Trastuzumab deruxtecan interacts in the following cases:
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. The potential need for dose adjustment in patients with severe renal impairment or end-stage renal disease cannot be determined as severe renal impairment was an exclusion criterion in clinical studies. A higher incidence of Grade 1 and 2 ILD/pneumonitis leading to an increase in discontinuation of therapy has been observed in patients with moderate renal impairment. In patients with moderate renal impairment at baseline who received trastuzumab deruxtecan 6.4 mg/kg, a higher incidence of serious adverse reactions was observed compared to those with normal renal function. Patients with moderate or severe renal impairment should be monitored carefully for adverse reactions including ILD/pneumonitis.
The potential need for dose adjustment in patients with total bilirubin >1.5 times ULN, irrespective of AST value, cannot be determined due to limited data; therefore, these patients should be monitored carefully.
As metabolism and biliary excretion are the primary routes of elimination of the topoisomerase I inhibitor, DXd, trastuzumab deruxtecan should be administered with caution in patients with moderate and severe hepatic impairment.
No dedicated fertility studies have been conducted with trastuzumab deruxtecan. Based on results from animal toxicity studies, trastuzumab deruxtecan 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 trastuzumab deruxtecan.
There is no available data on the use of trastuzumab deruxtecan 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 trastuzumab deruxtecan, DXd, can be expected to cause embryo-foetal harm when administered to a pregnant woman.
Administration of trastuzumab deruxtecan 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 trastuzumab deruxtecan or within 7 months following the last dose of trastuzumab deruxtecan, close monitoring is recommended.
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 trastuzumab deruxtecan 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 trastuzumab deruxtecan for the mother.
Pregnancy status of women of childbearing potential should be verified prior to initiation of trastuzumab deruxtecan.
Women of childbearing potential should use effective contraception during treatment with trastuzumab deruxtecan and for at least 7 months following the last dose.
Men with female partners of childbearing potential should use effective contraception during treatment with trastuzumab deruxtecan and for at least 4 months following the last dose.
No dedicated fertility studies have been conducted with trastuzumab deruxtecan. Based on results from animal toxicity studies, trastuzumab deruxtecan 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 trastuzumab deruxtecan.
Trastuzumab deruxtecan 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 trastuzumab deruxtecan.
The pooled safety population has been evaluated for patients who received at least one dose of trastuzumab deruxtecan 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 trastuzumab deruxtecan. 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 trastuzumab deruxtecan. 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 trastuzumab deruxtecan. The most frequent adverse reaction associated with permanent discontinuation was ILD (9.2%).
The pooled safety population has been evaluated for patients who received at least one dose of trastuzumab deruxtecan 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 trastuzumab deruxtecan. 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 trastuzumab deruxtecan. 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 trastuzumab deruxtecan. The most frequent adverse reaction associated with permanent discontinuation was ILD (12.9%).
In patients with gastric cancer treated with trastuzumab deruxtecan 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.
The adverse reactions in patients who received at least one dose of trastuzumab deruxtecan in clinical studies are presented in the table below. 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.
Adverse reactions in patients treated with trastuzumab deruxtecan 5.4 mg/kg and 6.4 mg/kg in multiple tumour types:
| System organ class Frequency category | 5.4 mg/kg Adverse reaction | 6.4 mg/kg Adverse reaction |
|---|---|---|
| Infections and infestations | ||
| Very common | upper respiratory tract infectiona | pneumonia, upper respiratory tract infectiona |
| Common | pneumonia | |
| Blood and lymphatic system disorders | ||
| Very common | anaemiab, neutropeniac, thrombocytopeniad, leukopeniae, lymphopeniaf | anaemiab, neutropeniac, thrombocytopeniad, leukopeniae, lymphopeniaf |
| Common | febrile neutropenia | |
| Uncommon | febrile neutropenia | |
| Metabolism and nutrition disorders | ||
| Very common | hypokalaemiag, decreased appetite | hypokalaemiag, decreased appetite |
| Common | dehydration | dehydration |
| Nervous system disorders | ||
| Very common | headacheh, dizziness | headacheh, dysgeusia |
| Common | dysgeusia | dizziness |
| Eye disorders | ||
| Common | dry eye, vision blurredi | dry eye, vision blurredi |
| Respiratory, thoracic and mediastinal disorders | ||
| Very common | interstitial lung diseasej, dyspnoea, cough, epistaxis | interstitial lung diseasej, dyspnoea, cough |
| Common | epistaxis | |
| Gastrointestinal disorders | ||
| Very common | nausea, vomiting, constipation, diarrhoea, abdominal paink, stomatitisl, dyspepsia | nausea, vomiting, diarrhoea, constipation, abdominal paink, stomatitisl |
| Common | abdominal distension, gastritis, flatulence | dyspepsia, abdominal distension, gastritis, flatulence |
| Hepatobiliary disorders | ||
| Very common | transaminases increasedm | transaminases increasedm |
| Skin and subcutaneous tissue disorders | ||
| Very common | alopecia | alopecia |
| Common | rashn, pruritus, skin hyperpigmentation° | rashn, pruritus, skin hyperpigmentation° |
| Musculoskeletal and connective tissue disorders | ||
| Very common | musculoskeletal painp | musculoskeletal painp |
| General disorders and administration site condition | ||
| Very common | fatigueq, pyrexia | fatigueq, pyrexia, oedema peripheral |
| Common | oedema peripheral | |
| Investigations | ||
| Very common | ejection fraction decreasedr, weight decreased | ejection fraction decreasedr, weight decreased |
| Common | blood alkaline phosphatase increased, blood bilirubin increaseds, blood creatinine increased | blood alkaline phosphatase increased, blood bilirubin increaseds, blood creatinine increased |
| Injury, poisoning and procedural complications | ||
| Common | infusion-related reactionst | infusion-related reactionst |
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.
In patients treated with trastuzumab deruxtecan 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).
In patients treated with trastuzumab deruxtecan 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).
In patients treated with trastuzumab deruxtecan 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.
In patients treated with trastuzumab deruxtecan 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.
In patients treated with trastuzumab deruxtecan 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 trastuzumab deruxtecan has not been studied in patients with LVEF less than 50% prior to initiation of treatment.
In patients treated with trastuzumab deruxtecan 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.
In patients treated with trastuzumab deruxtecan 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 trastuzumab deruxtecan 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.
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 trastuzumab deruxtecan. 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.
Safety has not been established in this population.
In patients treated with trastuzumab deruxtecan 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 trastuzumab deruxtecan 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.
In clinical studies, no relevant differences in exposure or efficacy were observed between patients of different ethnic groups. Asian patients receiving trastuzumab deruxtecan 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.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
