ENHERTU Powder for concentrate for solution for infusion Ref.[49749] Active ingredients: Trastuzumab deruxtecan

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).

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).

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).

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.

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.

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).

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.

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:

^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).

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.

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.