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/day 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/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks. Enhertu should be permanently discontinued in patients who are diagnosed with symptomatic (Grade 2 or greater) ILD/pneumonitis (see section 4.2). Patients with a history of ILD/pneumonitis or patients with moderate or severe renal impairment may be at increased risk of developing ILD/pneumonitis and should be monitored carefully (see section 4.2).

Neutropenia

Cases of neutropenia, including febrile neutropenia with a fatal outcome, 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. Standard cardiac function testing (echocardiogram or MUGA [multigated acquisition] scanning) should be performed to assess LVEF prior to initiation of Enhertu and at regular intervals during treatment as clinically indicated. LVEF decrease should be managed through treatment interruption. 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 Table 2 in 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 is 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

Enhertu 5.4 mg/kg

The pooled safety population has been evaluated for patients who received at least one dose of Enhertu 5.4 mg/kg (n=1449) across multiple tumour types in clinical studies. The median duration of treatment in this pool was 9.8 months (range: 0.7 to 45.1 months).

The most common adverse reactions were nausea (75.0%), fatigue (57.3%), vomiting (42.1%), alopecia (37.6%), neutropenia (35.2%), constipation (35.0%), anaemia (34.4%), decreased appetite (33.1%), diarrhoea (28.8%), transaminases increased (26.5%), musculoskeletal pain (26.2%), thrombocytopenia (24.5%) and leukopenia (23.7%).

The most common National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI-CTCAE v.5.0) Grade 3 or 4 adverse reactions were neutropenia (17.0%), anaemia (9.5%), fatigue (8.4%), leukopenia (6.4%), nausea (5.9%), thrombocytopenia (5.0%), lymphopenia (4.8%), hypokalaemia (3.8%), transaminases increased (3.6%), vomiting (2.7%), diarrhoea (2.0%), decreased appetite (1.7%), pneumonia (1.4%) and ejection fraction decreased (1.1%). Grade 5 adverse reactions occurred in 1.4% of patients, including ILD (1.0%).

Dose interruptions due to adverse reactions occurred in 34.3% of patients treated with Enhertu. The most frequent adverse reactions associated with dose interruption were neutropenia (13.3%), fatigue (5.0%), anaemia (4.7%), leukopenia (3.7%), thrombocytopenia (3.0%), upper respiratory tract infection (2.7%) and ILD (2.6%). Dose reductions occurred in 20.6% of patients treated with Enhertu. The most frequent adverse reactions associated with dose reduction were fatigue (5.0%), nausea (4.9%) neutropenia (3.5%) and thrombocytopenia (2.1%). Discontinuation of therapy due to an adverse reaction occurred in 13.0% of patients treated with Enhertu. The most frequent adverse reaction associated with permanent discontinuation was ILD (9.2%).

Enhertu 6.4 mg/kg

The pooled safety population has been evaluated for patients who received at least one dose of Enhertu 6.4 mg/kg (n=669), across multiple tumour types in clinical studies. The median duration of treatment in this pool was 5.7 months (range: 0.7 to 41.0 months).

The most common adverse reactions were nausea (72.2%), fatigue (58.4%), decreased appetite (53.5%), anaemia (44.7%), neutropenia (43.5%), vomiting (40.1%), diarrhoea (35.9%), alopecia (35.4%), constipation (32.3%), thrombocytopenia (30.8%), leukopenia (29.3%) and transaminases increased (24.2%).

The most common National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI-CTCAE v.5.0) Grade 3 or 4 adverse reactions were neutropenia (28.7%), anaemia (22.6%), leukopenia (13.3%), thrombocytopenia (9.1%), fatigue (8.4%), decreased appetite (7.8%), lymphopenia (6.9%), nausea (5.8%), transaminases increased (4.3%), hypokalaemia (4.3%), pneumonia (3.1%), febrile neutropenia (2.8%), vomiting (2.4%), diarrhoea (2.2%), weight decreased (1.9%), blood alkaline phosphatase increased (1.6%), interstitial lung disease (ILD, 1.5%), dyspnoea (1.2%), ejection fraction decreased (1.2%), and blood bilirubin increased (1.2%). Grade 5 adverse reactions occurred in 2.7% of patients, including ILD (2.1%).

Dose interruptions due to adverse reactions occurred in 40.7% of patients treated with Enhertu. The most frequent adverse reactions associated with dose interruption were neutropenia (16.6%), anaemia (7.8%), fatigue (5.7%), ILD (4.8%), leukopenia (4.2%), decreased appetite (3.7%), pneumonia (3.6%), upper respiratory tract infection (3.4%) and thrombocytopenia (3.1%). Dose reductions occurred in 31.1% of patients treated with Enhertu. The most frequent adverse reactions associated with dose reduction were fatigue (10.6%), neutropenia (6.6%), nausea (6.4%), decreased appetite (5.4%) and thrombocytopenia (3.0%). Discontinuation of therapy due to an adverse reaction occurred in 17.6% of patients treated with Enhertu. The most frequent adverse reaction associated with permanent discontinuation was ILD (12.9%).

In patients with gastric cancer treated with Enhertu 6.4 mg/kg (n=229), 25.3% received a transfusion within 28 days after onset of anaemia or thrombocytopenia. Transfusions were primarily for anaemia.

Tabulated list of adverse reactions

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 5.4 mg/kg and 6.4 mg/kg in multiple tumour types:

^a Includes influenza, influenza-like illness, nasopharyngitis, pharyngitis, sinusitis, rhinitis, laryngitis and upper respiratory tract infection.
^b For all tumour types at 5.4 mg/kg, includes anaemia, haemoglobin decreased, red blood cell count decreased and haematocrit decreased. For all tumour types at 6.4 mg/kg, includes anaemia, haemoglobin decreased and red blood cell count decreased.
^c Includes neutropenia and neutrophil count decreased.
^d Includes thrombocytopenia and platelet count decreased.
^e Includes leukopenia and white blood cell count decreased.
^f Includes lymphopenia and lymphocyte count decreased.
^g Includes hypokalaemia and blood potassium decreased.
^h For all tumour types at 5.4 mg/kg, includes headache, sinus headache and migraine. For all tumour types at 6.4 mg/kg, includes headache and migraine.
ⁱ Includes vision blurred and visual impairment.
^j For all tumour types at 5.4 mg/kg, interstitial lung disease includes events that were adjudicated as ILD: pneumonitis (n=88), interstitial lung disease (n=72), organising pneumonia (n=6),pneumonia (n=4), respiratory failure (n=5), radiation pneumonitis (n=2), alveolitis (n=2), pulmonary toxicity (n=2), pneumonia fungal (n=1), pulmonary mass (n=1), acute respiratory failure (n=1), lung infiltration (n=1), lymphangitis (n=1), pulmonary fibrosis (n=1), idiopathic interstitial pneumonia (n=1), lung disorder (n=1), hypersensitivity pneumonitis (n=1) and lung opacity (n=1). For all tumour types at 6.4 mg/kg, interstitial lung disease includes events that were adjudicated as ILD: pneumonitis (n=75), interstitial lung disease (n=39), organising pneumonia (n=4), respiratory failure (n=4), lung opacity (n=2), pneumonia (n=1) and radiation pneumonitis (n=1).
^k Includes abdominal discomfort, gastrointestinal pain, abdominal pain, abdominal pain lower and abdominal pain upper.
^l For all tumour types at 5.4 mg/kg, includes stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion and oral mucosal eruption. For all tumour types at 6.4 mg/kg, includes only stomatitis.
^m Includes transaminases increased, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased, hepatic function abnormal, liver function test abnormal, liver function test increased and hypertransaminasaemia.
ⁿ For all tumour types at 5.4 mg/kg, includes rash, rash pustular, rash maculo-papular, rash papular, rash macular and rash pruritic. For all tumour types at 6.4 mg/kg, includes rash, rash pustular, rash maculo-papular and rash pruritic.
° For all tumour types at 5.4 mg/kg, includes skin hyperpigmentation, skin discolouration and pigmentation disorder. For all tumour types at 6.4 mg/kg, includes skin hyperpigmentation and pigmentation disorder.
^p Includes back pain, myalgia, pain in extremity, musculoskeletal pain, muscle spasms, bone pain, neck pain, musculoskeletal chest pain and limb discomfort.
^q Includes asthenia, fatigue, malaise and lethargy.
^r For all tumour types at 5.4 mg/kg, ejection fraction decreased includes laboratory parameters of LVEF decrease (n=214) and/or preferred terms of ejection fraction decreased (n=52), cardiac failure (n=3), cardiac failure congestive (n=1) and left ventricular dysfunction (n=2). For all tumour types at 6.4 mg/kg, ejection fraction decreased includes laboratory parameters of LVEF decrease (n=97) and/or preferred terms of ejection fraction decreased (n=11) and left ventricular dysfunction (n=1).
^s For all tumour types at 5.4 mg/kg, includes blood bilirubin increased, hyperbilirubinaemia, bilirubin conjugated increased and blood bilirubin unconjugated increased. For all tumour types at 6.4 mg/kg, includes blood bilirubin increased, hyperbilirubinaemia and bilirubin conjugated increased.
^t For all tumour types at 5.4 mg/kg, cases of infusion-related reactions include infusion-related reaction (n=16) and hypersensitivity (n=2). For all tumour types at 6.4 mg/kg, cases of infusion-related reactions include infusion-related reaction (n=6) and hypersensitivity (n=1). All cases of infusion-related reactions were Grade 1 and Grade 2.

Description of selected adverse reactions

Interstitial lung disease/pneumonitis

In patients treated with Enhertu 5.4 mg/kg in clinical studies across multiple tumour types (n=1449), ILD occurred in 12.5% of patients. Most ILD cases were Grade 1 (3.2%) and Grade 2 (7.4%). Grade 3 cases occurred in 0.8% and no Grade 4 cases occurred. Grade 5 (fatal) events occurred in 1.0% of patients. Median time to first onset was 5.5 months (range: 26 days to 31.5 months) (see sections 4.2 and 4.4).

In patients treated with Enhertu 6.4 mg/kg in clinical studies across multiple tumour types (n=669), ILD occurred in 17.9% of patients. Most ILD cases were Grade 1 (4.9%) and Grade 2 (9.4%). Grade 3 cases occurred in 1.3% and Grade 4 cases occurred in 0.1% of patients. Grade 5 (fatal) events occurred in 2.1% of patients. One patient had pre-existing ILD that worsened post treatment leading to Grade 5 (fatal) ILD. Median time to first onset was 4.2 months (range: -0.5 to 21.0) (see sections 4.2 and 4.4).

Neutropenia

In patients treated with Enhertu 5.4 mg/kg in clinical studies (n=1449) across multiple tumour types, neutropenia was reported in 35.2% of patients and 17.0% had Grade 3 or 4 events. Median time of onset was 43 days (range: 1 day to 31.9 months), and median duration of the first event was 22 days (range: 1 day to 17.1 months). Febrile neutropenia was reported in 0.9% of patients and 0.1% were Grade 5 (see section 4.2).

In patients treated with Enhertu 6.4 mg/kg in clinical studies across multiple tumour types (n=669), neutropenia was reported in 43.5% of patients and 28.7% had Grade 3 or 4 events. Median time of onset was 16 days (range: 1 day to 24.8 months), and median duration of the first event was 9 days (range: 2 days to 17.2 months). Febrile neutropenia was reported in 3.0% of patients and 0.1% were Grade 5 (see section 4.2).

Left ventricular ejection fraction decrease

In patients treated with Enhertu 5.4 mg/kg in clinical studies across multiple tumour types (n=1449), LVEF decrease was reported in 57 patients (3.9%), of which 10 (0.7%) were Grade 1, 40 (2.8%) were Grade 2 and 7 (0.5%) were Grade 3. The observed frequency of LVEF decreased based on laboratory parameters (echocardiogram or MUGA scanning) was 202/1341 (15.1%) for Grade 2 and 12/1341 (0.9%) for Grade 3. Treatment with Enhertu has not been studied in patients with LVEF less than 50% prior to initiation of treatment (see section 4.2).

In patients treated with Enhertu 6.4 mg/kg in clinical studies across multiple tumour types (n=669), LVEF decrease was reported in 12 patients (1.8%), of which 1 (0.1%) was Grade 1, 8 (1.2%) were Grade 2, and 3 (0.4%) were Grade 3. The observed frequency of LVEF decreased based on laboratory parameters (echocardiogram or MUGA scanning) was 89/597 (14.9%) for Grade 2, and 8/597 (1.3%) for Grade 3.

Infusion-related reactions

In patients treated with Enhertu 5.4 mg/kg in clinical studies (n=1449) across multiple tumour types, infusion-related reactions were reported in 18 patients (1.2%), all of which were Grade 1 or Grade 2 severity. No Grade 3 events were reported. Three events (0.2%) of infusion-related reactions led to dose interruptions, and no events led to discontinuation.

In patients treated with Enhertu 6.4 mg/kg in clinical studies (n=669) across multiple tumour types, infusion-related reactions were reported in 7 patients (1.0%), all of which were Grade 1 or Grade 2 severity. No Grade 3 events were reported. One event (0.1%) of infusion-related reaction led to dose interruption, and no events led to discontinuation.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. Across all doses evaluated in clinical studies, 2.1% (47/2213) of evaluable patients developed antibodies against trastuzumab deruxtecan following treatment with Enhertu. The incidence of treatment-emergent neutralising antibodies against trastuzumab deruxtecan was 0.1% (2/2213). There was no association between development of antibodies and allergic-type reactions.

Paediatric population

Safety has not been established in this population.

Elderly

In patients treated with Enhertu 5.4 mg/kg in clinical studies across multiple tumour types (n=1449), 24.2% were 65 years or older and 4.3% were 75 years or older. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged 65 years or older (50.0%) as compared to patients younger than 65 years old (42.7%), leading to more discontinuations due to adverse reactions.

Of the 669 patients across multiple tumour types in clinical studies treated with Enhertu 6.4 mg/kg, 39.2% were 65 years or older and 7.6% were 75 years or older. The incidence of Grade 3-4 adverse reactions observed in patients 65 years or older was 59.9% and 62.9% in younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients 75 years of age or older (64.7%) compared to patients less than 75 years of age (61.5%). In patients 75 years or older, there was a higher incidence of serious adverse reactions (37.3%) and fatal events (7.8%) compared to patients less than 75 years (20.7% and 2.3%). Data are limited to establish the safety in patients 75 years or older.

Ethnic differences

In clinical studies, no relevant differences in exposure or efficacy were observed between patients of different ethnic groups. Asian patients receiving Enhertu 6.4 mg/kg had a higher incidence (≥10% difference) of neutropenia (58.1% vs. 18.6%), anaemia (51.1% vs. 32.4%), leukopenia (42.7% vs. 6.9%), thrombocytopenia (40.5% vs. 15.4%) and lymphopenia (17.6% vs. 7.3%) compared to non- Asian patients. In Asian patients, 4.3% experienced a bleeding event within 14 days after onset of thrombocytopenia compared to 1.6% of non-Asian patients.

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.