Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Daiichi Sankyo Europe GmbH, Zielstattstrasse 48, 81379 Munich, Germany
Enhertu as monotherapy is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received one or more prior anti-HER2-based regimens.
Enhertu as monotherapy is indicated for the treatment of adult patients with unresectable or metastatic HER2-low breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy (see section 4.2).
Enhertu as monotherapy is indicated for the treatment of adult patients with advanced NSCLC whose tumours have an activating HER2 (ERBB2) mutation and who require systemic therapy following platinum-based chemotherapy with or without immunotherapy.
Enhertu as monotherapy is indicated for the treatment of adult patients with advanced HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.
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 for breast cancer 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.
Patients treated with trastuzumab deruxtecan should have documented HER2-low tumour status, defined as a score of IHC 1+ or IHC 2+/ISH-, as assessed by a CE-marked IVD medical device. If a CE-marked IVD is not available, the HER2 status should be assessed by an alternate validated test (see section 5.1).
Patients treated with trastuzumab deruxtecan for advanced NSCLC should have an activating HER2 (ERBB2) mutation detected by a CE-marked in vitro diagnostic (IVD) medical device. If a CE-marked IVD is not available, the HER2 mutation status should be assessed by an alternate validated test.
Patients treated with trastuzumab deruxtecan for gastric or gastroesophageal junction cancer should have documented HER2-positive tumour status, defined as a score of 3+ by immunohistochemistry (IHC) or a ratio of ≥2 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.
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 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 recommended dose of Enhertu is 6.4 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.
The infusion rate of Enhertu should be slowed or interrupted if the patient develops infusion-related symptoms (see section 4.8). Enhertu should be permanently discontinued in case of severe infusion reactions.
Enhertu is emetogenic (see section 4.8), which includes delayed nausea and/or vomiting. Prior to each dose of Enhertu, patients should be premedicated with a combination regimen of two or three medicinal products (e.g., dexamethasone with either a 5-HT3 receptor antagonist and/or an NK1 receptor antagonist, as well as other medicinal products as indicated) for prevention of chemotherapy- induced nausea and vomiting.
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 | Breast cancer and NSCLC | Gastric cancer |
|---|---|---|
| Recommended starting dose | 5.4 mg/kg | 6.4 mg/kg |
| First dose reduction | 4.4 mg/kg | 5.4 mg/kg |
| Second dose reduction | 3.2 mg/kg | 4.4 mg/kg |
| Requirement for further dose reduction | Discontinue treatment | 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). | |
| 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 5.0 (NCI-CTCAE v.5.0).
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.
No dose adjustment of Enhertu is required in patients aged 65 years or older. Limited data are available in patients ≥75 years of age.
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 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 Enhertu 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 (see section 4.4).
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 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 (see sections 4.4 and 5.2).
The safety and efficacy of Enhertu in children and adolescents below the age of 18 years have not been established. No data are available.
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.
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.
Unopened vial:
4 years.
Reconstituted solution:
Chemical and physical in-use stability has been demonstrated for up to 48 hours at 2ºC to 8ºC.
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 would normally not be longer than 24 hours at 2 ºC to 8 ºC, unless reconstitution has taken place in controlled and validated aseptic condit
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 (≤30ºC) for up to 4 hours including preparation and infusion or in a refrigerator at 2ºC to 8ºC for up to 24 hours, protected from light.
Store in a refrigerator (2ºC-8ºC).
Do not freeze.
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.
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.
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:
Dilution:
Administration:
Disposal:
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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