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The most common adverse reactions were nausea (76.8%), fatigue (56.1%), vomiting (44.6%), alopecia (39.1%), anaemia (35.1%), neutropenia (34.4%), constipation (34.3%), decreased appetite (33.1%), diarrhoea (29.3%), transaminases increased (27.6%), musculoskeletal pain (26.5%), leukopenia (24.3%), and thrombocytopenia (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 (16.3%), anaemia (9.2%), fatigue (7.5%), leukopenia (6.3%), thrombocytopenia (5.9%), nausea (5.6%), lymphopenia (4.8%), transaminases increased (3.9%), hypokalaemia (3.5%), vomiting (2.2%), pneumonia (1.9%), diarrhoea (1.8%), decreased appetite (1.7%), febrile neutropenia (1.2%), dyspnoea (1.2%), blood bilirubin increased (1.1%), ejection fraction decreased (1.1%), and musculoskeletal pain (1.1%). Grade 5 adverse reactions occurred in 1.5% of patients, including ILD (1.2%).
Dose interruptions due to adverse reactions occurred in 32.2% of patients treated with Enhertu. The most frequent adverse reactions associated with dose interruption were neutropenia (12.2%), fatigue (4.6%), anaemia (3.9%), leukopenia (3.6%), ILD (2.8%), thrombocytopenia (2.8%), upper respiratory tract infection (2.3%), nausea (2.1%), and pneumonia (2.1%). Dose reductions occurred in 19.7% of patients treated with Enhertu. The most frequent adverse reactions associated with dose reduction were nausea (4.8%), fatigue (4.0%), neutropenia (3.0%), and thrombocytopenia (2.3%). Discontinuation of therapy due to an adverse reaction occurred in 12.1% of patients treated with Enhertu. The most frequent adverse reaction associated with permanent discontinuation was ILD (8.5%).
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 = 619), across multiple tumour types in clinical studies. The median duration of treatment in this pool was 5.6 months (range: 0.7 to 41.0 months).
The most common adverse reactions were nausea (71.1%), fatigue (58.8%), decreased appetite (53.8%), anaemia (43.5%), neutropenia (42.2%), vomiting (39.1%), diarrhoea (35.5%), alopecia (35.5%), constipation (31.8%), thrombocytopenia (30.5%), leukopenia (28.3%) and transaminases increased (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 (27.9%), anaemia (23.1%), leukopenia (12.9%), thrombocytopenia (9.0%), fatigue (8.2%), decreased appetite (8.1%), lymphopenia (7.4%), nausea (5.8%), transaminases increased (4.7%), hypokalaemia (4.2%), pneumonia (2.9%), febrile neutropenia (2.9%), vomiting (2.4%), diarrhoea (2.1%), weight decreased (2.1%), blood alkaline phosphatase increased (1.8%), interstitial lung disease (ILD, 1.6%), dyspnoea (1.3%), and ejection fraction decreased (1.1%). Grade 5 adverse reactions occurred in 2.6% of patients, including ILD (1.9%).
Dose interruptions due to adverse reactions occurred in 39.1% of patients treated with Enhertu. The most frequent adverse reactions associated with dose interruption were neutropenia (16.0%), anaemia (7.8%), fatigue (5.5%), leukopenia (4.0%), decreased appetite (4.0%), ILD (3.9%), pneumonia (3.6%), upper respiratory tract infection (3.6%), and thrombocytopenia (2.7%). Dose reductions occurred in 30.7% of patients treated with Enhertu. The most frequent adverse reactions associated with dose reduction were fatigue (10.7%), nausea (6.5%), neutropenia (6.1%), decreased appetite (5.7%), and thrombocytopenia (2.9%). Discontinuation of therapy due to an adverse reaction occurred in 17.0% of patients treated with Enhertu. The most frequent adverse reaction associated with permanent discontinuation was ILD (12.4%).
In patients with gastric cancer treated with Enhertu 6.4 mg/kg (n = 229), 22.7% 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 7. 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. (See Table 7.)
Click on icon to see table/diagram/imageDescription 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 = 944), ILD occurred in 12.2% of patients. Most ILD cases were Grade 1 (3.0%) and Grade 2 (7.1%). Grade 3 cases occurred in 1.0% and no Grade 4 cases occurred. Grade 5 (fatal) events occurred in 1.2% of patients. Median time to first onset was 5.5 months (range: 26 days to 23.3 months) (see Dosage & Administration and Precautions).
In patients treated with Enhertu 6.4 mg/kg in clinical studies across multiple tumour types (n = 619), ILD occurred in 16.6% of patients. Most ILD cases were Grade 1 (4.7%) and Grade 2 (8.4%). Grade 3 cases occurred in 1.5% and Grade 4 cases occurred in 0.2% of patients. Grade 5 (fatal) events occurred in 1.9% 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 Dosage & Administration and Precautions).
Neutropenia: In patients treated with Enhertu 5.4 mg/kg in clinical studies (n = 944) across multiple tumour types, neutropenia was reported in 34.4% of patients and 16.3% had Grade 3 or 4 events. Median time of onset was 43 days (range: 1 day to 24.8 months), and median duration of the first event was 22 days (range: 1 day to 14.7 months). Febrile neutropenia was reported in 1.3% of patients and 0.1% were Grade 5 (see Dosage & Administration).
In patients treated with Enhertu 6.4 mg/kg in clinical studies across multiple tumour types (n = 619), neutropenia was reported in 42.2% of patients and 27.9% 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 3.1% of patients (see Dosage & Administration).
Left ventricular ejection fraction decrease: In patients treated with Enhertu 5.4 mg/kg in clinical studies across multiple tumour types (n = 944), LVEF decrease was reported in 36 patients (3.8%), of which 4 (0.4%) were Grade 1, 27 (2.9%) were Grade 2, and 5 (0.5%) were Grade 3. The observed frequency of LVEF decreased based on laboratory parameters (echocardiogram or MUGA scanning) was 139/874 (15.9%) for Grade 2, and 7 (0.8%) for Grade 3. Treatment with Enhertu has not been studied in patients with LVEF less than 50% prior to initiation of treatment (see Dosage & Administration).
In patients treated with Enhertu 6.4 mg/kg in clinical studies across multiple tumour types (n = 619), LVEF decrease was reported in 11 patients (1.8%), of which 1 (0.2%) were Grade 1, 7 (1.1%) were Grade 2, and 3 (0.5%) were Grade 3. The observed frequency of LVEF decreased based on laboratory parameters (echocardiogram or MUGA scanning) was 81/557 (14.5%) for Grade 2, and 7/557 (1.3%) for Grade 3.
Infusion-related reactions: In patients treated with Enhertu 5.4 mg/kg in clinical studies (n = 944) across multiple tumour types, infusion-related reactions were reported in 16 patients (1.7%), all of which were Grade 1 or Grade 2 severity. No Grade 3 events were reported. Three events (0.3%) 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 = 619) across multiple tumour types, infusion-related reactions were reported in 13 patients (2.1%), all of which were Grade 1 or Grade 2 severity. No Grade 3 events were reported. One event (0.2%) 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, 2.0% (34/1668) 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% (1/1668). 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 = 944), 23.8% were 65 years or older and 4% were 75 years or older. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged 65 years or older (51%) as compared to patients younger than 65 years old (42%), leading to more discontinuations due to adverse reactions.
Of the 619 patients across multiple tumour types in clinical studies treated with Enhertu 6.4 mg/kg, 39.9% were 65 years or older and 7.4% were 75 years or older. The incidence of Grade 3-4 adverse reactions observed in patients 65 years or older was 59.9% and 62.4% in younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients 75 years of age or older (67.4%) compared to patients less than 75 years of age (60.9%). In patients 75 years or older, there was a higher incidence of serious adverse reactions (32.6%) and fatal events (6.5%) compared to patients less than 75 years (20.6% 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.
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