Enhertu

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Enhertu 100 mg powder for concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One vial of powder for concentrate for solution for infusion contains 100 mg of trastuzumab 
deruxtecan. After reconstitution, one vial of 5 mL solution contains 20 mg/mL of trastuzumab 
deruxtecan (see section 6.6). 
 
Trastuzumab deruxtecan is an antibody-drug conjugate (ADC) that contains a humanised 
anti-HER2 IgG1 monoclonal antibody (mAb) with the same amino acid sequence as trastuzumab, 
produced by mammalian (Chinese Hamster Ovary) cells, covalently linked to DXd, an exatecan 
derivative and a topoisomerase I inhibitor, via a tetrapeptide-based cleavable linker. Approximately 
8 molecules of deruxtecan are attached to each antibody molecule. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for concentrate for solution for infusion. 
 
White to yellowish-white lyophilised powder. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Enhertu as monotherapy is indicated for the treatment of adult patients with unresectable or metastatic 
HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens. 
 
4.2 Posology and method of administration 
 
Enhertu should be prescribed by a physician and administered under the supervision of a healthcare 
professional experienced in the use of anticancer medicinal products. 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 Enhertu (trastuzumab deruxtecan) and not trastuzumab or trastuzumab 
emtansine. 
 
Enhertu should not be substituted with trastuzumab or trastuzumab emtansine. 
 
Patients treated with trastuzumab deruxtecan should have documented 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. 
 



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Posology 
 
The recommended dose of Enhertu is 5.4 mg/kg given as an intravenous infusion once every 3 weeks 
(21-day cycle) until disease progression or unacceptable toxicity.  
 
The initial dose should be administered as a 90-minute intravenous infusion. If the prior infusion was 
well tolerated, subsequent doses of Enhertu may be administered as 30-minute infusions. Antiemetics 
may be administered in accordance with local medical practice as per patient tolerance for prophylaxis 
or management. 
 
The infusion rate of Enhertu should be slowed or interrupted if the patient develops infusion-related 
symptoms. Enhertu should be permanently discontinued in case of severe infusion reactions. 
 
Dose modifications 
 
Management of adverse reactions may require temporary interruption, dose reduction, or treatment 
discontinuation of Enhertu per guidelines provided in Tables 1 and 2. 
 
Enhertu dose should not be re-escalated after a dose reduction is made. 
 
Table 1: Dose reduction schedule 

Dose reduction schedule 
(Starting dose is 5.4 mg/kg) 

Dose to be administered 

First dose reduction 4.4 mg/kg 
Second dose reduction 3.2 mg/kg 
Requirement for further dose reduction Discontinue treatment 

 
Table 2: Dose modifications for adverse reactions 
Adverse reaction Severity Treatment modification 
Interstitial lung 
disease 
(ILD)/pneumonitis 

Asymptomatic ILD/pneumonitis 
(Grade 1) 
 

Interrupt Enhertu until resolved to 
Grade 0, then: 
• if resolved in 28 days or less from 

date of onset, maintain dose. 
• if resolved in greater than 28 days 

from date of onset, reduce dose 
one level (see Table 1). 

• consider corticosteroid treatment 
as soon as ILD/pneumonitis is 
suspected (see section 4.4). 

Symptomatic ILD/pneumonitis 
(Grade 2 or greater) 
 

• Permanently discontinue Enhertu. 
• Promptly initiate corticosteroid 

treatment as soon as 
ILD/pneumonitis is suspected (see 
section 4.4). 

Neutropenia Grade 3 (less than 1.0-0.5 × 109/L) • Interrupt Enhertu until resolved to 
Grade 2 or less, then maintain 
dose. 

Grade 4 (less than 0.5 × 109/L) • Interrupt Enhertu until resolved to 
Grade 2 or less. 

• Reduce dose by one level (see 
Table 1). 

Febrile neutropenia Absolute neutrophil count of less 
than 1.0 × 109/L and temperature 
greater than 38.3 °C or a sustained 
temperature of 38 °C or greater for 
more than one hour. 

• Interrupt Enhertu until resolved. 
• Reduce dose by one level (see 

Table 1). 



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Adverse reaction Severity Treatment modification 
Left ventricular 
ejection fraction 
(LVEF) decreased 

LVEF greater than 45% and 
absolute decrease from baseline is 
10% to 20% 

• Continue treatment with Enhertu. 

LVEF 
40% to 45% 

And absolute 
decrease from 
baseline is less than 
10% 

• Continue treatment with Enhertu. 
• Repeat LVEF assessment within 

3 weeks. 

And absolute 
decrease from 
baseline is 
10% to 20% 

• Interrupt Enhertu. 
• Repeat LVEF assessment within 

3 weeks. 
• If LVEF has not recovered to within 

10% from baseline, permanently 
discontinue Enhertu. 

• If LVEF recovers to within 10% 
from baseline, resume treatment 
with Enhertu at the same dose. 

LVEF less than 40% or absolute 
decrease from baseline is greater 
than 20% 

• Interrupt Enhertu 
• Repeat LVEF assessment within 

3 weeks. 
• If LVEF of less than 40% or 

absolute decrease from baseline of 
greater than 20% is confirmed, 
permanently discontinue Enhertu. 

Symptomatic congestive heart 
failure (CHF) 

• Permanently discontinue Enhertu. 

Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for 
Adverse Events Version 4.03 (NCI-CTCAE v.4.03). 
 
Delayed or missed dose 
 
If a planned dose is delayed or 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 infusion should be administered at the dose and rate the patient tolerated 
in the most recent infusion. 
 
Special populations 
 
Elderly 
No dose adjustment of Enhertu is required in patients aged 65 years or older. Limited data are 
available in patients ≥ 75 years of age. 
 
Renal impairment 
No dose adjustment is required in patients with mild (creatinine clearance [CLcr] ≥ 60 and 
< 90 mL/min) or moderate (CLcr ≥ 30 and < 60 mL/min) 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. A higher incidence of Grade 1 and 2 ILD has been observed in patients with 
moderate renal impairment. Patients with moderate or severe renal impairment should be monitored 
carefully (see section 5.2). 
 
Hepatic impairment 
No dose adjustment is required in patients with total bilirubin ≤ 1.5 times upper limit of normal 
(ULN), irrespective of aspartate transaminase (AST) value. The potential need for dose adjustment in 



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patients with total bilirubin > 1.5 times ULN, irrespective of AST value, cannot be determined due to 
insufficient data; therefore, these patients should be monitored carefully (see sections 4.4 and 5.2). 
 
Paediatric population 
The safety and efficacy of Enhertu in children and adolescents below the age of 18 years have not 
been established. No data are available. 
 
Method of administration 
 
Enhertu is for intravenous use. It must be reconstituted and diluted by a healthcare professional and 
administered as an intravenous infusion. Enhertu 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 prevent medicinal product errors, it is important to check the vial labels to ensure that the 
medicinal product being prepared and administered is Enhertu (trastuzumab deruxtecan) and not 
trastuzumab or trastuzumab emtansine. 
 
Traceability 
 
In order to improve the traceability of biological medicinal products, the name and the batch number 
of the administered product should be clearly recorded. 
 
Interstitial lung disease/pneumonitis 
 
Cases of interstitial lung disease (ILD), and/or pneumonitis, have been reported with Enhertu (see 
section 4.8). Fatal outcomes have been observed. Patients should be advised to immediately report 
cough, dyspnoea, fever, and/or any new or worsening respiratory symptoms. Patients should be 
monitored for signs and symptoms of ILD/pneumonitis. Evidence of ILD/pneumonitis should be 
promptly investigated. Patients with suspected ILD/pneumonitis should be evaluated by radiographic 
imaging, preferably a computed tomography (CT) scan. Consultation with a pulmonologist should be 
considered. For asymptomatic (Grade 1) ILD/pneumonitis, consider corticosteroid treatment (e.g. 
≥ 0.5 mg/kg prednisolone or equivalent). Enhertu should be withheld until recovery to Grade 0 and 
may be resumed according to instructions in Table 2 (see section 4.2). For symptomatic 
ILD/pneumonitis (Grade 2 or greater), promptly initiate corticosteroid treatment (e.g. ≥ 1 mg/kg 
prednisolone or equivalent) and continue for at least 14 days or until complete resolution of clinical 
and chest CT findings. Then gradually taper for at least 4 weeks. Enhertu should be permanently 
discontinued in patients who are diagnosed with any symptomatic (Grade 2 or greater) 
ILD/pneumonitis (see section 4.2). Patients with a history of ILD/pneumonitis may be at increased risk 
of developing ILD/pneumonitis. 
 
Neutropenia 
 
Cases of neutropenia, including febrile neutropenia, were reported in clinical studies of Enhertu. 
Complete blood counts should be monitored prior to initiation of Enhertu and prior to each dose, and 
as clinically indicated. Based on the severity of neutropenia, Enhertu may require dose interruption or 
reduction (see section 4.2). 
 



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Left ventricular ejection fraction decrease 
 
Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies. In the 
234 patients with unresectable or metastatic HER2-positive breast cancer who received Enhertu 
5.4 mg/kg, three cases (1.3%) of asymptomatic LVEF decrease, of which 2 (0.9%) were Grade 2 and 1 
(0.4%) was Grade 3, were reported. Observed frequency of LVEF decreased based on laboratory 
parameters (echocardiogram or multigated acquisition [MUGA] scanning) was 37 (16.9%); all were 
Grade 2. No decreases of LVEF to less than 40% or absolute decrease from baseline of greater than 
20% were observed. Treatment with Enhertu has not been studied in patients with LVEF less than 
50% prior to initiation of treatment (see section 4.8). 
 
Standard cardiac function testing (echocardiogram or MUGA scanning) should be performed to assess 
LVEF prior to initiation of Enhertu and at regular intervals during treatment as clinically indicated. 
Enhertu should be permanently discontinued if LVEF of less than 40% or absolute decrease from 
baseline of greater than 20% is confirmed. Enhertu should be permanently discontinued in patients 
with symptomatic congestive heart failure (CHF) (see section 4.2). 
 
Embryo-foetal toxicity 
 
Enhertu can cause foetal harm when administered to a pregnant woman. In post-marketing reports, use 
of trastuzumab, a HER2 receptor antagonist, during pregnancy resulted in cases of oligohydramnios 
manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Based on 
findings in animals and its mechanism of action, the topoisomerase I inhibitor component of Enhertu, 
DXd, can also cause embryo-foetal harm when administered to a pregnant woman (see section 4.6). 
 
The pregnancy status of females of reproductive potential should be verified prior to the initiation of 
Enhertu. The patient should be informed of the potential risks to the foetus. Females of reproductive 
potential should be advised to use effective contraception during treatment and for at least 7 months 
following the last dose of Enhertu. Male patients with female partners of reproductive potential should 
be advised to use effective contraception during treatment with Enhertu and for at least 4 months after 
the last dose of Enhertu (see section 4.6). 
 
Patients with moderate or severe hepatic impairment 
 
There are limited data in patients with moderate hepatic impairment and no data in patients with 
severe hepatic impairment. As metabolism and biliary excretion are the primary routes of elimination 
of the topoisomerase I inhibitor, DXd, Enhertu should be administered with caution in patients with 
moderate and severe hepatic impairment (see sections 4.2 and 5.2). 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Co-administration with ritonavir, an inhibitor of OATP1B, CYP3A and P-gp, or with itraconazole, a 
strong inhibitor of CYP3A and P-gp, resulted in no clinically meaningful (approximately 10-20%) 
increase in exposures of trastuzumab deruxtecan or the released topoisomerase I inhibitor, DXd. No 
dose adjustment is required during co-administration of trastuzumab deruxtecan with medicinal 
products that are inhibitors of CYP3A or OATP1B or P-gp transporters (see section 5.2). 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/Contraception in males and females 
 
Pregnancy status of women of childbearing potential should be verified prior to initiation of Enhertu. 
 
Women of childbearing potential should use effective contraception during treatment with Enhertu and 
for at least 7 months following the last dose. 
 



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Men with female partners of childbearing potential should use effective contraception during treatment 
with Enhertu and for at least 4 months following the last dose. 
 
Pregnancy 
 
There are no available data on the use of Enhertu in pregnant women. However, trastuzumab, a 
HER2 receptor antagonist, can cause foetal harm when administered to a pregnant woman. In 
post-marketing reports, use of trastuzumab during pregnancy resulted in cases of oligohydramnios in 
some cases manifested as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death. 
Based on findings in animals and its mechanism of action, the topoisomerase I inhibitor component of 
Enhertu, DXd, can be expected to cause embryo-foetal harm when administered to a pregnant woman 
(see section 5.3). 
 
Administration of Enhertu to pregnant women is not recommended, and patients should be informed 
of the potential risks to the foetus before they become pregnant. Women who become pregnant must 
immediately contact their doctor. If a woman becomes pregnant during treatment with Enhertu or 
within 7 months following the last dose of Enhertu, close monitoring is recommended. 
 
Breast-feeding 
 
It is not known if trastuzumab deruxtecan is excreted in human milk. Human IgG is secreted in human 
milk, and the potential for absorption and serious adverse reactions to the infant is unknown. 
Therefore, women should not breast-feed during treatment with Enhertu or for 7 months after the last 
dose. A decision should be made to discontinue breast-feeding or to discontinue treatment taking into 
account the benefit of breast-feeding for the child and/or benefit of treatment with Enhertu for the 
mother. 
 
Fertility 
 
No dedicated fertility studies have been conducted with trastuzumab deruxtecan. Based on results 
from animal toxicity studies, Enhertu may impair male reproductive function and fertility. It is not 
known whether trastuzumab deruxtecan or its metabolites are found in seminal fluid. Before starting 
treatment, male patients should be advised to seek counselling on sperm storage. Male patients must 
not freeze or donate sperm throughout the treatment period, and for at least 4 months after the final 
dose of Enhertu. 
 
4.7 Effects on ability to drive and use machines 
 
Enhertu may have a minor influence on the ability to drive and use machines. Patients should be 
advised to use caution when driving or operating machinery in case they experience fatigue, headache 
or dizziness during treatment with Enhertu (see section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The most common adverse reactions were nausea (79.9%), fatigue (60.3%), vomiting (48.7%), 
alopecia (46.2%), constipation (35.9%), decreased appetite (34.6%), anaemia (33.8%), neutropenia 
(32.5%), diarrhoea (30.8%), thrombocytopenia (23.1%), cough (21.4%), leukopenia (20.5%), and 
headache (20.1%).  
 
The most common National Cancer Institute – Common Terminology Criteria for Adverse Events 
(NCI-CTCAE v.4.03) Grade ≥ 3 adverse reactions were neutropenia (18.8%), anaemia (9.0%), nausea 
(6.8%), fatigue (6.4%), leukopenia (5.6%), lymphopenia (5.1%), vomiting (4.3%), thrombocytopenia 
(4.3%), hypokalaemia (3.4%), interstitial lung disease (ILD, 3.0%), diarrhoea (2.6%), febrile 
neutropenia (1.7%), dyspnoea (1.7%), abdominal pain (1.3%), decreased appetite (1.3%), and alanine 
aminotransferase increased (1.3%). In 2.6% of patients, ILD led to death. 



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Dose interruptions due to adverse reactions occurred in 27% of patients treated with Enhertu. The 
most frequent adverse reactions associated with dose interruption were neutropenia (14.5%), anaemia 
(3.4%), upper respiratory tract infection (3.0%), leukopenia (3.0%), ILD (2.6%), thrombocytopenia 
(2.6%), and fatigue (2.1%). Dose reductions occurred in 15% of patients treated with Enhertu. The 
most frequent adverse reactions associated with dose reduction were fatigue (3.8%), nausea (3.4%), 
and neutropenia (3.4%). Discontinuation of therapy due to an adverse reaction occurred in 12% of 
patients treated with Enhertu. The most frequent adverse reaction associated with permanent 
discontinuation was ILD (9.4%). 
 
Tabulated list of adverse reactions 
 
The safety of Enhertu has been evaluated in a pooled analysis of 234 patients with unresectable or 
metastatic HER2-positive breast cancer who received at least one dose of Enhertu 5.4 mg/kg in 
clinical studies. The median duration of exposure to Enhertu was 9.8 months (range: 
0.7 to 37.1 months). 
 
The adverse reactions in patients who received at least one dose of Enhertu in clinical studies are 
presented in Table 3. The adverse reactions are listed 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, adverse reactions are presented in the order of decreasing seriousness. 
 
Table 3: Adverse reactions in patients treated with trastuzumab deruxtecan 

System organ class/preferred term or grouped term Frequency 

Infections and infestations 

Upper respiratory tract infectiona Very common 

Blood and lymphatic system disorders 

Neutropeniab Very common 

Anaemiac Very common 

Leukopeniad Very common 

Lymphopeniae Very common 

Thrombocytopeniaf Very common 

Febrile neutropenia Common 

Metabolism and nutrition disorders 

Hypokalaemia Very common 

Decreased appetite Very common 

Nervous system disorders 

Headacheg Very common 

Dizziness Very common 

Eye disorders 

Dry eye Very common 

Respiratory, thoracic and mediastinal disorders 

Interstitial lung diseaseh Very common 



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System organ class/preferred term or grouped term Frequency 

Dyspnoea Very common 

Cough Very common 

Epistaxis Very common 

Gastrointestinal disorders 

Nausea  Very common 

Vomiting Very common 

Diarrhoea Very common 

Abdominal paini Very common 

Constipation Very common 

Stomatitisj Very common 

Dyspepsia  Very common 

Skin and subcutaneous tissue disorders 

Alopecia Very common 

Rashk Very common 

General disorders and administration site conditions 

Fatiguel Very common 

Investigations 

Alanine aminotransferase increased Very common 

Aspartate aminotransferase increased Very common 

Ejection fraction decreasedm Very common 

Injury, poisoning and procedural complications 

Infusion-related reactionsn Common 
a Includes influenza, influenza-like illness, and upper respiratory tract infection. 
b Includes neutropenia and neutrophil count decreased. 
c Includes anaemia, haemoglobin decreased, red blood cell count decreased, and haematocrit decreased. 
d Includes leukopenia and white blood cell count decreased. 
e Includes lymphopenia and lymphocyte count decreased. 
f Includes thrombocytopenia and platelet count decreased. 
g Includes headache, sinus headache, and migraine. 
h Interstitial lung disease includes events that were adjudicated as ILD: pneumonitis, interstitial lung disease, 

respiratory failure, organising pneumonia, acute respiratory failure, lung infiltration, lymphangitis, and 
alveolitis. 

i Includes abdominal discomfort, gastrointestinal pain, abdominal pain, abdominal pain lower, and 
abdominal pain upper. 

j Includes stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosal blistering. 
k Includes rash, rash pustular, and rash maculopapular. 
l Includes fatigue and asthenia. 
m Includes laboratory parameters of LVEF decrease (n = 37) and/or preferred terms of ejection fraction 

decreased (n = 3), cardiac failure (n = 1) and cardiac failure congestive (n = 1). 
n Cases of infusion-related reactions include infusion-related reaction (n = 4), hypersensitivity (n = 1), and 

flushing (n = 1). 
 



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Description of selected adverse reactions 
 
Interstitial lung disease 
In clinical studies (n = 234), ILD occurred in 15.0% of patients. Most ILD cases were Grade 1 (3.0%), 
Grade 2 (8.5%) or Grade 3 (0.4%). Grade 5 events occurred in 3.0% of patients. Median time to first 
onset was 5.5 months (range: 1.2 to 20.8) (see sections 4.2 and 4.4). 
 
Neutropenia 
In clinical studies (n = 234), a decrease in neutrophil count was reported in 32.5% of patients and 
18.8% had Grade 3 or 4 events. Median time of onset was 53 days (range: 8 days to 18.0 months), and 
median duration of the first event was 22 days (range: 2 days to 9.0 months). Febrile neutropenia was 
reported in 1.7% of patients (see section 4.2). 
 
Immunogenicity 
 
As with all therapeutic proteins, there is a potential for immunogenicity. Across all doses evaluated in 
clinical studies, 0.6% (4/640) of evaluable patients developed antibodies against trastuzumab 
deruxtecan following treatment with Enhertu. There was no association between development of 
antibodies and allergic-type reactions. 
 
Paediatric population 
 
Safety has not been established in this population. 
 
Elderly 
 
Of the 234 patients with HER2-positive breast cancer treated with Enhertu 5.4 mg/kg, 26% were 
65 years or older and 5% were 75 years or older. There was a higher incidence of Grade 3-4 adverse 
reactions observed in patients aged 65 years or older (49%) as compared to younger patients (39%), 
leading to more discontinuations due to adverse reactions. 
 
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 
 
The maximum tolerated dose of trastuzumab deruxtecan has not been determined. In clinical studies, 
single doses higher than 8.0 mg/kg have not been tested. In case of overdose, patients must be closely 
monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment 
initiated. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: trastuzumab deruxtecan, ATC code: L01XC41 
 
Mechanism of action 
 
Enhertu, trastuzumab deruxtecan, is a HER2-targeted antibody-drug conjugate. The antibody is a 
humanised anti-HER2 IgG1 attached to deruxtecan, a topoisomerase I inhibitor (DXd) bound by a 
tetrapeptide-based cleavable linker. The antibody-drug conjugate is stable in plasma. The function of 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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the antibody portion is to bind to HER2 expressed on the surface of certain tumour cells. After 
binding, the trastuzumab deruxtecan complex then undergoes internalisation and intracellular linker 
cleavage by lysosomal enzymes that are upregulated in cancer cells. Upon release, the 
membrane-permeable DXd causes DNA damage and apoptotic cell death. DXd, an exatecan 
derivative, is approximately 10 times more potent than SN-38, the active metabolite of irinotecan. 
 
In vitro studies indicate that the antibody portion of trastuzumab deruxtecan, which has the same 
amino acid sequence as trastuzumab, also binds to FcγRIIIa and complement C1q. The antibody 
mediates antibody-dependent cellular cytotoxicity (ADCC) in human breast cancer cells that 
overexpress HER2. In addition, the antibody inhibits signalling through the phosphatidylinositol 
3-kinase (PI3-K) pathway in human breast cancer cells that overexpress HER2. 
 
Clinical efficacy 
 
The efficacy and safety of Enhertu were studied in DESTINY-Breast01, a multicentre, open-label, 
single-arm Phase 2 study that enrolled patients with HER2-positive, unresectable and/or metastatic 
breast cancer who had received two or more prior anti-HER2-based regimens, including trastuzumab 
emtansine (100%), trastuzumab (100%), and pertuzumab (65.8%). Archival breast tumour samples 
were required to show HER2 positivity defined as HER2 IHC 3+ or ISH-positive. The study excluded 
patients with a history of treated ILD or ILD at screening, patients with untreated or symptomatic 
brain metastases, and patients with a history of clinically significant cardiac disease. Patients enrolled 
had at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). 
Enhertu was administered by intravenous infusion at 5.4 mg/kg once every three weeks until disease 
progression, death, withdrawal of consent, or unacceptable toxicity. The primary efficacy outcome 
measure was confirmed objective response rate (ORR) according to RECIST v1.1 in the intent-to-treat 
(ITT) population as evaluated by independent central review. The secondary efficacy outcome 
measure was duration of response (DOR). 
 
Of the 184 patients enrolled in DESTINY-Breast01, baseline demographic and disease characteristics 
were: median age 55 years (range: 28 to 96); 65 years or older (23.9%); female (100%); White 
(54.9%), Asian (38.0%), Black or African-American (2.2%); Eastern Cooperative Oncology Group 
(ECOG) performance status 0 (55.4%) or 1 (44.0%); hormone receptor status (positive: 52.7%); 
presence of visceral disease (91.8%); previously treated and stable brain metastases (13.0%); median 
number of prior therapies in the metastatic setting: 5 (range: 2 to 17); sum of diameters of target 
lesions (< 5 cm: 42.4%, ≥ 5 cm: 50.0%). 
 
An earlier analysis (median duration of follow-up 11.1 months [range: 0.7 to 19.9 months]) showed a 
confirmed objective response rate of 60.9% (95% CI: 53.4, 68.0) with 6.0% being complete 
responders and 54.9% being partial responders; 36.4% had stable disease, 1.6% had progressive 
disease and 1.1% were not evaluable. Median duration of response at that time was 14.8 months 
(95% CI: 13.8, 16.9) with 81.3% of responders having a response of ≥ 6 months (95% CI: 71.9, 87.8). 
Efficacy results from an updated data cutoff with median duration of follow-up of 20.5 months (range: 
0.7 to 31.4 months) are shown in Table 4. 
 
Table 4: Efficacy results in DESTINY-Breast01 (intent-to-treat analysis set) 

 DESTINY-Breast01 
N = 184 

Confirmed objective response rate (95% CI)*† 61.4% (54.0, 68.5) 

Complete response (CR) 6.5% 

Partial response (PR) 54.9% 

Duration of response‡  

Median, months (95% CI) 20.8 (15.0, NR) 
% with duration of response ≥ 6 months (95% 
CI)§ 81.5% (72.2, 88.0) 



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ORR 95% CI calculated using Clopper-Pearson method 
CI = confidence interval 
95% CIs calculated using Brookmeyer-Crowley method 
*Confirmed responses (by blinded independent central review) were defined as a recorded response of either 
CR/PR, confirmed by repeat imaging not less than 4 weeks after the visit when the response was first observed. 
†Of the 184 patients, 35.9% had stable disease, 1.6% had progressive disease and 1.1% were not evaluable. 
‡Includes 73 patients with censored data 
§Based on Kaplan-Meier estimation 
NR = not reached 

 
Consistent anti-tumour activity was observed across pre-specified subgroups based on prior 
pertuzumab therapy and hormone receptor status. 
 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies in all 
subsets of the paediatric population in breast cancer (see section 4.2 for information on paediatric use). 
 
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This 
means that further evidence on this medicinal product is awaited. 
The European Medicines Agency will review new information on this medicinal product at least every 
year and this SmPC will be updated as necessary. 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
Trastuzumab deruxtecan is administered intravenously. There have been no studies performed with 
other routes of administration. 
 
Distribution 
 
Based on population pharmacokinetic analysis, the volume of distribution of the central compartment 
(Vc) of trastuzumab deruxtecan and topoisomerase I inhibitor, DXd, were estimated to be 2.77 L and 
27.4 L, respectively. 
 
In vitro, the mean human plasma protein binding of DXd was approximately 97%. 
 
In vitro, the blood to plasma concentration ratio of DXd was approximately 0.6. 
 
Biotransformation 
 
Trastuzumab deruxtecan undergoes intracellular cleavage by lysosomal enzymes to release the DXd. 
 
The humanised HER2 IgG1 monoclonal antibody is expected to be degraded into small peptides and 
amino acids via catabolic pathways in the same manner as endogenous IgG. 
 
In vitro metabolism studies in human liver microsomes indicate that DXd is metabolised mainly by 
CYP3A4 via oxidative pathways. 
 
Elimination 
 
Based on population pharmacokinetic analysis, following intravenous administration of trastuzumab 
deruxtecan in patients with metastatic HER2-positive breast cancer, the clearance of trastuzumab 
deruxtecan was estimated to be 0.42 L/day and the clearance of DXd was 19.2 L/h. In cycle 3, the 
apparent elimination half-life (t1/2) of trastuzumab deruxtecan and released DXd was approximately 
7 days. Moderate accumulation (approximately 35% in cycle 3 compared to cycle 1) of trastuzumab 
deruxtecan was observed. 



13 

 
Following intravenous administration of DXd to rats, the major excretion pathway was faeces via the 
biliary route. DXd was the most abundant component in urine, faeces, and bile. Following single 
intravenous administration of trastuzumab deruxtecan (6.4 mg/kg) to monkeys, unchanged released 
DXd was the most abundant component in urine and faeces. DXd excretion was not studied in 
humans. 
 
In vitro interactions 
 
Effects of Enhertu on the pharmacokinetics of other medicinal products 
In vitro studies indicate DXd does not inhibit major CYP450 enzymes including CYP1A2, 2B6, 2C8, 
2C9, 2C19, 2D6 and 3A. In vitro studies indicate that DXd does not inhibit OAT1, OAT3, OCT1, 
OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, P-gp, BCRP, or BSEP transporters. 
 
Effects of other medicinal products on the pharmacokinetics of Enhertu 
In vitro, DXd was a substrate of P-gp, OATP1B1, OATP1B3, MATE2-K, MRP1, and BCRP.  
No clinically meaningful interaction is expected with medicinal products that are inhibitors of 
MATE2-K, MRP1, P-gp, OATP1B1, or BCRP transporters (see section 4.5). 
 
Linearity/non-linearity 
 
The exposure of trastuzumab deruxtecan and released DXd when administered intravenously 
increased in proportion to dose in the 3.2 mg/kg to 8.0 mg/kg dose range (approximately 
0.6 to 1.5 times the recommended dose) with low to moderate inter-subject variability. Based on 
population pharmacokinetic analysis, inter-subject variability in trastuzumab deruxtecan and DXd 
elimination clearances was approximately 25% and for central volume of distribution was 
approximately 16% and 42%, respectively. The intra-subject variability in trastuzumab deruxtecan and 
DXd AUC values (area under the serum concentration versus time curve) was approximately 8% and 
14%, respectively. 
 
Special populations 
 
Based on population pharmacokinetic analysis, age (23-96 years), race, ethnicity, sex and body weight 
did not have a clinically meaningful effect on exposure of trastuzumab deruxtecan or released DXd. 
 
Elderly 
The population PK analysis showed that age (range: 23-96 years) did not affect the PK of trastuzumab 
deruxtecan. 
 
Renal impairment 
No dedicated renal impairment study was conducted. Based on population pharmacokinetic analysis 
including patients with mild (creatinine clearance [CLcr] ≥ 60 and <90 mL/min) or moderate 
(CLcr ≥ 30 and <60 mL/min) renal impairment (estimated by Cockcroft-Gault), the pharmacokinetics 
of the released DXd was not affected by mild or moderate renal impairment as compared to normal 
renal function (CLcr ≥ 90 mL/min). 
 
Hepatic impairment 
No dedicated hepatic impairment study was conducted. Based on population pharmacokinetic 
analysis, the impact of changes on pharmacokinetics of trastuzumab deruxtecan in patients with total 
bilirubin ≤ 1.5 times ULN, irrespective of AST level, is not clinically meaningful. There are 
insufficient data for patients with total bilirubin > 1.5 to 3 times ULN, irrespective of AST level, to 
draw conclusions, and no data is available for patients with total bilirubin > 3 times ULN, irrespective 
of AST level (see sections 4.2 and 4.4). 
 



14 

Paediatric population 
No studies have been conducted to investigate the pharmacokinetics of trastuzumab deruxtecan in 
children or adolescents. 
 
5.3 Preclinical safety data 
 
In animals, toxicities were observed in lymphatic and haematopoietic organs, intestines, kidneys, 
lungs, testes and skin following the administration of trastuzumab deruxtecan at exposure levels of the 
topoisomerase I inhibitor (DXd) below clinical plasma exposure. In these animals, antibody-drug 
conjugate (ADC) exposure levels were similar or above clinical plasma exposure. 
 
DXd was clastogenic in both an in vivo rat bone marrow micronucleus assay and an in vitro Chinese 
hamster lung chromosome aberration assay and was not mutagenic in an in vitro bacterial reverse 
mutation assay. 
 
Carcinogenicity studies have not been conducted with trastuzumab deruxtecan. 
 
Dedicated fertility studies have not been conducted with trastuzumab deruxtecan. Based on results 
from general animal toxicity studies, trastuzumab deruxtecan may impair male reproductive function 
and fertility. 
 
There were no animal reproductive or developmental toxicity studies conducted with trastuzumab 
deruxtecan. Based on results from general animal toxicity studies, trastuzumab deruxtecan and DXd 
were toxic to rapidly dividing cells (lymphatic/haematopoietic organs, intestine, or testes), and DXd 
was genotoxic, suggesting the potential for embryotoxicity and teratogenicity. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
L-histidine 
L-histidine hydrochloride monohydrate 
Sucrose 
Polysorbate 80 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products except those mentioned in section 6.6.  
 
Sodium chloride solution for infusion must not be used for reconstitution or dilution since it may cause 
particulate formation. 
 
6.3 Shelf life 
 
Unopened vial 
 
2 years. 
 
Reconstituted solution 
 
Chemical and physical in-use stability has been demonstrated for up to 24 hours at 2 ºC to 8 ºC. 
 
From a microbiological point of view, the product should be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and 



15 

would normally not be longer than 24 hours at 2 ºC to 8 ºC, unless reconstitution has taken place in 
controlled and validated aseptic conditions. 
 
Diluted solution 
 
It is recommended that the diluted solution be used immediately. If not used immediately, the 
reconstituted solution diluted in infusion bags containing 5% glucose solution may be stored at room 
temperature (≤ 30 ºC) for up to 4 hours or in a refrigerator at 2 ºC to 8 ºC for up to 24 hours, protected 
from light. These storage times start from the time of reconstitution. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2 ºC - 8 ºC). 
 
Do not freeze. 
 
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Enhertu is provided in 10 mL Type 1 amber borosilicate glass vial sealed with a fluoro-resin laminated 
butyl rubber stopper, and a polypropylene/aluminium yellow flip-off crimp cap.  
Each carton contains 1 vial. 
 
6.6 Special precautions for disposal and other handling 
 
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 Enhertu (trastuzumab deruxtecan) and not 
trastuzumab or trastuzumab emtansine. 
 
Appropriate procedures for the preparation of chemotherapeutic medicinal products should be used. 
Appropriate aseptic technique should be used for the following reconstitution and dilution procedures. 
 
Reconstitution 
 
• Reconstitute immediately before dilution. 
• More than one vial may be needed for a full dose. Calculate the dose (mg), the total volume of 

reconstituted Enhertu solution required, and the number of vial(s) of Enhertu needed (see 
section 4.2). 

• Reconstitute each 100 mg vial using a sterile syringe to slowly inject 5 mL of water for injection 
into each vial to obtain a final concentration of 20 mg/mL. 

• Swirl the vial gently until completely dissolved. Do not shake. 
• Inspect the reconstituted solution for particulates and discolouration. The solution should be 

clear and colourless to light yellow. Do not use if visible particles are observed or if the solution 
is cloudy or discoloured. 

• If not used immediately, store the reconstituted Enhertu vials in a refrigerator at 2 ºC to 8 ºC for 
up to 24 hours from the time of reconstitution, protected from light. Do not freeze. 

• The reconstituted product contains no preservative and is intended for single use only. 
 
Dilution 
 
• Dilute the calculated volume of reconstituted Enhertu in an infusion bag containing 100 mL of 

5% glucose solution. Do not use sodium chloride solution (see section 6.2). An infusion bag 
made of polyvinylchloride or polyolefin (copolymer of ethylene and polypropylene) is 
recommended. 

• Gently invert the infusion bag to thoroughly mix the solution. Do not shake. 



16 

• Cover the infusion bag to protect from light. 
• If not used immediately, store at room temperature for up to 4 hours including preparation and 

infusion or in a refrigerator at 2 ºC to 8 ºC for up to 24 hours, protected from light. Do not 
freeze. 

• Discard any unused portion left in the vial. 
 
Administration 
 
• If the prepared infusion solution was stored refrigerated (2 ºC to 8 ºC), it is recommended that 

the solution be allowed to equilibrate to room temperature prior to administration, protected 
from light. 

• Administer Enhertu as an intravenous infusion only with a 0.20 or 0.22 micron in-line 
polyethersulfone (PES) or polysulfone (PS) filter.  

• The initial dose should be administered as a 90-minute intravenous infusion. If the prior 
infusion was well tolerated, subsequent doses of Enhertu may be administered as 30-minute 
infusions. Do not administer as an intravenous push or bolus (see section 4.2). 

• Do not mix Enhertu with other medicinal products or administer other medicinal products 
through the same intravenous line. 

 
Disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Daiichi Sankyo Europe GmbH 
Zielstattstrasse 48 
81379 Munich 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1508/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
 
 
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/


17 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE 
SUBSTANCE(S) AND MANUFACTURER(S) 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 

 
E. SPECIFIC OBLIGATION TO COMPLETE POST-

AUTHORISATION MEASURES FOR THE CONDITIONAL 
MARKETING AUTHORISATION 

 



18 

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

 
Name and address of the manufacturers of the biological active substance 
 
Daiichi Sankyo Chemical Pharma Co., Ltd. 
Onahama Plant 
389-4, Izumimachi Shimokawa Aza Otsurugi, Iwaki, 
Fukushima 971-8183 
Japan 
 
 
Name and address of the manufacturer responsible for batch release 
 
Daiichi Sankyo Europe GmbH 
Luitpoldstrasse 1 
85276 Pfaffenhofen 
Germany 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to 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 (PSURs) 
 
The requirements for submission of PSURs 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. 
 
The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 
6 months following authorisation.  
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT   
 
• Risk management plan (RMP) 

 
The marketing authorisation holder (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. 
 

Additional risk minimisation measures are necessary for the safe and effective use of the product. 
 



19 

Prior to the launch in each Member State the MAH must agree about the content and format of the 
educational materials, including communication media, distribution modalities, and any other aspects 
of the programme with the National Competent Authority. The MAH shall ensure that in each 
Member State where ENHERTU (trastuzumab deruxtecan) is marketed, all healthcare professionals 
and patients/carers who are expected to prescribe, dispense and receive ENHERTU (trastuzumab 
deruxtecan) have access to/are provided with the following educational materials to be disseminated 
through professional bodies consisting of the following: 
 
I) Healthcare Professional (HCP) Guide for ILD/pneumonitis 
 
The HCP Guide will contain the following key elements:   

• Summary of important findings of trastuzumab deruxtecan-induced ILD/pneumonitis (eg, 
frequency, grade, time to onset) observed in the clinical trial setting 

• Description of the appropriate monitoring and evaluation of ILD/pneumonitis in patients 
receiving trastuzumab deruxtecan  

• Detailed description of management of ILD/pneumonitis in patients treated with trastuzumab 
deruxtecan including guidance on drug interruption, reduction and treatment discontinuation for 
ILD/pneumonitis 

• Reminder to HCP that they should repeat the information about signs and symptoms of 
ILD/pneumonitis at each patient visit, including when the patient should seek attention from an 
HCP (eg, the symptoms to watch for; the importance to adhere to scheduled appointments). 

• Reminder to HCP to provide the patient with the Patient Card (PC), including advice that the PC 
should be kept with the patient at all times. 

 
Patient Card 
 
The Patient Card will contain the following key elements: 

• Description of the important risks of ILD/pneumonitis associated with the use of trastuzumab 
deruxtecan 

• Description of key signs and symptoms of ILD/pneumonitis and guidance on when to seek 
attention from an HCP 

• Contact details of the trastuzumab deruxtecan prescriber 
• Cross-reference to Patient Information Leaflet 
 

II) Healthcare Professional Guide for prevention of medication errors 
 

The HCP Guide will contain the following key elements:   
 

• Alert to HCPs about a potential risk of confusion between Enhertu (trastuzumab deruxtecan) 
and other trastuzumab-containing products and the HER2-targeted antibody-drug conjugate 
Kadcyla® (trastuzumab emtansine)  

• Mitigation measures for prescribing errors due to similarities in active ingredient names and 
measures to avoid errors during prescription phase by physicians 

• Comparison of commercial appearance between Enhertu (trastuzumab deruxtecan) and other 
trastuzumab-containing products and the HER2-targeted antibody-drug conjugate Kadcyla® 
(trastuzumab emtansine). 

• Potential mitigation strategies to avoid errors during preparation phase by pharmacists 
• Detailed Information about the dosage, method of administration and preparation as well as 

instructions to avoid medication errors during administration phase by nurses 
 
 
E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES 

FOR THE CONDITIONAL MARKETING AUTHORISATION 
 



20 

This being a conditional marketing authorisation and pursuant to Article 14a(4) of Regulation (EC) 
No726/2004, the MAH shall complete, within the stated timeframe, the following measure: 
 

Description Due date 
In order to confirm the efficacy and safety of Enhertu in the treatment of adult 
patients with unresectable or metastatic HER2 positive breast cancer who have 
received two or more prior anti-HER2-based regimens, the MAH should submit 
the interim results of study DS-8201-A-U301, a phase 3, multicentre, 
randomised, open-label, active-controlled study of Enhertu versus treatment of 
investigator’s choice for HER2-positive, unresectable and/or metastatic breast 
cancer subjects pre-treated with prior standard of care HER2 therapies, including 
T-DM1. 

March 2022 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 



21 

 
LABELLING AND PACKAGE LEAFLET 

  



22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



23 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Enhertu 100 mg powder for concentrate for solution for infusion 
trastuzumab deruxtecan 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One vial of powder for concentrate for solution for infusion contains: 100 mg of trastuzumab 
deruxtecan.  
After reconstitution, one vial of 5 mL solution contains 20 mg/mL of trastuzumab deruxtecan 
 
 
3. LIST OF EXCIPIENTS 
 
L-histidine, L-histidine hydrochloride monohydrate, Sucrose, Polysorbate 80. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 vial 
 
 
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  
 
Enhertu should not be substituted with trastuzumab or trastuzumab emtansine. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (2°C to 8°C). 



24 

Do not freeze. 
 
 
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 
 
Daiichi Sankyo Europe GmbH 
Zielstattstrasse 48 
81379 Munich 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1508 /001 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
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  



25 

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



26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
  



27 

 
Package leaflet: Information for the patient 

 
Enhertu 100 mg powder for concentrate for solution for infusion 

trastuzumab deruxtecan 
 

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you are 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 or nurse. 
• If you get any side effects, talk to your doctor or nurse. This includes any possible side effects 

not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Enhertu is and what it is used for 
2. What you need to know before you are given Enhertu 
3. How you are given Enhertu 
4. Possible side effects 
5. How to store Enhertu 
6. Contents of the pack and other information 
 
 
1. What Enhertu is and what it is used for 
 
What Enhertu is 
 
Enhertu is a cancer medicine that contains the active substance trastuzumab deruxtecan. One part of 
the medicine is a monoclonal antibody that attaches specifically to cells that have the protein HER2 on 
their surface (HER2-positive), as some breast cancer cells do. The other active part of Enhertu is DXd, 
a substance that can kill cancer cells. Once the medicine has attached to HER2-positive cancer cells, 
the DXd enters the cells and kills them. 
 
What Enhertu is used for 
 
Enhertu is used to treat adults who have: 
• HER2-positive breast cancer that has spread to other parts of the body or cannot be removed 

by surgery, and 
• tried at least two other treatments specifically for HER2-positive breast cancer. 
 
 
2. What you need to know before you are given Enhertu 
 
You must not be given Enhertu 
 
• if you are allergic to trastuzumab deruxtecan or any of the other ingredients of this medicine 

(listed in section 6). 
 

If you are not sure if you are allergic, talk to your doctor or nurse before you are given Enhertu. 
 
Warnings and precautions 
 
Talk to your doctor or nurse before you are given Enhertu, or during treatment, if you have: 



28 

• cough, shortness of breath, fever, or other new or worsening breathing problems. These may be 
symptoms of a serious and potentially fatal lung disease called interstitial lung disease. 

• chills, fever, sores in your mouth, stomach pain or pain when urinating. These may be 
symptoms of an infection caused by a reduced number of white blood cells called neutrophils. 

• new or worsening shortness of breath, cough, tiredness, swelling of ankles or legs, irregular 
heartbeat, sudden weight gain, dizziness, or loss of consciousness. These may be symptoms of a 
condition in which your heart cannot pump blood well enough (decreased left ventricular 
ejection fraction). 

• liver problems. Your doctor may have to monitor your liver while you are taking this medicine. 
  
Your doctor will carry out tests before and during treatment with Enhertu. 
 
Children and adolescents 
 
Enhertu 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 Enhertu 
 
Tell your doctor or nurse if you are taking, have recently taken or might take any other medicines. 
 
Pregnancy, breast-feeding, contraception and fertility 
 
• Pregnancy 

Enhertu is not recommended during pregnancy because this medicine may harm the unborn 
baby. 
Speak with your doctor immediately if you are pregnant, think you may be pregnant or are 
planning to become pregnant before or during treatment. 

 
• Breast-feeding  

You should not breast-feed during treatment with Enhertu and for at least 7 months after your 
last dose. This is because it is not known whether Enhertu passes into breast milk. Talk to your 
doctor about this. 

 
• Contraception 

Use effective contraception (birth control) to avoid becoming pregnant while being treated with 
Enhertu.  
 
Women taking Enhertu should continue contraception for at least 7 months after the last dose of 
Enhertu.  
 
Men taking Enhertu whose partner may become pregnant should use effective contraception: 
- during treatment and 
- for at least 4 months after the last dose of Enhertu. 

 
Talk to your doctor about the best contraception for you. Also talk to your doctor before you 
stop your contraception. 

 
• Fertility 

If you are a man being treated with Enhertu, you should not father a child for 4 months after 
treatment and take advice on conserving sperm before treatment because the medicine may 
reduce your fertility. Therefore, discuss this with your doctor before starting treatment. 

 
Driving and using machines 
 
Enhertu is not likely to reduce your ability to drive or use machines. Be careful if you feel tired, dizzy, 
or have a headache. 



29 

 
 
3. How you are given Enhertu 
 
Enhertu will be given to you in a hospital or clinic: 
• The recommended dose of Enhertu is 5.4 mg for every kilogram of your weight, every 3 weeks.  
• Your doctor or nurse will give you Enhertu by infusion (drip) into your vein. 
• Your first infusion will be given over 90 minutes. If this goes well, the infusion on your next 

visits may be given over 30 minutes. 
• Your doctor will decide how many treatments you need. 
• If you get infusion-related symptoms, your doctor or nurse may slow down your infusion or 

interrupt or stop your treatment. 
• Before and during treatment with Enhertu, your doctor will carry out tests that may include: 

- blood tests to check your blood cells, liver and kidneys 
- testing to check your heart and lungs. 

• Your doctor may lower your dose, or temporarily or permanently stop your treatment depending 
on your side effects. 

 
If you miss an appointment to get Enhertu 
 
Contact your doctor right away to reschedule your appointment. 
 
It is very important that you do not miss a dose of this medicine.  
 
If you stop receiving Enhertu 
 
Do not stop treatment with Enhertu without checking with your doctor. 
 
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 if you get any side effects, including those not listed in this leaflet. 
 
Speak with your doctor immediately if you notice any of the following symptoms. They may be 
signs of a serious, possibly fatal, condition. Getting medical treatment right away may help keep these 
problems from becoming more serious. 
 
Very common (may affect more than 1 in 10 people) 
• A lung disease called interstitial lung disease with symptoms that can include cough, shortness 

of breath, fever, or other new or worsening breathing problems 
• An infection caused by reduced number of neutrophils (a type of white blood cell) with 

symptoms that can include chills, fever, sores in your mouth, stomach pain or pain when 
urinating 

• A heart problem called decreased left ventricular ejection fraction with symptoms that can 
include new or worsening shortness of breath, cough, tiredness, swelling of ankles or legs, 
irregular heartbeat, sudden weight gain, dizziness or unconsciousness 

 
Other side effects 
Tell your doctor or nurse if you notice any of the following side effects: 
 
Very common (may affect more than 1 in 10 people) 
• nausea (feeling sick), vomiting 
• constipation 
• abdominal (belly) pain, indigestion 



30 

• decreased appetite 
• diarrhoea 
• tiredness 
• hair loss, rash 
• cough 
• headache 
• infections of the nose and throat, including flu-like symptoms 
• blisters in or around your mouth  
• breathing difficulties 
• nosebleed 
• dry eye 
• dizziness 
• blood tests showing low blood potassium level 
• blood tests showing decreased red or white blood cells, or platelets 
• blood tests showing increased levels of the liver enzymes aspartate aminotransferase or alanine 

aminotransferase 
 
Common (may affect up to 1 in 10 people) 
• reactions related to the infusion of the medicine which may include fever, chills, flushing, 

itching or rash 
• fever along with a decreased number of white blood cells called neutrophils 
 
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.  
 
 
5. How to store Enhertu 
 
Enhertu will be stored by healthcare professionals at the hospital or clinic where you receive 
treatment. The storage details are as follows: 
• 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 (2 °C - 8 °C). Do not freeze. 
• The prepared solution for infusion is stable for up to 24 hours at 2 °C - 8 °C protected from light 

and must be discarded thereafter. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Enhertu contains 
 
• The active substance is trastuzumab deruxtecan. 

One vial of powder for concentrate for solution for infusion contains 100 mg of trastuzumab 
deruxtecan. After reconstitution, one vial of 5 mL solution contains 20 mg/mL of trastuzumab 
deruxtecan. 

• The other ingredients are L-histidine, L-histidine hydrochloride monohydrate, sucrose, 
polysorbate 80. 

 
What Enhertu looks like and contents of the pack 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


31 

 
Enhertu is a white to yellowish-white lyophilised powder supplied in a clear amber vial with a rubber 
stopper, aluminium seal and plastic flip-off cap. 
Each carton contains 1 vial. 
 
Marketing Authorisation Holder 
Daiichi Sankyo Europe GmbH 
Zielstattstrasse 48 
81379 Munich 
Germany 
 
Manufacturer 
Daiichi Sankyo Europe GmbH 
Luitpoldstrasse 1 
85276 Pfaffenhofen 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
 
België/Belgique/Belgien 
Daiichi Sankyo Belgium N.V.-S.A  
Tél/Tel: +32-(0) 2 227 18 80 

Lietuva 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

 
България 
Daiichi Sankyo Europe GmbH 
тел.: +49-(0) 89 7808 0 

 
Luxembourg/Luxemburg 
Daiichi Sankyo Belgium N.V.-S.A  
Tél/Tel: +32-(0) 2 227 18 80 

 
Česká republika 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

 
Magyarország 
Daiichi Sankyo Europe GmbH 
Tel.: +49-(0) 89 7808 0 

 
Danmark 
Daiichi Sankyo Nordics ApS 
Tlf: +45 (0) 33 68 19 99 

 
Malta 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

 
Deutschland 
Daiichi Sankyo Deutschland GmbH  
Tel: +49-(0) 89 7808 0 

 
Nederland 
Daiichi Sankyo Nederland B.V.  
Tel: +31-(0) 20 4 07 20 72 

 
Eesti 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

 
Norge 
Daiichi Sankyo Nordics ApS 
Tlf: +47 (0) 21 09 38 29 

 
Ελλάδα 
Daiichi Sankyo Europe GmbH 
Τηλ: +49-(0) 89 7808 0 

 
Österreich 
Daiichi Sankyo Austria GmbH  
Tel: +43 (0) 1 485 86 42 0 

 
España 
Daiichi Sankyo España, S.A.  
Tel: +34 91 539 99 11 

 
Polska 
Daiichi Sankyo Europe GmbH 
Tel.: +49-(0) 89 7808 0 

 
France 
Daiichi Sankyo France S.A.S.  
Tél: +33 (0) 1 55 62 14 60 

 
Portugal 
Daiichi Sankyo Portugal, Unip. LDA 
Tel: +351 21 4232010 

  



32 

Hrvatska 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

România 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

 
Ireland 
Daiichi Sankyo Ireland Ltd  
Tel: +353-(0) 1 489 3000 

 
Slovenija 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

 
Ísland 
Daiichi Sankyo Nordics ApS 
Sími: +45 (0) 33 68 19 99 

 
Slovenská republika 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

 
Italia 
Daiichi Sankyo Italia S.p.A.  
Tel: +39-06 85 2551 

 
Suomi/Finland 
Daiichi Sankyo Nordics ApS 
Puh/Tel: +358 (0) 9 3540 7081 

 
Κύπρος 
Daiichi Sankyo Europe GmbH 
Τηλ: +49-(0) 89 7808 0 

 
Sverige 
Daiichi Sankyo Nordics ApS 
Tel: +46 (0) 40 699 2524 

 
Latvija 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

 
United Kingdom 
Daiichi Sankyo UK Ltd  
Tel: +44 (0) 800 028 5122 

 
This leaflet was last revised  
 
This medicine has been given ‘conditional approval’. This means that there is more evidence to come 
about this medicine. 
The European Medicines Agency will review new information on this medicine at least every year and 
this leaflet will be updated as necessary. 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
------------------------------------------------------------------------------------------------------------------- 
The following information is intended for healthcare professionals only: 
 
In order to prevent medicinal product errors, check the vial labels to ensure that the medicinal product 
being prepared and administered is Enhertu (trastuzumab deruxtecan) and not trastuzumab or 
trastuzumab emtansine. 
 
Appropriate procedures for the preparation of chemotherapeutic medicinal products should be used. 
Appropriate aseptic technique should be used for the following reconstitution and dilution procedures 
 
Reconstitution 
• Reconstitute immediately before dilution. 
• More than one vial may be needed for a full dose. Calculate the dose (mg), the total volume of 

reconstituted Enhertu solution required, and the number of vial(s) of Enhertu needed. 
• Reconstitute each 100 mg vial using a sterile syringe to slowly inject 5 mL of water for injection 

into each vial to obtain a final concentration of 20 mg/mL. 
• Swirl the vial gently until completely dissolved. Do not shake. 
• Inspect the reconstituted solution for particulates and discolouration. The solution should be 

clear and colourless to light yellow. Do not use if visible particles are observed or if the solution 
is cloudy or discoloured. 

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


33 

• If not used immediately, store the reconstituted Enhertu vials in a refrigerator at 2 °C to 8 °C for 
up to 24 hours from the time of reconstitution, protected from light. Do not freeze. 

• The reconstituted product contains no preservative and is intended for single use only. 
 
Dilution 
• Dilute the calculated volume of reconstituted Enhertu in an infusion bag containing 100 mL of 

5% glucose solution. Do not use sodium chloride solution. An infusion bag made of 
polyvinylchloride or polyolefin (copolymer of ethylene and polypropylene) is recommended. 

• Gently invert the infusion bag to thoroughly mix the solution. Do not shake. 
• Cover the infusion bag to protect from light. 
• If not used immediately, store at room temperature for up to 4 hours including preparation and 

infusion or in a refrigerator at 2 °C to 8 °C for up to 24 hours, protected from light. Do not 
freeze. 

• Discard any unused portion left in the vial. 
 
Administration 
• If the prepared infusion solution was stored refrigerated (2 ºC to 8 ºC), it is recommended that 

the solution be allowed to equilibrate to room temperature prior to administration, protected 
from light. 

• Administer Enhertu as an intravenous infusion only with a 0.20 or 0.22 micron in-line 
polyethersulfone (PES) or polysulfone (PS) filter. 

• The initial dose should be administered as a 90-minute intravenous infusion. If the prior 
infusion was well tolerated, subsequent doses of Enhertu may be administered as 30-minute 
infusions. Do not administer as an intravenous push or bolus. 

• Do not mix Enhertu with other medicinal products or administer other medicinal products 
through the same intravenous line. 

 
Disposal 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



34 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX IV 

CONCLUSIONS ON THE GRANTING OF THE CONDITIONAL MARKETING 
AUTHORISATION PRESENTED BY THE EUROPEAN MEDICINES AGENCY 



35 

Conclusions presented by the European Medicines Agency on: 

• Conditional marketing authorisation 

The CHMP having considered the application is of the opinion that the risk-benefit balance is 
favourable to recommend the granting of the conditional marketing authorisation as further explained 
in the European Public Assessment Report. 

 

 
 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCES 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  
	E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET
	CONCLUSIONS ON THE GRANTING OF THE CONDITIONAL MARKETING AUTHORISATION PRESENTED BY THE EUROPEAN MEDICINES AGENCY