Dosage & Administration
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Enhertu Prescribing Information
- Interstitial Lung Disease (ILD) and pneumonitis, including fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and the need to immediately report symptoms [see Dosage and Administration (2.3), Warnings and Precautions (5.1)].
- Embryo-Fetal Toxicity: Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)].
HER2-Positive Metastatic Breast Cancer
ENHERTU is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH positive) breast cancer who have received a prior anti-HER2-based regimen either:
- in the metastatic setting, or
- in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy.
HER2-Low and HER2-Ultralow Metastatic Breast Cancer
ENHERTU is indicated for the treatment of adult patients with unresectable or metastatic
- Hormone receptor (HR)-positive HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by an FDA-approved test, that has progressed on one or more endocrine therapies in the metastatic setting [see Dosage and Administration (2.1)].
- HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy [see Dosage and Administration (2.1)].
HER2-Mutant Unresectable or Metastatic Non-Small Cell Lung Cancer
ENHERTU is indicated for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy.
This indication is approved under accelerated approval based on objective response rate and duration of response [see Clinical Studies (14.3)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
HER2-Positive Locally Advanced or Metastatic Gastric Cancer
ENHERTU is indicated for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.
HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors
ENHERTU is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.
This indication is approved under accelerated approval based on objective response rate and duration of response [see Clinical Studies (14.5)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Patient Selection
HER2-Low or HER2-Ultralow Unresectable or Metastatic Breast Cancer
Select patients for treatment of unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer with ENHERTU based on HER2 expression [see Clinical Studies (14.2)].
HER2-Mutant Unresectable or Metastatic NSCLC
Select patients for the treatment of unresectable or metastatic HER2-mutant NSCLC with ENHERTU based on the presence of activating HER2 (ERBB2) mutations in tumor or plasma specimens [see Clinical Studies (14.3)]. If no mutation is detected in a plasma specimen, test tumor tissue.
HER2-Positive Locally Advanced or Metastatic Gastric Cancer
Select patients with locally advanced or metastatic HER2-positive gastric cancer based on HER2 protein overexpression or HER2 gene amplification (IHC 3+ or IHC 2+/ISH positive). Reassess HER2 status if it is feasible to obtain a new tumor specimen after prior trastuzumab-based therapy and before treatment with ENHERTU.
HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors
Select patients for treatment of unresectable or metastatic solid tumors with ENHERTU based on HER2-positive (IHC 3+) specimens [see Clinical Studies (14.5)]. An FDA-approved test for the detection of HER2-positive (IHC 3+) solid tumors for treatment with ENHERTU is not currently available.
Additional Patient Selection Information
Information on FDA-approved tests for the detection of HER2 protein expression, HER2 gene amplification, and activating HER2 mutations is available at: http://www.fda.gov/CompanionDiagnostics.
Recommended Dosage and Schedules
Do not substitute ENHERTU for or with trastuzumab or ado-trastuzumab emtansine.
Slow or interrupt the infusion rate if the patient develops infusion-related symptoms.
Permanently discontinue ENHERTU in case of severe infusion reactions.
Premedication
ENHERTU is highly emetogenic [see Adverse Reactions (6.1)], which includes delayed nausea and/or vomiting. Administer prophylactic antiemetic medications per local institutional guidelines for prevention of chemotherapy-induced nausea and vomiting.
Recommended Dosage for HER2-Positive, HER2-Low, or HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant Unresectable or Metastatic NSCLC, and HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors.
The recommended dosage 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.
Recommended Dosage for HER2-Positive Locally Advanced or Metastatic Gastric Cancer
The recommended dosage 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.
Dosage Modifications
Management of adverse reactions may require temporary interruption, dose reduction, or treatment discontinuation of ENHERTU as described in Tables 1 and 2.
Do not re-escalate the ENHERTU dose after a dose reduction is made.
If a planned dose is delayed or missed, administer as soon as possible; do not wait until the next planned cycle. Adjust the schedule of administration to maintain a 3-week interval between doses. Administer the infusion at the dose and rate the patient tolerated in the most recent infusion.
| Dose Reduction Schedule | Breast Cancer, NSCLC, and IHC 3+ Solid Tumors | 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. |
| Adverse Reaction | Severity | Treatment Modification | |
|---|---|---|---|
| Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v.5.0). | |||
| Interstitial Lung Disease (ILD)/ Pneumonitis [see Warnings and Precautions (5.1)] | Asymptomatic ILD/pneumonitis (Grade 1) | Interrupt ENHERTU until resolved to Grade 0, then:
| |
| Symptomatic ILD/pneumonitis (Grade 2 or greater) |
| ||
| Neutropenia [see Warnings and Precautions (5.2)] | Grade 3 (less than 1.0 to 0.5 × 109/L) |
| |
| Grade 4 (less than 0.5 × 109/L) |
| ||
| Febrile Neutropenia [see Warnings and Precautions (5.2)] | 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 |
| |
| Thrombocytopenia [see Adverse Reactions (6.1)] | Grade 3 (platelets less than 50 to 25 × 109/L) |
| |
| Grade 4 (platelets less than 25 × 109/L) |
| ||
| Left Ventricular Dysfunction [see Warnings and Precautions (5.3)] | LVEF greater than 45% and absolute decrease from baseline is 10% to 20% |
| |
| LVEF 40% to 45% | And absolute decrease from baseline is less than 10% |
| |
| And absolute decrease from baseline is 10% to 20% |
| ||
| LVEF less than 40% or absolute decrease from baseline is greater than 20% |
| ||
| Symptomatic congestive heart failure (CHF) |
| ||
Preparation and Administration
In order to prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is ENHERTU (fam-trastuzumab deruxtecan-nxki) and not trastuzumab or ado-trastuzumab emtansine.
Reconstitute and further dilute ENHERTU prior to intravenous infusion. Use appropriate aseptic technique.
ENHERTU (fam-trastuzumab deruxtecan-nxki) is a hazardous drug. Follow applicable special handling and disposal procedures.1
Reconstitution
- Reconstitute immediately before dilution.
- More than one vial may be needed for a full dose. Calculate the dose (mg), the total volume of reconstituted ENHERTU solution required, and the number of vial(s) of ENHERTU needed [see Dosage and Administration (2.2)].
- Reconstitute each 100 mg vial by using a sterile syringe to slowly inject 5 mL of Sterile Water for Injection, USP into each vial to obtain a final concentration of 20 mg/mL.
- Swirl the vial gently until completely dissolved. Do not shake.
- If not used immediately, store the reconstituted ENHERTU vials in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) for up to 24 hours from the time of reconstitution, protect the vial from light. Do not freeze.
- The product does not contain a preservative. Discard unused ENHERTU after 24 hours refrigerated.
Dilution
- Withdraw the calculated amount from the vial(s) using a sterile syringe. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The solution should be clear and colorless to light yellow. Do not use if visible particles are observed or if the solution is cloudy or discolored.
- Dilute the calculated volume of reconstituted ENHERTU in an intravenous infusion bag containing 100 mL of 5% Dextrose Injection, USP. DO NOT use Sodium Chloride Injection, USP. ENHERTU is compatible with an infusion bag made of polyvinylchloride or polyolefin (copolymer of ethylene and polypropylene).
- Gently invert the infusion bag to thoroughly mix the solution. Do not shake.
- Cover the infusion bag to protect from light.
- Discard any unused portion left in the vials.
Administration
- If not used immediately, store the diluted ENHERTU in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) for up to 24 hours or at room temperature between 20ºC to 25ºC (68ºF to 77 ºF) for up to 4 hours including preparation and infusion time.
- Protect from light. Do not freeze.
- The maximum time from reconstitution of the vial through the end of administration should not exceed 24 hours.
- If the prepared infusion solution was stored refrigerated (2ºC to 8ºC [36ºF to 46ºF]), allow the solution to reach room temperature prior to administration. Cover the infusion bag to protect from light.
- Administer ENHERTU as an intravenous infusion only with an infusion set made of polyolefin or polybutadiene.
- Administer ENHERTU with a 0.20 or 0.22 micron in-line polyethersulfone (PES) or polysulfone (PS) filter.
- Do NOT administer as an intravenous push or bolus.
- Cover the infusion bag to protect from light during administration.
- Do not mix ENHERTU with other drugs or administer other drugs through the same intravenous line.
- First infusion: Administer infusion over 90 minutes.
- Subsequent infusions: Administer over 30 minutes if prior infusions were well tolerated.
For injection: 100 mg of fam-trastuzumab deruxtecan-nxki as a white to yellowish white lyophilized powder in a single-dose vial for reconstitution and further dilution
Pregnancy
Risk Summary
Based on its mechanism of action, ENHERTU can cause fetal harm when administered to a pregnant woman. There are no available data on the use of ENHERTU in pregnant women. In postmarketing reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death (see Data). Based on its mechanism of action, the topoisomerase inhibitor component of ENHERTU, DXd, can also cause embryo-fetal harm when administered to a pregnant woman because it is genotoxic and targets actively dividing cells [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)]. Advise patients of the potential risks to a fetus.
There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months after the last dose of ENHERTU (see Clinical Considerations).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Monitor women who received ENHERTU during pregnancy or within 7 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care.
Data
Human Data
There are no available data on the use of ENHERTU in pregnant women. In postmarketing reports in pregnant women receiving a HER2-directed antibody, cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death have been reported. These case reports described oligohydramnios in pregnant women who received a HER2-directed antibody either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after use of a HER2-directed antibody was stopped.
Animal Data
There were no animal reproductive or developmental toxicity studies conducted with fam-trastuzumab deruxtecan-nxki.
Lactation
Risk Summary
There is no data regarding the presence of fam-trastuzumab deruxtecan-nxki in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose.
Females and Males of Reproductive Potential
Pregnancy Testing
Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU.
Contraception
Females
ENHERTU can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for 7 months after the last dose.
Males
Because of the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose [see Nonclinical Toxicology (13.1)].
Infertility
Based on findings in animal toxicity studies, ENHERTU may impair male reproductive function and fertility [see Nonclinical Toxicology (13.1)].
Pediatric Use
Safety and effectiveness of ENHERTU have not been established in pediatric patients.
Animal Data
Juvenile animal studies have not been conducted with fam-trastuzumab deruxtecan-nxki. In a six-week repeat-dose toxicity study in rats, intravenous administration of fam-trastuzumab deruxtecan-nxki resulted in incisor tooth toxicity including single cell necrosis in the base area (e.g., ameloblasts, odontoblasts) and degeneration of the enamel at ≥60 mg/kg (approximately ≥9 times the human recommended dose of 5.4 mg/kg based on AUC), abnormal formation or hypoplasia of the dentin, hemorrhage in the sub-enamel organ tissue, and focal lack of the cementum at 197 mg/kg (approximately 19 times the human recommended dose of 5.4 mg/kg based on AUC). Degeneration of the enamel organ, abnormal dentin formation, hemorrhage in the sub-enamel organ tissue, focal lack of the cementum, and root fracture were observed at 197 mg/kg following a 9-week recovery period.
Geriatric Use
Of the 1741 patients with HER2-positive, HER2-low, or HER2-ultralow breast cancer treated with ENHERTU 5.4 mg/kg, 24% were 65 years or older and 4.9% were 75 years or older. No overall differences in efficacy within clinical studies were observed between patients ≥65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged 65 years or older (61%) as compared to younger patients (52%).
Of the 101 patients with HER2-mutant unresectable or metastatic NSCLC treated with ENHERTU 5.4 mg/kg, 40% were 65 years or older and 8% were 75 years or older. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients.
Of the 125 patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in DESTINY-Gastric01, 56% were 65 years or older and 14% were 75 years or older. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients.
Of the 192 patients with HER2-positive (IHC 3+) unresectable or metastatic solid tumors treated with ENHERTU 5.4 mg/kg in DESTINY-PanTumor02, DESTINY-Lung01 or DESTINY-CRC02, 39% were 65 years or older and 9% were 75 years or older. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients.
Renal Impairment
No dose adjustment of ENHERTU 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 Clinical Pharmacology (12.3)]. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment [see Warnings and Precautions (5.1)]. Monitor patients with moderate renal impairment more frequently. The recommended dosage of ENHERTU has not been established for patients with severe renal impairment (CLcr <30 mL/min) [see Clinical Pharmacology (12.3)].
Hepatic Impairment
No dose adjustment of ENHERTU is required in patients with mild (total bilirubin ≤ULN and any AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST) or moderate (total bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment. In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor, DXd [see Dosage and Administration (2.3)]. The recommended dosage of ENHERTU has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST) [see Clinical Pharmacology (12.3)].
None.