripheral neuropathy until resolution to ≤ Grade 2. At retreatment a dose reduction may be 
considered according to the dose reduction schedule (see Table 1). 
 
Special populations 
 
Elderly patients  
No dose adjustment is required in patients aged ≥ 65 years. There are insufficient data to establish the 
safety and efficacy in patients ≥ 75 years due to limited data in this subgroup. Population 
pharmacokinetic analysis indicates that age does not have a clinically meaningful effect on the 
pharmacokinetics of trastuzumab emtansine (see sections 5.1 and 5.2). 
 



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Renal impairment 
No adjustment to the starting dose is needed in patients with mild or moderate renal impairment (see 
section 5.2). The potential need for dose adjustment in patients with severe renal impairment cannot be 
determined due to insufficient data and therefore patients with severe renal impairment should be 
monitored carefully. 
 
Hepatic impairment 
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 of 
patients with hepatic impairment should be undertaken with caution due to known hepatotoxicity 
observed with trastuzumab emtansine (see section 4.4 and 5.2). 
 
Paediatric population 
The safety and efficacy in children and adolescents below 18 years of age have not been established as 
there is no relevant use in the paediatric population for the indication of breast cancer .  
 
Method of administration 
 
Kadcyla is for intravenous use. Trastuzumab emtansine must be reconstituted and diluted by a 
healthcare professional and administered as an intravenous infusion. It must not be administered as an 
intravenous push or bolus. 
 
For instructions on reconstitution and dilution of the medicinal product before administration, see 
section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
In order to improve traceability of biological medicinal products, the tradename and the batch number 
of 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 the 
medicinal product being prepared and administered is Kadcyla (trastuzumab emtansine) and not 
Herceptin (trastuzumab). 
 
Thrombocytopenia 
Thrombocytopenia, or decreased platelet counts, was commonly reported with trastuzumab emtansine 
and was the most common adverse reaction leading to treatment discontinuation, dose reduction, and 
dose interruption (see section 4.8). In clinical studies, the incidence and severity of thrombocytopenia 
were 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 anti-coagulant treatment (e.g. 
warfarin, heparin, low molecular weight heparins) should be monitored closely while on trastuzumab 
emtansine 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 or 
greater (< 50,000/mm3), do not administer trastuzumab emtansine until platelet counts recover to 
Grade 1 (≥ 75,000/mm3) (see section 4.2).  
 
Haemorrhage 
Cases of haemorrhagic events, including central nervous system, respiratory and gastrointestinal 
haemorrhage, have been reported with trastuzumab emtansine treatment. Some of these bleeding 
events resulted in fatal outcomes. In some of the observed cases the patients had thrombocytopenia, or 
were also receiving anti-coagulant therapy or antiplatelet therapy; in others there were no known 



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additional risk factors. Use caution with these agents and consider additional monitoring when 
concomitant use is medically necessary. 
 
Hepatotoxicity 
Hepatotoxicity, predominantly in the form of asymptomatic increases in the concentrations of serum 
transaminases (Grade 1-4 transaminitis), has been observed during treatment with trastuzumab 
emtansine in clinical studies (see section 4.8). Transaminase elevations were generally transient with 
peak elevation at day 8 after administration of therapy and subsequent recovery to Grade 1 or less 
prior to the next cycle. A cumulative effect on transaminases has also been observed (the proportion of 
patients 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 of 
trastuzumab emtansine in the majority of the cases (see section 4.8).  
 
Serious hepatobiliary disorders, including nodular regenerative hyperplasia (NRH) of the liver and 
some with a fatal outcome due to drug-induced liver injury have been observed in patients treated with 
trastuzumab emtansine. Observed cases may have been confounded by comorbidities and/or 
concomitant medicinal products with known hepatotoxic potential. 
 
Liver function should be monitored prior to initiation of treatment and each dose. Patients with 
baseline elevation of ALT (e.g. due to liver metastases) may be predisposed to liver injury with a 
higher risk of a Grade 3-5 hepatic event or liver function test increase. Dose reductions or 
discontinuation 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 biopsies 
in patients treated with trastuzumab emtansine. NRH is a rare liver condition characterised by 
widespread benign transformation of hepatic parenchyma into small regenerative nodules; NRH may 
lead 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/or 
cirrhosis-like pattern seen on the computed tomography (CT) scan of the liver but with normal 
transaminases and no other manifestations of cirrhosis. Upon diagnosis of NRH, trastuzumab 
emtansine treatment must be permanently discontinued.  
 
Trastuzumab emtansine has not been studied in patients with serum transaminases > 2.5 ¥ ULN or 
total bilirubin > 1.5 ¥ ULN prior to initiation of treatment. Treatment in patients with serum 
transaminases > 3 ¥ ULN and concomitant total bilirubin > 2 ¥ ULN should be permanently 
discontinued. Treatment of patients with hepatic impairment should be undertaken with caution (see 
sections 4.2 and 5.2). 
 
Neurotoxicity 
Peripheral neuropathy, mainly Grade 1 and predominantly sensory, has been reported in clinical 
studies with trastuzumab emtansine. MBC patients with Grade  ≥ 3 and EBC patients with Grade  ≥ 2 
peripheral neuropathy at baseline were excluded from clinical studies. Treatment with trastuzumab 
emtansine should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral 
neuropathy until symptoms resolve or improve to ≤ Grade 2. Patients should be clinically monitored 
on an ongoing basis for signs/symptoms of neurotoxicity.  
 
Left ventricular dysfunction  
Patients treated with trastuzumab emtansine are at increased risk of developing left ventricular 
dysfunction. Left ventricular ejection fraction (LVEF) < 40% has been observed in patients treated 
with trastuzumab emtansine, and therefore symptomatic congestive heart failure (CHF) is a potential 
risk (see section 4.8). General risk factors for a cardiac event and those identified in adjuvant breast 
cancer studies with trastuzumab therapy include advancing age (> 50 years), low baseline LVEF 
values (< 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 an 
anthracycline and high BMI (> 25 kg/m2). 
 



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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 three 
months) during treatment. The dosing should be delayed, or treatment discontinued as necessary in 
cases 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 arrhythmia 
requiring treatment, history of myocardial infarction or unstable angina within 6 months of 
randomization, or current dyspnoea at rest due to advanced malignancy were excluded from clinical 
studies. Events of LVEF drop of >10% from baseline and/or CHF were observed in an observational 
study (BO39807) of MBC patients with baseline LVEF of 40-49% in a real world setting.  The 
decision to administer trastuzumab emtansine in MBC patients with low LVEF must be made only 
after careful benefit risk assessment and cardiac function should be closely monitored in these patients 
(see section 4.8). 
 
Pulmonary toxicity 
Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratory 
distress syndrome or a fatal outcome, have been reported in clinical studies with trastuzumab 
emtansine (see section 4.8). Signs and symptoms include dyspnoea, cough, fatigue, and pulmonary 
infiltrates.  
 
It is recommended that treatment with trastuzumab emtansine be permanently discontinued in patients 
who 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 not 
responding to standard treatment. (see section 4.2). 
 
Patients with dyspnoea at rest due to complications of advanced malignancy, co-morbidities, and 
receiving concurrent pulmonary radiation therapy may be at increased risk of pulmonary events. 
 
Infusion-related reactions 
Trastuzumab emtansine treatment has not been studied in patients who had trastuzumab permanently 
discontinued 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), characterized by one or more of the following 
symptoms have been reported: flushing, chills, pyrexia, dyspnoea, hypotension, wheezing, 
bronchospasm, and tachycardia. In general, these symptoms were not severe (see section 4.8). In most 
patients, these reactions resolved over the course of several hours to a day after the infusion was 
terminated. Treatment should be interrupted in patients with a severe IRR until signs and symptoms 
resolve. Consideration for re-treatment should be based on clinical assessment of the severity of the 
reaction. Treatment must be permanently discontinued in the event of a life threatening infusion-
related reaction (see section 4.2).  
 
Hypersensitivity reactions 
Trastuzumab emtansine treatment has not been studied in patients who had trastuzumab permanently 
discontinued due to hypersensitivity; treatment with trastuzumab emtansine is not recommended for 
these patients.  
 
Patients should be observed closely for hypersensitivity/allergic reactions, which may have the same 
clinical presentation as an IRR. Serious, anaphylactic reactions have been observed in clinical studies 
with trastuzumab emtansine. Medicinal products to treat such reactions, as well as emergency 
equipment, should be available for immediate use. In the event of a true hypersensitivity reaction (in 
which severity of reaction increases with subsequent infusions), trastuzumab emtansine treatment must 
be permanently discontinued.  
 
Sodium content in excipients 
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium- 
free’. 
 



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4.5 Interaction with other medicinal products and other forms of interaction 
 
No formal interaction studies have been performed.  
 
In vitro metabolism studies in human liver microsomes suggest that DM1, a component of 
trastuzumab 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 exposure 
and 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 trastuzumab 
emtansine treatment until the strong CYP3A4 inhibitors have cleared from the circulation 
(approximately 3 elimination half-lives of the inhibitors) when possible.  If a strong CYP3A4 inhibitor 
is coadministered and trastuzumab emtansine treatment cannot be delayed, patients should be closely 
monitored for adverse reactions.  
 
4.6 Fertility, pregnancy and lactation 
 
Contraception in males and females 
 
Women of childbearing potential should use effective contraception while receiving trastuzumab 
emtansine and for 7 months following the last dose of trastuzumab emtansine. Male patients or their 
female partners should also use effective contraception. 
 
Pregnancy 
 
There are no data from the use of trastuzumab emtansine in pregnant women. Trastuzumab, a 
component of trastuzumab emtansine, can cause foetal harm or death when administered to a pregnant 
woman. In the post-marketing setting, cases of oligohydramnios, some associated with fatal 
pulmonary hypoplasia, have been reported in pregnant women receiving trastuzumab. Animal studies 
of 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 be 
teratogenic and potentially embryotoxic (see section 5.3). 
 
Administration of trastuzumab emtansine to pregnant women is not recommended and women should 
be informed of the possibility of harm to the foetus before they become pregnant. Women who 
become pregnant must immediately contact their doctor. If a pregnant woman is treated with 
trastuzumab emtansine, close monitoring by a multidisciplinary team is recommended. 
 
Breast-feeding 
 
It is not known whether trastuzumab emtansine is excreted in human milk. Since many medicinal 
products are excreted in human milk and because of the potential for serious adverse reactions in 
breast-feeding infants, women should discontinue breast-feeding prior to initiating treatment with 
trastuzumab emtansine. Women may begin breast-feeding 7 months after concluding treatment.  
 
Fertility 
 
No reproductive and developmental toxicology studies have been conducted with trastuzumab 
emtansine.  
 
4.7 Effects on ability to drive and use machines 
 
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 vision 
on the ability to drive or use machines is unknown. Patients experiencing infusion-related reactions 



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(flushing, chills, pyrexia, dyspnoea, hypotension, wheezing, bronchospasm, and tachycardia) should 
be advised not to drive and use machines until symptoms abate. 
 
4.8 Undesirable effects 
 
Summary of the safety profile  
 
The safety of trastuzumab emtansine has been evaluated in 2,611 breast cancer patients in clinical 
studies. In this patient population:  
 
∑ the most common serious ADRs (> 0.5% of patients) were haemorrhage, pyrexia, 

thrombocytopenia, dyspnoea, abdominal pain, musculoskeletal pain, and vomiting. 
∑ the most common adverse drug reactions (ADRs) (≥25%) with trastuzumab emtansine were 

nausea, fatigue, musculoskeletal pain, haemorrhage, headache, transaminases increased, 
thrombocytopenia, and peripheral 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. 

 
Tabulated list of adverse reactions 
 
The ADRs in 2,611 patients treated with trastuzumab emtansine are presented in Table 3.  The ADRs 
are listed below by MedDRA system organ class (SOC) and categories of frequency. Frequency 
categories are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 
to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated 
from the available data). Within each frequency grouping and SOC, adverse reactions are presented in 
order 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 clinical 
trials 
 

System Organ Class Very Common Common Uncommon 
Infections and infestations Urinary tract 

infection 
  

Blood and lymphatic system 
disorders 

Thrombocytopenia, 
Anaemia 

Neutropenia, 
Leucopoenia 

 

Immune system disorders   Drug hypersensitivity  
Metabolism and nutrition 
disorders  

 Hypokalaemia  

Psychiatric disorders Insomnia   
Nervous system disorders Neuropathy 

peripheral, Headache  
Dizziness, 
Dysgeusia, Memory 
impairment 

 

Eye disorders  Dry eye, 
Conjunctivitis, 
Vision blurred, 
Lacrimation 
increased 

 

Cardiac disorders  Left ventricular 
dysfunction 

 

Vascular disorders Haemorrhage Hypertension  
Respiratory, thoracic and 
mediastinal disorders 

Epistaxis, Cough, 
Dyspnoea 

 Pneumonitis (ILD) 
 

Gastrointestinal disorders Stomatitis, Dyspepsia, Gingival  



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System Organ Class Very Common Common Uncommon 
Diarrhoea, Vomiting, 
Nausea, 
Constipation, Dry 
mouth, Abdominal 
pain 

bleeding 

Hepatobiliary disorders Transaminases 
increased 

Blood alkaline 
phosphatase 
increased, blood 
bilirubin increased 

Hepatotoxicity, 
Hepatic failure, 
Nodular 
regenerative 
hyperplasia, Portal 
hypertension 

Skin and subcutaneous 
tissue disorders 

 Rash, Pruritus, 
Alopecia, Nail 
disorder, Palmar-
plantar 
erythrodysaesthesia 
syndrome, Urticaria 

 

Musculoskeletal and 
connective tissue disorders 

Musculoskeletal 
pain, Arthralgia, 
Myalgia 

  

General disorders and 
administration site 
conditions  

Fatigue, Pyrexia, 
Asthenia 

Peripheral oedema, 
Chills 

Injection site 
extravasation 

Injury, poisoning and 
procedural complications 

 Infusion-related 
reactions  

Radiation 
pneumonitis 

 
Table 3 shows pooled data from the overall treatment period in the MBC studies (N= 1871; median 
number of cycles of trastuzumab emtansine was 10) and in KATHERINE (N=740; median number of 
cycles was 14).  
 
Description of selected adverse reactions 
 
Thrombocytopenia 
Thrombocytopenia or decreased platelet counts were reported in 24.9% of patients in MBC clinical 
studies with trastuzumab emtansine and was the most common adverse reaction leading to treatment 
discontinuation (2.6%). Thrombocytopenia was reported in 28.5% of patients in EBC clinical studies 
with trastuzumab emtansine and was the most common reported adverse reaction for all grades and 
grades ≥ 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 of 
thrombocytopenia were higher in Asian patients. Independent of race, the incidence of Grade 3 or 4 
events (< 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.   
 
Haemorrhage 
Haemorrhagic events were reported in 34.8% of patients in MBC clinical trials with trastuzumab 
emtansine and the incidence of severe haemorrhagic events (Grade ≥3) occurred in 2.2%. 
Haemorrhagic events were reported in 29% of patients with EBC and the incidence of severe 
haemorrhagic events (Grade ≥3) was 0.4%, including one Grade 5 event. In some of the observed 
cases the patients had thrombocytopenia, or were also receiving anti-coagulant therapy or antiplatelet 
therapy; in others there were no known additional risk factors. Cases of bleeding events with a fatal 
outcome have been observed in both MBC and EBC.  
 



13 

Transaminases increased (AST/ALT) 
Increase in serum transaminases (Grade 1-4) has been observed during treatment with trastuzumab 
emtansine in clinical studies (see section 4.4). Transaminase elevations were generally transient. A 
cumulative effect of trastuzumab emtansine on transaminases has been observed, and generally 
recovered when treatment was discontinued. Increased transaminases were reported in 24.2% of 
patients in MBC clinical studies. Grade 3 or 4 increased AST and ALT were reported in 4.2% and 
2.7% of patients with MBC respectively and usually occurred in the early treatment cycles (1-6). 
Increased transaminases were reported in 32.4% of patients with EBC. Grade 3 and 4 increased 
transaminases were reported in 1.5% of patients with EBC. In general, the Grade ≥ 3 hepatic events 
were not associated with poor clinical outcome; subsequent follow-up values tended to show 
improvement to ranges allowing the patient to remain on study and continue to receive study treatment 
at 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 of 
increased transaminases, see sections 4.2 and 4.4.  
 
Left ventricular dysfunction 
Left ventricular dysfunction was reported in 2.2% of patients in MBC clinical studies with 
trastuzumab 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 of 
these patients had other cardiovascular risk factors. Left ventricular dysfunction occurred in 3.0% of 
patients with EBC, with Grade 3 or 4 in 0.5% of patients. For dose modifications in the event of LVEF 
decrease, see Table 2 in section 4.2 and section 4.4.  
 
Peripheral neuropathy 
Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported in clinical trials of 
trastuzumab emtansine. In patients with MBC, the overall incidence of peripheral neuropathy was 
29.0% and 8.6% for Grade ≥ 2. In patients with EBC, the overall incidence was 32.3% and 10.3% for 
Grade ≥ 2.  
 
Infusion-related reactions 
Infusion-related reactions are characterised by one or more of the following symptoms: flushing, chills, 
pyrexia, dyspnoea, hypotension, wheezing, bronchospasm and tachycardia. Infusion-related reactions 
were reported in 4.0% of patients in MBC clinical studies with trastuzumab emtansine, with six 
Grade 3 and no Grade 4 events reported. Infusion-related reactions were reported in 1.6% of patients 
with EBC, with no Grade 3 or 4 events reported. Infusion-related reactions resolved over the course of 
several hours to a day after the infusion was terminated. No dose relationship was observed in clinical 
studies. For dose modifications in the event of infusion-related reactions, see sections 4.2 and 4.4.  
 
Hypersensitivity reactions 
Hypersensitivity was reported in 2.6% of patients in MBC clinical studies with trastuzumab emtansine, 
with one Grade 3 and one Grade 4 events reported. Hypersensitivity was reported in 2.7% of patients 
with EBC, with Grade 3 or 4 in 0.4% of patients. Overall, the majority 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.  
 
Immunogenicity 
As with all therapeutic proteins, there is the potential for an immune response to trastuzumab 
emtansine. A total of 1243 patients from seven clinical studies were tested at multiple time points for 
anti-drug antibody (ADA) responses to trastuzumab emtansine. Following trastuzumab emtansine 
dosing, 5.1% (63/1243) of patients tested positive for anti-trastuzumab emtansine antibodies at one or 
more post-dose time points. In the Phase I and Phase II studies, 6.4% (24/376) of patients tested 
positive 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 were 
also positive for neutralizing antibodies. In the KATHERINE (BO27938) study, 3.7% (15/401) of 



14 

patients tested positive for anti-trastuzumab emtansine antibodies, of which 5 were also positive for 
neutralizing antibodies. Due to the low incidence of ADA, conclusions cannot be made on the impact 
of anti- trastuzumab emtansine antibodies on the pharmacokinetics, safety, and efficacy of 
trastuzumab emtansine.  
 
Extravasation 
Reactions secondary to extravasation have been observed in clinical studies with trastuzumab 
emtansine. These reactions were usually mild or moderate and comprised erythema, tenderness, skin 
irritation, pain, or swelling at the infusion site. These reactions have been observed more frequently 
within 24 hours of infusion. Specific treatment for trastuzumab emtansine extravasation is unknown at 
this time.  
 
Laboratory abnormalities 
 
Tables 4 and 5 displays laboratory abnormalities observed in patients treated with trastuzumab 
emtansine in clinical study TDM4370g/BO21977/EMILIA and study BO27938/KATHERINE. 
 
Table 4 Laboratory abnormalities observed in patients treated with trastuzumab emtansine in 

study TDM4370g/BO21977/EMILIA 
 

Parameter 

Trastuzumab emtansine (N=490) 
All 

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 
Potassium 
Decreased potassium 35 3 < 1 

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

Parameter 
Trastuzumab emtansine (N=740) 

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 
Potassium 
Decreased potassium 26 2 <1 

 



15 

Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
There is no known antidote for trastuzumab emtansine overdose. In case of overdose, the patient 
should be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatic 
treatment 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 patient 
incorrectly received trastuzumab emtansine 6 mg/kg and died approximately 3 weeks following the 
overdose; a causal relationship to trastuzumab emtansine was not established. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, monoclonal 
antibodies, ATC code: L01XC14 
 
Mechanism of action 
 
Kadcyla, trastuzumab emtansine, is a HER2-targeted antibody-drug conjugate which contains the 
humanised anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitor DM1 (a 
maytansine derivative) via the stable thioether linker 
MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate). Emtansine refers to the MCC-DM1 
complex. 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 to 
malignant cells. Upon binding to HER2, trastuzumab emtansine undergoes receptor-mediated 
internalization and subsequent lysosomal degradation, resulting in release of DM1-containing 
cytotoxic 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, like 
trastuzumab, inhibits shedding of the HER2 ECD, inhibits signalling through the 
phosphatidylinositol 3-kinase (PI3-K) pathway, and mediates antibody-dependent cell-mediated 
cytotoxicity (ADCC) in human breast cancer cells that overexpress HER2.   
 

∑ DM1, the cytotoxic component of trastuzumab emtansine, binds to tubulin. By inhibiting tubulin 
polymerization, both DM1 and trastuzumab emtansine cause cells to arrest in the G2/M phase of 
the cell cycle, ultimately leading to apoptotic cell death. Results from in vitro cytotoxicity assays 
show 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, as 
demonstrated by detection of very low levels of free DM1 in plasma.  

 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


16 

Clinical efficacy  
 
Early Breast Cancer 
 
BO27938 (KATHERINE)  
BO27938 (KATHERINE) was a randomized, multicenter, open-label trial of 1486 patients with 
HER2-positive, early breast cancer with residual invasive tumor (patients who had not achieved 
pathological complete response (pCR)) in the breast and/or axillary lymph nodes following completion 
of preoperative systemic therapy that included chemotherapy and HER2-targeted therapy. Patients 
may have received more than one HER2-targeted therapy. Patients received radiotherapy and/or 
hormonal therapy concurrent with study treatment as per local guidelines. Breast tumor samples were 
required to show HER2 overexpression defined as 3+ IHC or ISH amplification ratio ≥ 2.0 determined 
at a central laboratory. Patients were randomized (1:1) to receive trastuzumab or trastuzumab 
emtansine. Randomization was stratified by clinical stage at presentation (operable vs. inoperable), 
hormone receptor status, preoperative HER2-directed therapy (trastuzumab, trastuzumab plus 
additional 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 treated 
with trastuzumab emtansine or trastuzumab for a total of 14 cycles unless there was recurrence of 
disease, withdrawal of consent, or unacceptable toxicity, whichever occurred first. Patients who 
discontinued trastuzumab emtansine could complete the duration of their intended study treatment up 
to 14 cycles of HER2-directed therapy with trastuzumab if appropriate based on toxicity 
considerations and investigator discretion. 
 
The primary efficacy endpoint of the study was Invasive Disease-Free Survival (IDFS). IDFS was 
defined as the time from the date of randomization to first occurrence of ipsilateral invasive breast 
tumor recurrence, ipsilateral local or regional invasive breast cancer recurrence, distant recurrence, 
contralateral invasive breast cancer, or death from any cause. Additional endpoints included IDFS 
including second primary non-breast cancer, disease-free survival (DFS), overall survival (OS), and 
distant recurrence-free interval (DRFI). 
 
Patient demographics and baseline tumor characteristics were balanced between treatment arms.  The 
median age was approximately 49 years (range 23-80 years), 72.8% were White, 8.7% were Asian and 
2.7% were Black or African American.  All but 5 patients were women; 3 men were included in the 
trastuzumab 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.  Tumor prognostic 
characteristics including hormone receptor status (positive: 72.3%, negative: 27.7%), clinical stage at 
presentation (inoperable: 25.3%, operable: 74.8%) and pathological nodal status after preoperative 
therapy (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 neoadjuvant 
chemotherapy regimen.19.5% percent of patients received another HER2-targeted agent in addition to 
trastuzumab as a component of neoadjuvant therapy; 93.8% of these patients received pertuzumab. All 
of the patients had received taxanes as part of neoadjuvant chemotherapy. 
 
A clinically meaningful and statistically significant improvement in IDFS was observed in patients 
who received trastuzumab emtansine compared with trastuzumab (HR = 0.50, 95% CI [0.39, 0.64], p 
<0.0001. Estimates of 3 years IDFS rates were 88.3% vs. 77.0% in trastuzumab emtansine vs. 
trastuzumab arms, respectively. See Table 6 and Figure 1. 
 



17 

Table 6 Summary of efficacy from study BO27938 (KATHERINE)  

 
Trastuzumab  

N = 743 

Trastuzumab 
Emtansine 

N = 743 

Primary Endpoint  

Invasive Disease-Free Survival (IDFS)    

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) <0.0001 

3 year event-free rate2,% [95% CI]  77.02 [73.78, 80.26] 88.27 [85.81, 90.72] 

Secondary Endpoints1  

Overall Survival (OS)  

Number (%) of patients with event 56 (7.5%) 42 (5.7%) 

HR [95% CI]  0.70 [0.47, 1.05] 

p-value (Log-Rank test, unstratified) 0.0848 

5 year survival rate2,% [95% CI] 86.8 [80.95, 92.63] 92.1 [89.44, 94.74] 

IDFS including second primary non-breast 
cancer3  

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) <0.0001 

3 year event-free rate2,% [95% CI]  76.9 [73.65, 80.14] 87.7 [85.18, 90.18] 

Disease-Free Survival (DFS)3   

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) <0.0001 

3 year event-free rate2,% [95% CI] 76.9 [73.65, 80.14] 87.41 [84.88, 89.93] 

Distant recurrence-free interval (DRFI)3  

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) 0.0003 

3 year event-free rate2,% [95% CI] 83.0 [80.10, 85.92 ] 89.7 [87.37, 92.01 ] 
Data from first interim analysis 25 July 2018 
Key to abbreviations (Table6): HR: Hazard Ratio; CI: Confidence Intervals,  
1. Hierarchical testing applied for IDFS and OS  
2. 3-year event-free rate and 5-year survival rate derived from Kaplan-Meier estimates 
3. These secondary endpoints were not adjusted for multiplicity  
 



18 

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

 

 
 
In KATHERINE, consistent treatment benefit of trastuzumab emtansine for IDFS was seen in all the 
pre-specified subgroups evaluated, supporting the overall result.  
 
Metastatic Breast Cancer 
 
TDM4370g/BO21977(EMILIA) 
A Phase III, randomised, multicentre, international, open-label clinical study was conducted in patients 
with HER2-positive unresectable locally advanced breast cancer (LABC) or MBC who had received 
prior taxane and trastuzumab-based therapy, including patients who received prior therapy with 
trastuzumab and a taxane in the adjuvant setting and who relapsed during or within six months of 
completing 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 be 
centrally confirmed for HER2-positive status defined as a score of 3 + by IHC or gene amplification 
by 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 to 
control 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% had 
oestrogen-receptor and/or progesterone-receptor positive disease. The study compared the safety and 
efficacy of trastuzumab emtansine with that of lapatinib plus capecitabine. A total of 991 patients were 
randomised to trastuzumab emtansine or lapatinib plus capecitabine as follows: 
 
∑ Trastuzumab emtansine arm: trastuzumab emtansine 3.6 mg/kg intravenously over 30-90 minutes 

on Day 1 of a 21-day cycle  
∑ Control arm (lapatinib plus capecitabine): lapatinib 1250 mg/day orally once per day of a 21-day 

cycle plus capecitabine 1000 mg/m2 orally twice daily on Days 1-14 of a 21-day cycle 
 



19 

The co-primary efficacy endpoints of the study were progression-free survival (PFS) as assessed by an 
independent review committee (IRC) and overall survival (OS) (see Table 7 and Figures 2 to 3).  
 
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 of 
5 points in the TOI-B is considered clinically significant. Kadcyla delayed patient-reported time to 
symptom progression for 7.1 months compared with 4.6 months for the control arm (Hazard Ratio 
0.796 (0.667, 0.951); p-value 0.0121). The data are from an open-label study and no firm conclusions 
can be drawn. 
 



20 

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

 
Lapatinib + Capecitabine 

n = 496 

Trastuzumab 
emtansine 

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*) 0.650 
95% 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*) 0.682 
95% 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 
test*) 

0.0002 

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: objective 
response; IRC: independent review committee; HR: hazard ratios; CI: confidence interval 

* Stratified by: world region (United States, Western Europe, other), number of prior 
chemotherapeutic 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 efficacy 
boundary 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 of 
completing adjuvant treatment and had not received any prior systemic anti-cancer therapy in the 
metastatic 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 were 



21 

10.8 months and not reached, respectively, compared with 5.7 months and 27.9 months, respectively, 
for the lapatinib plus capecitabine group.  
 
Figure 2 Kaplan-meier curve of IRC-assessed progression-free survival 
 

 
 
Figure 3 Kaplan-meier curve of overall survival 
 

 
 
In study TDM4370g/BO21977, consistent treatment benefit of trastuzumab emtansine was seen in the 
majority of pre-specified subgroups evaluated, supporting the robustness of the overall result. In the 



22 

subgroup 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 of 
patients 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, the 
hazard 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 for 
progression-free survival (PFS) and Overall Survival (OS) were 1.06 (95% CI: 0.68, 1.66) and 1.05 
(95% CI: 0.58, 1.91), respectively. 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 of 
patients 75 years or above did not demonstrate a benefit for PFS or OS, but was too small (n=25) to 
draw 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 compared 
with 25.9 months in the lapatinib plus capecitabine arm. At the time of the descriptive follow-up 
overall survival analysis, a total of 27.4% of the patients had crossed over from the lapatinib plus 
capecitabine arm to the trastuzumab emtansine arm. In a sensitivity analysis censoring patients at the 
time of cross-over, the hazard ratio was 0.69 (95% CI 0.59, 0.82). The results of this descriptive 
follow-up analysis are consistent with the confirmatory OS analysis. 
 
TDM4450g 
A randomised, multicentre, open-label phase II study evaluated the effects of trastuzumab emtansine 
versus trastuzumab plus docetaxel in patients with HER2-positive MBC who had not received prior 
chemotherapy for metastatic disease. Patients were randomised to receive trastuzumab emtansine 
3.6 mg/kg intravenously every 3 weeks (n = 67) or trastuzumab 8 mg/kg intravenous loading dose 
followed by 6 mg/kg intravenously every 3 weeks plus docetaxel 75-100 mg/m2 intravenously every 
3 weeks (n = 70). 
 
The primary endpoint was investigator assessed Progression-Free Survival (PFS). The median PFS 
was 9.2 months in the trastuzumab plus docetaxel arm and 14.2 months in the trastuzumab emtansine 
arm (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% with 
trastuzumab emtansine. The median duration of response was not reached with trastuzumab emtansine 
vs. 9.5 months in the control arm. 
 
TDM4374g  
A Phase II, single-arm, open-label study evaluated the effects of trastuzumab emtansine in patients 
with HER2-positive incurable, LABC or MBC. All patients were previously treated with 
HER2-directed therapies (trastuzumab and lapatinib), and chemotherapy (anthracycline, taxane, and 
capecitabine) in the neoadjuvant, adjuvant, locally advanced, or metastatic setting. The median 
number of anti-cancer agents that patients had received in any setting was 8.5 (range, 5-19) and in the 
metastatic setting was 7.0 (range, 3-17), including all agents intended for the treatment of breast 
cancer.  
 
Patients (n = 110) received 3.6 mg/kg of trastuzumab emtansine intravenously every 3 weeks until 
disease progression or unacceptable toxicity.  
 
The key efficacy analyses were ORR based on independent radiologic review and duration of 
objective response. The ORR was 32.7% (95% CI: 24.1, 42.1), n = 36 responders, by both IRC and 
investigator review. The median duration of response by IRC was not reached (95% CI, 4.6 months to 
not estimable). 
 



23 

Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
trastuzumab emtansine in all subsets of the paediatric population in breast cancer (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
The population pharmacokinetic analysis suggested no difference in trastuzumab emtansine exposure 
based on disease status (adjuvant vs. metastatic setting). 
 
Absorption  
Trastuzumab emtansine is administered intravenously. There have been no studies performed with 
other routes of administration.  
 
Distribution  
Patients in Study TDM4370g/BO21977 and Study BO29738 who received 3.6 mg/kg of trastuzumab 
emtansine intravenously every 3 weeks had a mean Cycle 1 maximum serum concentration (Cmax) of 
trastuzumab emtansine of 83.4 (± 16.5) mg/mL and 72.6 (± 24.3) mg/mL, respectively. Based on 
population PK analysis, following intravenous administration, the central volume of distribution of 
trastuzumab 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 proteolysis 
in cellular lysosomes.  
 
In vitro metabolism studies in human liver microsomes suggest that DM1, a small molecule 
component 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, trastuzumab 
emtansine catabolites MCC-DM1, Lys-MCC-DM1, and DM1 were detected at low levels.  In vitro, 
DM1 was a substrate of P-glycoprotein (P-gp). 
 
Elimination 
Based on population pharmacokinetic (PK) analysis, following intravenous administration of 
trastuzumab emtansine in patients with HER2-positive metastatic breast cancer, the clearance of 
trastuzumab 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 infusion 
every 3 weeks. 
 
Based on population PK analysis, body weight, albumin, sum of longest diameter of target lesions by 
Response Evaluation Criteria In Solid Tumors (RECIST), HER2 shed extracellular domain (ECD), 
baseline trastuzumab concentrations, and aspartate aminotransferase (AST) were identified as 
statistically significant covariates for trastuzumab emtansine PK parameters. However, the magnitude 
of effect of these covariates on trastuzumab emtansine exposure suggests that these covariates are 
unlikely 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 the 
pharmacokinetics of total trastuzumab and DM1 was limited and was not clinically relevant. In 
nonclinical 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 across 
doses ranging from 2.4 to 4.8 mg/kg; patients who received doses less than or equal to 1.2 mg/kg had 
faster clearance. 
 



24 

Elderly patients   
The population PK analysis showed that age did not affect the PK of trastuzumab emtansine. No 
significant 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). 
 
Renal impairment  
No formal PK study has been conducted in patients with renal impairment. The population PK 
analysis showed that creatinine clearance does not affect the PK of trastuzumab emtansine. 
Pharmacokinetics of trastuzumab emtansine in patients with mild (creatinine clearance CLcr 60 to 
89 mL/min, n = 254) or moderate (CLcr 30 to 59 mL/min, n = 53) renal impairment were similar to 
those in patients with normal renal function (CLcr ≥ 90 mL/min, n = 361). Pharmacokinetic data in 
patients with severe renal impairment (CLcr 15 to 29 mL/min) are limited (n = 1), therefore no dosage 
recommendations can be made. 
 
Hepatic impairment  
The liver is a primary organ for eliminating DM1 and DM1-containing catabolites. The 
pharmacokinetics of trastuzumab emtansine and DM1-containing catabolites were evaluated after the 
administration of 3.6 mg/kg of trastuzumab emtansine to metastatic HER2+ breast cancer patients with 
normal hepatic function (n=10), mild (Child-Pugh A; n=10) and moderate (Child-Pugh B; n=8) 
hepatic impairment.  
 
- Plasma concentrations of DM1 and DM1-containing catabolites (Lys-MCC-DM1 and MCC-DM1) 
were low and comparable between patients with and without hepatic impairment. 
 
- Systemic exposures (AUC) of trastuzumab emtansine at Cycle 1 in patients with mild and moderate 
hepatic impairment were approximately 38% and 67% lower than that of patients with normal hepatic 
function, respectively. Trastuzumab emtansine exposure (AUC) at Cycle 3 after repeated dosing in 
patients with mild or moderate hepatic dysfunction was within the range observed in patients with 
normal hepatic function.   
 
No formal pharmacokinetic study has been conducted and no population PK data was collected in 
patients with severe hepatic impairment (Child-Pugh class C). 
 
Other special populations 
The population PK analysis showed that race did not appear to influence the PK of trastuzumab 
emtansine. Because most of the patients in trastuzumab emtansine clinical studies were females, the 
effect of gender on the PK of trastuzumab emtansine was not formally evaluated. 
 
5.3 Preclinical safety data 
 
Animal toxicology and/or pharmacology 
 
Administration of trastuzumab emtansine was well tolerated in rats and monkeys at doses up to 20 and 
10 mg/kg, respectively, corresponding to 2040 mg DM1/m2 in both species, which is approximately 
equivalent to the clinical dose of trastuzumab emtansine in patients.  In the GLP toxicity studies, with 
the exception of irreversible peripheral axonal toxicity (observed only in monkeys at ≥ 10 mg/kg) and 
reproductive organ toxicity (observed only in rats at 60 mg/kg), partially or completely reversible dose 
dependent toxicities were identified in both animal models. Principal toxicities included liver (liver 
enzyme elevations) at ≥ 20 mg/kg and ≥ 10 mg/kg, bone marrow (reduced platelet and white blood 
cell count)/hematologic at ≥ 20 mg/kg and ≥ 10 mg/kg, and lymphoid organs at ≥ 20 mg/kg 
and ≥ 3 mg/kg,  in rat and monkey, respectively. 
 
Mutagenicity 
 
DM1 was aneugenic or clastogenic in an in vivo single-dose rat bone marrow micronucleus assay at 
exposures that were comparable to mean maximum concentrations of DM1 measured in humans 



25 

administered 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 be 
expected. 
 
Dedicated embryo-foetal development studies have not been conducted in animals with trastuzumab 
emtansine. Developmental toxicity of trastuzumab has been identified in the clinical setting although it 
was not predicted in the non-clinical program. In addition, developmental toxicity of maytansine has 
been identified in non-clinical studies which suggests that DM1, the microtubule-inhibiting cytotoxic 
maytansinoid component of trastuzumab emtansine, will be similarly teratogenic and potentially 
embryotoxic. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Succinic acid 
Sodium hydroxide 
Sucrose 
Polysorbate 20 
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed or diluted with other medicinal products except those 
mentioned in section 6.6. 
 
Glucose (5%) solution should not be used for reconstitution or dilution since it causes aggregation of 
the protein. 
 
6.3 Shelf life 
 
Unopened vial 
 
3 years. 
 
Reconstituted solution 
  
Chemical and physical in-use stability of the reconstituted solution has been demonstrated for up to 
24 hours at 2°C to 8°C. From a microbiological point of view, the product should be used immediately. 
If not used immediately, the reconstituted vials can be stored for up to 24 hours at 2°C to 8°C, 
provided it was reconstituted under controlled and validated aseptic conditions, and must be discarded 
thereafter. 
 
Diluted solution  
 
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 for 
up to 24 hours at 2°C to 8°C, provided it was prepared under controlled and validated aseptic 
conditions. Particulates may be observed on storage if diluted in 0.9% sodium chloride 
(see section 6.6). 
 



26 

6.4 Special precautions for storage 
 
Store in a refrigerator (2∞C – 8∞C). 
 
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container  
 
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 stopper 
coated 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 stopper 
coated with fluoro resin laminate, and sealed with an aluminium seal with a purple plastic flip-off cap. 
 
Pack of 1 vial. 
 
6.6 Special precautions for disposal and other handling 
 
Appropriate aseptic technique should be used. Appropriate procedures for the preparation of 
chemotherapeutic 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 when 
the 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 the 
medicinal product being prepared is Kadcyla (trastuzumab emtansine) and not Herceptin 
(trastuzumab). 
 
Instructions for reconstitution 
 
∑ 100 mg trastuzumab emtansine vial: Using a sterile syringe, slowly inject 5 mL of sterile water for 

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

injection 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 to 
administration. The reconstituted solution should be free of visible particulates, clear to slightly 
opalescent. The colour of the reconstituted solution should be colourless to pale brown. Do not use if 
the reconstituted solution contains visible particulates, or is cloudy or discoloured. 
 



27 

Instructions for dilution 
 
Determine the volume of the reconstituted solution required based on a dose of 3.6 mg trastuzumab 
emtansine/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 bag 
containing 250 mL of sodium chloride 4.5 mg/mL (0.45%) solution for infusion or sodium chloride 
9 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 used 
for infusion, a 0.20 or 0.22 micron in-line polyethersulfone (PES) filter is required. Once the infusion 
is prepared it should be administered immediately. Do not freeze or shake the infusion during storage.  
 
Disposal 
 
The reconstituted product contains no preservative and is intended for single use only. Discard any 
unused portion. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/885/001 
EU/1/13/885/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 November 2013 
Date of latest renewal: 17 September 2018 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

http://www.ema.europa.eu/


28 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE 
SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR 
BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT   

 
 



29 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer of the biological active substance 
 
Lonza Ltd. 
Lonzastrasse 
CH-3930 Visp 
Switzerland 
 
Name and address of the manufacturer responsible for batch release 
 
Roche Pharma AG 
Emil-Barell-Strasse 1 
D-79639 Grenzach-Whylen 
Germany 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
∑ Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are 
set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of 
Directive 2001/83/EC and any subsequent updates published on the European medicines web-
portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT   
 
∑ Risk Management Plan (RMP) 

 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in 
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 
subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

∑ At the request of the European Medicines Agency; 
∑ Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result 
of an important (pharmacovigilance or risk minimisation) milestone being reached. 

 



30 

∑ Additional risk minimisation measures  
 
The MAH shall agree the content and format of the Kadcyla (trastuzumab emtansine) educational 
material and a communication plan with the National Competent Authority in the Member State 
before Kadcyla (trastuzumab emtansine) is launched in each Member State. 
 
The MAH shall ensure that in parallel to the launch of Kadcyla (trastuzumab emtansine), all health 
care professionals who may prescribe, dispense or administer Kadcyla (trastuzumab emtansine) and/or 
Herceptin (trastuzumab) are provided with a health care professional (HCP) educational pack.  This 
HCP educational pack shall consist of the following: 
 

∑ Kadcyla (trastuzumab emtansine) SPC 
∑ Health care professional information  

The HCP information shall contain the following key messages: 
 

1. Kadcyla (trastuzumab emtansine) and Herceptin (trastuzumab) are two very different products 
with different active substances never to be used interchangeably.  Kadcyla (trastuzumab 
emtansine) is NOT a generic version of Herceptin (trastuzumab) and has different properties, 
indications and dose. 

2. Trastuzumab emtansine is an antibody-drug conjugate containing humanized anti-HER2 IgG1 
antibody trastuzumab and DM1, a microtubule-inhibitory maytansinoid.  

3. Do not substitute or combine trastuzumab emtansine with or for trastuzumab 
4. Do not administer trastuzumab emtansine in combination with chemotherapy 
5. Do not administer trastuzumab emtansine at doses greater than 3.6 mg/kg once every 3 weeks  
6. If a prescription for Kadcyla (trastuzumab emtansine) is written electronically, it is important to 

ensure that the medicinal product prescribed is trastuzumab emtansine and not trastuzumab.  
7. Both the invented name Kadcyla and its full non-proprietary name (trastuzumab emtansine) should 

be used and confirmed when prescribing, preparing the infusion solution and administering 
Kadcyla (trastuzumab emtansine) to patients. It must be verified that the non-proprietary name is 
trastuzumab emtansine. 

8. In order to prevent medicinal product errors it is important to review the Summary of Product 
Characteristics and to check the outer carton and vial labels to ensure that the medicinal product 
being prepared and administered is Kadcyla (trastuzumab emtansine) and not trastuzumab.  

9. Description of the key differences between trastuzumab emtansine and trastuzumab in relation to 
indication, dose, administration and packaging differences.  

 
Obligation to conduct post-authorisation measures 
 
The MAH shall complete, within the stated timeframe, the below measures: 
 
Description Due date 
PAES: In order to further investigate the efficacy of trastuzumab 
emtansine in the adjuvant treatment of adult patients with HER2-positive 
early breast cancer who have residual invasive disease, in the breast 
and/or lymph nodes, after neoadjuvant taxane-based and HER2-targeted 
therapy, the MAH should submit the final analysis of OS from the phase 
3, randomised, open-label study KATHERINE (BO27938). 

30 June 2024 

 



31 

 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 



32 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



33 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kadcyla 100 mg powder for concentrate for solution for infusion  
trastuzumab emtansine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One vial of powder for concentrate for solution for infusion contains 100 mg of trastuzumab 
emtansine. After reconstitution one vial of 5 mL solution contains 20 mg/mL of trastuzumab 
emtansine. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: 
Succinic acid, sodium hydroxide, sucrose, polysorbate 20. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion 
1 vial of 100 mg 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use after reconstitution and dilution 
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic 
 
To be administered under the supervision of a physician experienced in the use of cytotoxic agents. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



34 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (2ºC – 8ºC) 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/885/001 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  



35 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Kadcyla 100 mg powder for concentrate for solution for infusion 
trastuzumab emtansine 
Intravenous use 
 
 
2. METHOD OF ADMINISTRATION 
 
For intravenous use after reconstitution and dilution 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
100 mg 
 
 
6. OTHER 
 



36 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kadcyla 160 mg powder for concentrate for solution for infusion  
trastuzumab emtansine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
 
One vial of powder for concentrate for solution for infusion contains 160 mg of trastuzumab 
emtansine. After reconstitution one vial of 8 mL solution contains 20 mg/mL of trastuzumab 
emtansine. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: 
Succinic acid, sodium hydroxide, sucrose, polysorbate 20. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion 
1 vial of 160 mg 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use after reconstitution and dilution 
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic 
 
To be administered under the supervision of a physician experienced in the use of cytotoxic agents. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



37 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (2ºC – 8ºC) 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/885/002 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  



38 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Kadcyla 160 mg powder for concentrate for solution for infusion 
trastuzumab emtansine 
Intravenous use 
 
 
2. METHOD OF ADMINISTRATION 
 
For intravenous use after reconstitution and dilution 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
160 mg 
 
 
6. OTHER 
 



39 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



40 

Package leaflet: Information for the user 
 

Kadcyla100 mg powder for concentrate for solution for infusion 
Kadcyla 160 mg powder for concentrate for solution for infusion 

trastuzumab emtansine 
 
Read all of this leaflet carefully before you start being given this medicine because it contains 
important information for you. 
∑ Keep this leaflet. You may need to read it again. 
∑ If you have any further questions, ask your doctor, pharmacist or nurse. 
∑ If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Kadcyla is and what it is used for 
2. What you need to know before you are given Kadcyla 
3. How you are given Kadcyla  
4. Possible side effects 
5. How to store Kadcyla 
6. Contents of the pack and other information 
 
 
1. What Kadcyla is and what it is used for 
 
What Kadcyla is 
Kadcyla contains the active substance trastuzumab emtansine, which is made up of two parts that are 
linked together: 
∑ trastuzumab - a monoclonal antibody that binds selectively to an antigen (a target protein) called 

human epidermal growth factor receptor 2 (HER2). HER2 is found in large amounts on the surface 
of some cancer cells where it stimulates their growth. When trastuzumab binds to HER2 it can 
stop the cancer cells growth and cause them to die. 

∑ DM1 – an anti-cancer substance that becomes active once Kadcyla enters the cancer cell.  
 

What Kadcyla is used for 
Kadcyla is used to treat breast cancer in adults when: 
∑ the cancer cells have many HER2 proteins on them - your doctor will test your cancer cells for this.  
∑ you have already received the medicine trastuzumab and a medicine known as a taxane. 
∑ the cancer has spread to areas near the breast or to other parts of your body (metastasized) 
∑ the cancer has not spread to other parts of the body and treatment is going to be given after surgery 

(treatment after surgery is called adjuvant therapy). 
 
 
2. What you need to know before you are given Kadcyla 
 
You must not be given Kadcyla 
∑ if you are allergic to trastuzumab emtansine or any of the other ingredients of this medicine (listed 

in section 6).  
You should not be given Kadcyla if the above applies to you. If you are not sure, talk to your doctor or 
nurse before you are given Kadcyla. 
 
Warnings and precautions 
Talk to your doctor or nurse before you are given Kadcyla if: 
∑ you have ever had a serious infusion-related reaction from using trastuzumab characterised by 

symptoms such as flushing, chills, fever, shortness of breath, difficulty breathing, rapid heartbeat 
or a drop in blood pressure. 



41 

∑ you are receiving treatment with blood thinning medicines (e.g. warfarin, heparin). 
∑ you have any history of liver problems. Your doctor will check your blood to test your liver 

function before and regularly during treatment 
 
If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before you are 
given Kadcyla. 
 
Look out for side effects 
Kadcyla can make some existing conditions worse, or cause side effects. See section 4 for more details 
about what side effects to look out for. 
 
Tell your doctor or nurse straight away if you notice any of the following serious side effects 
while you are given Kadcyla: 
 
∑ Breathing problems: Kadcyla can cause serious breathing problems such as shortness of breath 

(either at rest or while performing any type of activity) and cough.  These may be signs of 
inflammation of your lung, which may be serious, and even fatal. If you develop lung disease your 
doctor may stop treatment with this medicine. 
 

∑ Liver problems: Kadcyla can cause inflammation or damage to cells in the liver that can stop the 
liver from functioning normally. Inflamed or injured liver cells may leak higher than normal 
amounts of certain substances (liver enzymes) into the bloodstream, resulting in elevated liver 
enzymes in blood tests. In most cases you will not have any symptoms. Some symptoms could be 
yellowing of your skin and whites of your eyes (jaundice). Your doctor will check your blood to 
test your liver function before and regularly during treatment. 
 
Another rare abnormality that can occur in the liver is a condition known as nodular regenerative 
hyperplasia (NRH). This abnormality causes the structure of the liver to change and can change 
how the liver functions. Over time, this may lead to symptoms such as a bloated sensation or 
swelling of the abdomen due to fluid accumulation or bleeding from abnormal blood vessels in the 
gullet or rectum. 
 

∑ Heart problems: Kadcyla can weaken the heart muscle. When the heart muscle is weak, patients 
may develop symptoms such as shortness of breath at rest or when sleeping, chest pain, swollen 
legs or arms, and a sensation of rapid or irregular heartbeats. Your doctor will check your heart 
function before and regularly during treatment. You should tell your doctor immediately if you 
notice any of the above symptoms. 
 

∑ Infusion-related reactions or allergic reactions: Kadcyla can cause flushing, shivering fits, fever, 
trouble breathing, low blood pressure, rapid heartbeat, sudden swelling of your face, tongue, or 
trouble swallowing during the infusion or after the infusion on the first day of treatment. Your 
doctor or nurse will check to see whether you are having any of these side effects. If you develop a 
reaction, they will slow down or stop the infusion and may give you treatment to counteract the 
side effects. The infusion may be continued after the symptoms improve. 
 

∑ Bleeding problems: Kadcyla can lower the number of platelets in your blood. Platelets help your 
blood to clot so you might get unexpected bruising or bleeding (such as nose bleeds, bleeding 
from gums). Your doctor will check your blood regularly for decreased platelets. You should tell 
your doctor immediately if you notice any unexpected bruising or bleeding. 
 

∑ Neurological problems: Kadcyla can damage nerves. You may experience tingling, pain, 
numbness, itching, crawling sensation, pins and needles in your hands and feet. Your doctor will 
monitor you for signs and symptoms of neurological problems.  

 
Tell your doctor or nurse straight away if you notice any of the side effects above. 
 



42 

Children and adolescents 
Kadcyla is not recommended for anyone under the age of 18 years. This is because there is no 
information on how well it works in this age group. 
 
Other medicines and Kadcyla 
Tell your doctor or nurse if you are taking, have recently taken or might take any other medicines.  
 
In particular, tell your doctor or pharmacist if you are taking: 
∑ any medicines to thin your blood such as warfarin or decrease the ability to form blood clot such 

as aspirin 
∑ medicines for fungal infections called ketoconazole, itraconazole or voriconazole 
∑ antibiotics for infections called clarithromycin or telithromycin 
∑ medicines for HIV called atazanavir, indinavir, nelfinavir, ritonavir or saquinavir. 
∑ medicine for depression called nefazodone 
If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before you are 
given Kadcyla.   
 
Pregnancy 
Kadcyla is not recommended if you are pregnant because this medicine may cause harm to the unborn 
baby.  
∑ Tell your doctor before using Kadcyla if you are pregnant, think you may be pregnant or are 

planning to have a baby. 
∑ Use effective contraception to avoid becoming pregnant while you are being treated with Kadcyla. 

Talk to your doctor about the best contraception for you. 
∑ You should continue to take your contraception for at least 7 months after your last dose of 

Kadcyla. Talk to your doctor before stopping your contraception.  
∑ Male patients or their female partners should also use effective contraception.  
∑ If you do become pregnant during treatment with Kadcyla, tell your doctor straight away. 
 
Breast-feeding 
You should not breast-feed during treatment with Kadcyla. Also you should not breast-feed for 7 
months after your last infusion of Kadcyla. It is not known whether the ingredients in Kadcyla pass 
into breast-milk. Talk to your doctor about this. 
 
Driving and using machines 
It is not expected that Kadcyla will affect your ability to drive, cycle, use tools or machines. If you 
experience flushing, shivering fits, fever, trouble breathing, low blood pressure or a rapid heartbeat 
(infusion-related reaction), blurred vision, tiredness, headache, or dizziness, do not drive, cycle, use 
tools or machines until these reactions stop. 
 
Important information about some of the ingredients of Kadcyla 
This medicine contains less than 1 mmol sodium (23 mg) per dose. It is essentially ‘sodium- free’. 
 
 
3. How you are given Kadcyla 
 
Kadcyla will be given to you by a doctor or nurse in a hospital or clinic: 
∑ It is given by a drip into a vein (intravenous infusion). 
∑ You will be given one infusion every 3 weeks. 
 
How much you will be given 
∑ You will be given 3.6 mg of Kadcyla for every kilogram of your body weight. Your doctor will 

calculate the correct dose for you. 
∑ The first infusion will be given to you over 90 minutes. You will be observed by a doctor or nurse 

while it is being given and for at least 90 minutes following the initial dose, in case you have any 
side effects.  



43 

∑ If the first infusion is well tolerated, the infusion on your next visit may be given over 30 minutes. 
You will be observed by a doctor or nurse while it is being given and for at least 30 minutes 
following the dose, in case you have any side effects. 

∑ The total number of infusions that you will be given depends on how you respond to the treatment 
and which indication is treated. 

∑ If you experience side effects, your doctor may decide to continue your treatment but lower your 
dose, delay the next dose or stop the treatment. 

 
If you miss a Kadcyla treatment 
If you forget or miss your Kadcyla appointment, make another appointment as soon as possible. Do 
not wait until your next planned visit.  
 
If you stop Kadcyla treatment 
Do not stop treatment with this medicine without talking to your doctor first. 
 
If you have any further questions on the use of this medicine, ask your doctor or nurse.  
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Tell your doctor or nurse straight away if you notice any of following serious side effects. 

Very common (may affect more than 1 in 10 people): 
∑ Kadcyla may cause inflammation or damage to cells in the liver, resulting in elevated liver 

enzymes in blood tests. However, in most cases during Kadcyla treatment, liver enzyme levels are 
elevated mildly and temporarily, do not cause any symptoms, and do not affect liver function. 

∑ Unexpected bruising and bleeding (such as nose bleeds). 
∑ Tingling, pain, numbness, itching, crawling sensation, pins and needles in your hands and feet. 

These symptoms may indicate nerve damage. 

Common (may affect up to 1 in 10 people): 
∑ Flushing, shivering fits, fever, trouble breathing, low blood pressure or a rapid heartbeat during the 

infusion or up to 24 hours after the infusion – these are so-called infusion-related reactions.  
∑ Heart problems can occur. Most patients will not have symptoms from the heart problems. If 

symptoms do occur, cough shortness of breath at rest or when sleeping flat, chest pain and swollen 
ankles or arms, a sensation of rapid or irregular heartbeats may be observed.  

Uncommon (may affect up to 1 in 100 people): 
∑ Inflammation of your lungs can cause breathing problems such as shortness of breath (either at 

rest or while performing any type of activity), coughing or coughing spells with a dry cough – 
these are signs of inflammation of your lung tissue. 

∑ Your skin and whites of your eyes get yellow (jaundice) – these could be signs of severe liver 
damage. 

∑ Allergic reactions can occur and most patients will have mild symptoms such as itching or 
tightness in the chest. In more severe cases, swelling of your face or tongue, trouble swallowing or 
difficulty breathing may occur.  

 
Tell your doctor or nurse straight away if you notice any of the serious side effects above. 
 
Other side effects include 
 
Very common: 
∑ decreased red blood cells (shown in a blood test) 
∑ being sick (vomiting) 
∑ diarrhoea  
∑ dry mouth 



44 

∑ urinary tract infection 
∑ constipation 
∑ stomach ache 
∑ cough 
∑ shortness of breath 
∑ inflammation of the mouth 
∑ difficulty sleeping 
∑ muscle or joint pain 
∑ fever 
∑ headache 
∑ feeling tired 
∑ weakness 
 
Common: 
∑ chills or flu like symptoms  
∑ decrease in your potassium levels (shown in a blood test) 
∑ skin rashes 
∑ decreased white blood cells (shown in a blood test) 
∑ dry eyes, watery eyes or blurred vision 
∑ eye redness or infection 
∑ indigestion 
∑ swelling of legs and/or arms 
∑ bleeding from the gums 
∑ increase in blood pressure  
∑ feeling dizzy 
∑ taste disturbances 
∑ itching 
∑ difficulty in remembering 
∑ hair loss 
∑ hand-and-foot skin reaction (Palmar-plantar erythrodysaesthesia syndrome) 
∑ nail disorder 
 
Uncommon: 
∑ Another abnormality that can be caused by Kadcyla is a condition known as nodular 

regenerative hyperplasia of the liver. This abnormality causes the structure of the liver to change. 
Patients develop multiple nodules in the liver that can change how the liver functions. Over time, 
this may lead to symptoms such as a bloated sensation or swelling of the abdomen due to fluid 
accumulation or bleeding from abnormal blood vessels in the gullet or rectum. 

∑ If the Kadcyla infusion solution leaks into the area around the infusion site you may develop 
tenderness or redness of your skin, or swelling at the infusion site.  

 
If you get any of the side effects after your treatment with Kadcyla has stopped, talk to your doctor or 
nurse and tell them that you have been treated with Kadcyla. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 
listed in this leaflet.  
 
You can also report side effects directly via the national reporting system listed in Appendix V. By 
reporting side effects you can help provide more information on the safety of this medicine. 
 
 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


45 

5. How to store Kadcyla 
 
Kadcyla will be stored by the health professionals at the hospital or clinic. 
 
∑ Keep this medicine out of the sight and reach of children. 
∑ Do not use this medicine after the expiry date which is stated on the outer carton and vial after 

EXP. The expiry date refers to the last day of that month. 
∑ Store in a refrigerator at (2°C - 8°C). Do not freeze. 
∑ When prepared as a solution for infusion Kadcyla is stable for up to 24 hours at 2°C to 8°C, and 

must be discarded thereafter.  
∑ Do not throw away any medicines via wastewater or household waste. Ask your pharmacist 

how to dispose of medicines you no longer use. These measures will help to protect the 
environment. 

 
 
6. Contents of the pack and other information 
 
What Kadcyla contains 
∑ The active substance is trastuzumab emtansine.  
∑  Kadcyla 100mg: One vial of powder for concentrate for solution for infusion contains 100 mg of 

trastuzumab emtansine. After reconstitution one vial of 5 mL solution contains 20 mg/mL of 
trastuzumab emtansine. 

∑ Kadcyla 160mg: One vial of powder for concentrate for solution for infusion contains 160 mg of 
trastuzumab emtansine. After reconstitution one vial of 8 mL solution contains 20 mg/mL of 
trastuzumab emtansine. 

∑ The other ingredients are succinic acid, sodium hydroxide (see section 2 under ‘Important 
information about some of the ingredients of Kadcyla’), sucrose, and polysorbate 20. 

 
What Kadcyla looks like and contents of the pack 
∑ Kadcyla is a white to off-white lyophilised powder for concentrate for solution for infusion 

supplied in glass vials.  
∑ Kadcyla is available in packs containing 1 vial. 
 
Marketing Authorisation Holder 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
Manufacturer 
Roche Pharma AG 
Emil-Barell-Strasse 1 
D-79639 Grenzach-Wyhlen 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
N.V. Roche S.A. 
Tél/Tel: +32 (0) 2 525 82 11 
 
България 
Рош България ЕООД 
Тел: +359 2 818 44 44 
 

Lietuva 
UAB “Roche Lietuva” 
Tel: +370 5 2546799 
 
Luxembourg/Luxemburg 
(Voir/siehe Belgique/Belgien) 
 



46 

Česká republika 
Roche s. r. o. 
Tel: +420 - 2 20382111 
 

Magyarország 
Roche (Magyarország) Kft. 
Tel: +36 - 23 446 800 
 

Danmark 
Roche a/s 
Tlf: +45 - 36 39 99 99 
 

Malta 
(See Ireland) 

Deutschland 
Roche Pharma AG 
Tel: +49 (0) 7624 140 
 

Nederland 
Roche Nederland B.V. 
Tel: +31 (0) 348 438050 
 

Eesti 
Roche Eesti OÜ 
Tel: + 372 - 6 177 380 
 

Norge 
Roche Norge AS 
Tlf: +47 - 22 78 90 00 
 

Ελλάδα 
Roche (Hellas) A.E.  
Τηλ: +30 210 61 66 100 
 

Österreich 
Roche Austria GmbH 
Tel: +43 (0) 1 27739 
 

España 
Roche Farma S.A. 
Tel: +34 - 91 324 81 00 
 

Polska 
Roche Polska Sp.z o.o. 
Tel: +48 - 22 345 18 88 
 

France 
Roche 
Tél: +33 (0)1 47 61 40 00 
 

Portugal 
Roche Farmacêutica Química, Lda 
Tel: +351 - 21 425 70 00 
 

Hrvatska 
Roche d.o.o 
Tel:  +385 1 4722 333 

România 
Roche România S.R.L. 
Tel: +40 21 206 47 01 
 

Ireland 
Roche Products (Ireland) Ltd. 
Tel: +353 (0) 1 469 0700 
 

Slovenija 
Roche farmacevtska družba d.o.o. 
Tel: +386 - 1 360 26 00 
 

Ísland  
Roche a/s 
c/o Icepharma hf 
Sími: +354 540 8000 
 

Slovenská republika  
Roche Slovensko, s.r.o. 
Tel: +421 - 2 52638201 
 

Italia 
Roche S.p.A. 
Tel: +39 - 039 2471 

Suomi/Finland 
Roche Oy  
Puh/Tel: +358 (0) 10 554 500 
 

Kύπρος  
Γ.Α.Σταμάτης & Σια Λτδ. 
Τηλ: +357 - 22 76 62 76 
 

Sverige 
Roche AB 
Tel: +46 (0) 8 726 1200 
 

Latvija 
Roche Latvija SIA 
Tel: +371 - 6 7039831 
 

United Kingdom 
Roche Products Ltd. 
Tel: +44 (0) 1707 366000 
 

 



47 

This leaflet was last revised in  
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.  

http://www.ema.europa.eu/


48 

 
The following information is intended for medical or healthcare professionals only:  
 
In order to prevent medicinal product errors it is important to check the vial labels to ensure that the 
medicinal product being prepared is Kadcyla (trastuzumab emtansine) and not Herceptin 
(trastuzumab). 
 
Kadcyla must be reconstituted and diluted by a healthcare professional and administered as an 
intravenous infusion. It must not be administered as an intravenous push or bolus. 
 
Always keep this medicine in the closed original pack at a temperature of 2ºC – 8 ºC in a refrigerator. 
A vial of Kadcyla reconstituted with water for injections (not supplied) is stable for 24 hours at  
2ºC – 8 ºC after reconstitution and must not be frozen.  
 
Appropriate aseptic technique should be used. Appropriate procedures for the preparation of 
chemotherapeutic 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 when 
the concentrate for infusion is diluted with sodium chloride 9 mg/mL (0.9%) solution for infusion.  
 
Instructions for reconstitution 
∑ Kadcyla 100mg: using a sterile syringe, slowly inject 5 mL of sterile water for injection into the 

100 mg trastuzumab emtansine vial.  
∑ Kadcyla 160mg: using a sterile syringe, slowly inject 8 mL of sterile water for injection into the 

160 mg trastuzumab emtansine vial. 
∑ Swirl the vial gently until completely dissolved. Do not shake.  
 
Reconstituted solution should be inspected visually for particulate matter and discolouration prior to 
administration. The reconstituted solution should be free of visible particulates, clear to slightly 
opalescent. The colour of the reconstituted solution should be colourless to pale brown. Do not use if 
reconstituted solution is cloudy or discoloured. 
 
Discard any unused portion. The reconstituted product contains no preservative and is intended for 
single use only. 
 
Instructions for dilution 
Determine the volume of the reconstituted solution required based on a dose of 3.6 mg trastuzumab 
emtansine/kg body weight: 
 
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 bag 
containing 250 mL of sodium chloride 4.5 mg/mL (0.45%) solution for infusion or sodium chloride 
9 mg/mL (0.9%) solution for infusion. Glucose (5%) solution should not be used 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 used for infusion, a 
0.20 or 0.22 micron in-line polyethersulfone (PES) filter is required. Once the infusion is prepared it 
should be administered immediately. Do not freeze or shake the infusion during storage. If diluted 
aseptically, it may be stored for up to 24 hours at 2°C to 8°C. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  
	A. LABELLING
	B. PACKAGE LEAFLET