Dosing & Uses
Dosage Forms & Strengths
injection, lyophilized powder for reconstitution
- 100mg/vial
HER2-Positive Breast Cancer
Indicated for unresectable or metastatic HER2-positive breast cancer in adults who have received a prior anti-HER2-based regimen in the metastatic setting or neoadjuvant or adjuvant setting and developed recurrence during or within 6 months of completing therapy
5.4 mg/kg IV q3Weeks (21-day cycle)
Continue until disease progression or unacceptable toxicity
HER2-Low Breast Cancer
Indicated for unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer in patients who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy
5.4 mg/kg IV q3Weeks (21-day cycle)
Continue until disease progression or unacceptable toxicity
Non-small Cell Lung Cancer
Indicated for unresectable or metastatic HER2-mutant non-small cell lung cancer (NSCLC) in patients who have received prior systemic therapy based on presence of activating HER2 (ERBB2) mutations in tumor or plasma specimens
5.4 mg/kg IV q3Weeks (21-day cycle)
Continue until disease progression or unacceptable toxicity
Gastric Cancer
Indicated for locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma in adults previously treated with a trastuzumab-based regimen
6.4 mg/kg IV q3Weeks (21-day cycle)
Continue until disease progression or unacceptable toxicity
Dosage Modifications
Do not re-escalate dose following dose reduction
Dose reduction
-
Breast cancer or NSCLC
- First dose reduction: 4.4 mg/kg
- Second dose reduction: 3.2 mg/kg
- Further dose reduction required: Discontinue treatment
-
Gastric cancer
- First dose reduction: 5.4 mg/kg
- Second dose reduction: 4.4 mg/kg
- Further dose reduction required: Discontinue treatment
Interstitial lung disease (ILD)/pneumonitis
-
Asymptomatic ILD/pneumonitis (Grade 1)
- Interrupt dose until resolved to Grade 0
- Resolved in ≤28 days from date of onset: Maintain dose
- Resolved in >28 days from date of onset: Reduce dose 1 level
- Consider corticosteroid treatment (eg, ≥0.5 mg/kg/day prednisolone or equivalent) as soon as ILD/pneumonitis is suspected
-
Symptomatic ILD/pneumonitis (Grade ≥2)
- Permanently discontinue
- Promptly initiate corticosteroid treatment (eg, ≥1 mg/kg day prednisolone or equivalent) as soon as ILD/pneumonitis suspected and continue for at least 14 days followed by gradual taper for at least 4 weeks
Thrombocytopenia
- Grade 3 (platelets 25 to <50 x 109/L): Interrupt dose until resolved to Grade ≤1, then maintain dose
- Grade 4 (platelets <25 x 109/L): Interrupt dose until resolved to Grade ≤1, reduce dose by 1 level
Neutropenia
- Grade 3 (0.5 to <1 x 109/L): Interrupt until resolved to Grade ≤2, then maintain dose
- Grade 4 (<0.5 x 109/L): Interrupt until resolved to Grade ≤2; reduce dose by 1 level
Febrile neutropenia
- ANC <1 x 109/L and temperature >38.3ºC or sustained temperature of ≥38ºC for >1 hr
- Interrupt dose until resolved, then reduce to 1 dose level
Left ventricular dysfunction (LVEF)
- LVEF >45% and absolute decrease from baseline is 10-20%: Continue with treatment
- LVEF 40-45% and absolute decrease from baseline is <10%: Continue treatment; repeat LVEF assessment within 3 weeks
- LVEF 40-45% and absolute decrease from baseline is 10-20%: Repeat LVEF assessment within 3 weeks; permanently discontinue treatment (if LVEF has not recovered to within 10% from baseline) OR resume at the same dose (if LVEF recovers to within 10% from baseline)
- LVEF <40% or absolute decrease from baseline is >10%: Interrupt dose; repeat LVEF assessment within 3; if LVEF of <40% or absolute decrease from baseline of > 20% is confirmed, permanently discontinue treatment
- Symptomatic congestive heart failure (CHF): Permanently discontinue
Renal impairment
- Mild or moderate (CrCl 30 to <90 mL/min): No dose adjustment necessary
- Severe (CrCl <30 mL/min): Limited data available; monitor
Hepatic impairment
- Mild (total bilirubin [TB] ≤ULN and any AST >ULN or TB >1-1.5x ULN and any AST): No dose adjustment
- Moderate (TB >1.5-3x ULN and any AST): No dose adjustment; due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor, DXd
- Severe (TB >3 to 10x ULN and any AST): No data available
Dosing Considerations
Do not substitute for or with trastuzumab or ado-trastuzumab emtansine
Patient selection
- Unresectable or metastatic HER2-low breast cancer: Select patients based on HER2 expression (IHC 1+ or IHC 2+/ISH-)
- NSCLC: Select patients based on presence of activating HER2 (ERBB2) mutations in tumor or plasma specimens
- Locally advanced or metastatic gastric cancer: Select patients on HER2 overexpression or gene amplification; reassess HER2 status if able to obtain a new tumor specimen after prior trastuzumab-based therapy and before initiation
- Information on FDA-approved tests is available at: http://www.fda.gov/CompanionDiagnostics
Safety and efficacy not established
Adverse Effects
All grades of severities are listed unless otherwise indicated
>10%
HER2-Positive Breast Cancer
- Nausea (76%)
- Decreased white blood cell count (WBC) (74%)
- Decreased neutrophil count (70%)
- Increased AST (67%)
- Decreased hemoglobin (64%)
- Decreased lymphocyte count (55%)
- Increased ALT (53%)
- Decreased platelet count (52%)
- Vomiting (49%)
- Increased blood alkaline phosphatase (49%)
- Fatigue (49%)
- Alopecia (37%)
- Hypokalemia (35%)
- Constipation (34%)
- Anemia (33%)
- Musculoskeletal pain (31%)
- Diarrhea (29%)
- Decreased appetite (29%)
- Respiratory tract infection (22%)
- Headache (22%)
- Abdominal pain (21%)
- Increased blood bilirubin (20%)
- Stomatitis (20%)
- Decreased neutrophil count, Grade 3 or 4 (18%)
- Decreased lymphocyte count, Grade 3 or 4 (14%)
- Decreased weight (17%)
- Increased blood creatinine (0.8%)
- Peripheral neuropathy (13%)
- Dizziness (13%)
- Epistaxis (11%)
- Dyspepsia (11%)
- Cough (11%)
- Interstitial lung disease (11%)
HER2-Low Breast Cancer
- Nausea (79%)
- Decreased white blood cell count (WBC) (70%)
- Decreased hemoglobin (64%)
- Decreased neutrophil count (64%)
- Decreased lymphocyte count (55%)
- Fatigue (59%)
- Vomiting (47%)
- Alopecia (46%)
- Decreased platelet count (44%)
- Increased AST (38%)
- Increased ALT (36%)
- Constipation (35%)
- Increased blood alkaline phosphatase (34%)
- Decreased appetite (32%)
- Anemia (31%)
- Diarrhea (29%)
- Hypokalemia (25%)
- Cough (20%)
- Abdominal pain (19%)
- Headache (19%)
- Decreased lymphocyte count, Grade 3 or 4 (18%)
- Increased blood bilirubin (16%)
- Upper respiratory tract infection (15%)
- Increased blood creatinine (15%)
- Stomatitis (14%)
- Decreased neutrophil count, Grade 3 or 4 (14%)
- Epistaxis (13%)
- Dyspnea (13%)
- Dyspepsia (12%)
- Dry eye (11%)
1-10%
HER2-Positive Breast Cancer
- Decreased WBC, Grade 3 or 4 (8%)
- Decreased hemoglobin, Grade 3 or 4 (7%)
- Decreased platelet count, Grade 3 or 4 (7%)
- Nausea, Grade 3 or 4 (7%)
- Anemia, Grade 3 or 4 (7%)
- Fatigue, Grade 3 or 4 (6%)
- Hypokalemia, Grade 3 or 4 (4.7%)
- Vomiting, Grade 3 or 4 (1.6%)
- Decreased appetite, Grade 3 or 4 (1.6%)
- Increased ALT, Grade 3 or 4 (1.6%)
- Diarrhea, Grade 3 or 4 (1.2%)
- Decreased weight, Grade 3 or 4 (1.2%)
- Musculoskeletal pain, Grade 3 or 4 (1.2%)
HER2-Low Breast Cancer
- Rash (10%)
- Dizziness (10%)
- Interstitial lung disease (9%)
- Decreased WBC, Grade 3 or 4 (9%)
- Decreased hemoglobin, Grade 3 or 4 (8%)
- Nausea, Grade 3 or 4 (7%)
- Anemia, Grade 3 or 4 (7%)
- Fatigue, Grade 3 or 4 (6%)
- Decreased platelet count, Grade 3 or 4 (6%)
- Vomiting, Grade 3 or 4 (3.8%)
- Hypokalemia (3.3%)
- Increased blood bilirubin (2.7%)
- Interstitial lung disease , Grade 3 or 4 (2.6%)
- Increased AST, Grade 3 or 4 (2.2%)
- Diarrhea, Grade 3 or 4 (1.7%)
- Abdominal pain, Grade 3 or 4 (1.3%)
- Decreased appetite, Grade 3 or 4 (1.3%)
- Dyspnea, Grade 3 or 4 (1.3%)
- Increased blood creatinine, Grade 3 or 4 (1.1%)
<1%
HER2-Positive Breast Cancer
- Abdominal pain, Grade 3 or 4 (0.8%)
- Stomatitis, Grade 3 or 4 (0.8%)
- Interstitial lung disease, Grade 3 or 4 (0.8%)
- Respiratory tract infection, Grade 3 or 4 (0.8%)
- Increased blood creatinine, Grade 3 or 4 (0.8%)
- Increased blood alkaline phosphatase, Grade 3 or 4 (0.8%)
- Increased AST, Grade 3 or 4 (0.8%)
- Headache, Grade 3 or 4 (0.4%)
- Peripheral neuropathy, Grade 3 or 4 (0.4%)
- Dizziness, Grade 3 or 4 (0.4%)
- Cough, Grade 3 or 4 (0.4%)
- Alopecia, Grade 3 or 4 (0.4%)
HER2-Low Breast Cancer
- Constipation, Grade 3 or 4 (0.9%)
- Stomatitis, Grade 3 or 4 (0.9%)
- Increased ALT, Grade 3 or 4 (0.8%)
- Alopecia, Grade 3 or 4 (0.4%)
- Dry eye, Grade 3 or 4 (0.4%)
- Increased blood alkaline phosphatase (0.3%)
Warnings
Interstitial lung disease and pneumonitis
- Interstitial lung disease (ILD) and pneumonitis, including fatal cases, reported
- Monitor for, and, promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms
- Permanently discontinue in all patients with Grade 2 or higher ILD/pneumonitis
- Advise patients of the risk and to report symptoms
Embryofetal toxicity
- Exposure to trastuzumab deruxtecan during pregnancy can cause embryofetal harm
- Advise patients of these risks and the need for effective contraception
Contraindications
None
Cautions
Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur
Decrease in neutrophil count reported in metastatic breast cancer and HER2-mutant solid tumor (5.4 mg/kg); median time to first onset of decreased neutrophil count 22 days; in local advanced or metastatic gastric cancer (6.4 mg/kg) or GEJ adenocarcinoma, decrease in neutrophil count also reported; median time to first onset of decreased neutrophil count 16 days
Febrile neutropenia was reported; monitor complete blood cell counts before initiation and before each dose, and as clinically indicated
Left ventricular ejection fraction (LVEF) decrease reported in metastatic breast cancer and HER2-mutant solid tumors and locally advanced or metastatic gastric cancer; may be at increased risk of developing left ventricular dysfunction; asymptomatic LVEF decrease reported
May cause fetal harm when administered to a pregnant female
Interstitial lung disease
- Promptly investigate evidence of ILD; evaluate suspected ILD by radiographic imaging
- Consider pulmonology consult
- See Dosage Modifications for details regarding corticosteroid treatment
- Permanently discontinue for Grade ≥2
Drug interaction overview
- Trastuzumab deruxtecan is a substrate of OATP1B1, OATP1B3, MATE2-K, P-gp, CYP3A4, MRP1 and BCRP; in vitro studies did not show evidence of meaningful clinical impact
Pregnancy & Lactation
Pregnancy
Based on its mechanism of action, fetal harm may occur when administered to pregnant women
No data are available on use in pregnant women
Monitor women who received trastuzumab deruxtecan 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
Advise patients of potential fetal risks
Animal data
- 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
- Based on its mechanism of action, the topoisomerase inhibitor component, can also cause embryofetal harm when administered to a pregnant woman because it is genotoxic and targets actively dividing cells
Clinical considerations
- Monitor women who received treatment 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
Contraception
- Females of reproductive potential: Use effective contraception during treatment and for at least 7 months following the last dose
- Males with female partners of reproductive potential: Use effective contraception during treatment and for at least 4 months following the last dose
Infertility
- Based on findings in animal toxicity studies, may impair male reproductive function and fertility
Lactation
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
Advise women not to breastfeed during treatment and for 7 months after the last dose
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
HER2-targeted antibody-drug conjugate (ADC) which contains the humanized anti-HER2 IgG1, trastuzumab, covalently linked to the topoisomerase I inhibitor, deruxtecan
HER2 is a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells that is associated with aggressive disease and poorer prognosis in breast cancer patients; anti-HER2 antibodies inhibit growth in tumor cells that overexpress HER2
Topoisomerase I inhibitors bind to topoisomerase I-DNA complex and prevents ligation of the cleaved DNA strand; this results in double-strand DNA breaks, and ultimately, cell death and termination of cellular replication
Absorption
Peak plasma concentration: 122 mcg/mL (3.2 mg/kg); 4.4 ng/mL (8 mg/kg)
AUC: 735 mcg⋅day/mL (3.2 mg/kg); 28 ng⋅day/mL (8 mg/kg)
Accumulation of fam-trastuzumab deruxtecan-nxki was ~35% at steady state
Distribution
Vd (central): 2.77 L
Protein bound: ~97%
Elimination
Half-life: ~5.7 days
Clearance: 0.42L/day
Administration
IV Incompatibilities
0.9% NaCl
IV Compatibilities
Dextrose 5%
IV Preparation
Caution: In order to prevent medication errors, check vial labels to ensure drug being prepared and administered is fam-trastuzumab deruxtecan-nxki and not trastuzumab or ado-trastuzumab emtansine
Reconstitution
- Reconstitute immediately before dilution; more than 1 vial may be needed for full dose
- Slowly inject 5 mL of sterile water for injection to reconstitute each 100-mg vial to obtain final concentration of 20 mg/mL
- Swirl vial gently until completely dissolved; do not shake
- Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit; 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
Dilution
- Dilute calculated volume of reconstituted solution in 100 mL D%W IV infusion bag
- Compatible with polyvinylchloride or polyolefin (copolymer of ethylene and polypropylene) infusion bag
- Gently invert infusion bag to thoroughly mix the solution; do not shake
- Cover infusion bag to protect from light
Premedication
Moderately emetogenic
- Administer prophylactic antiemetic medications per local institutional guidelines for prevention of chemotherapy-induced nausea and vomiting
IV Administration
Do not substitute for or with trastuzumab or ado-trastuzumab emtansine
If prepared infusion solution was refrigerated, allow solution to reach room temperature prior to administration
Administer as an IV infusion only with an infusion set made of polyolefin or polybutadiene and a 0.20 or 0.22 micron in-line polyethersulfone (PES) or polysulfone (PS) filter
Do not administer as an IV push or bolus
Do not mix with other drugs or administer other drugs through the same IV line
-
Infusion time
- First infusion: Infuse over 90 min
- Subsequent infusions: Infuse over 30 min if prior infusions were well tolerated
- Slow or interrupt infusion rate if infusion-related symptoms develop
- Permanently discontinue in case of severe infusion reactions
-
Missed dose
- If a planned dose is delayed or missed, administer as soon as possible; do not wait until the next planned cycle
- Adjust treatment schedule to maintain a 3-week interval between doses
- Administer infusion at dose and rate tolerated in most recent infusion
Storage
Do not freeze
Protect from light
Do not shake the reconstituted or diluted solution
Unopened vials: Refrigerate at 2-8ºC (36-46ºF) in the original carton
Diluted vials: If not used immediately, refrigerate at 2-8ºC (36-46ºF) for up to 24 hr from the time of reconstitution; product does not contain a preservative
Diluted solutions: If not used immediately, store at room temperature for up to 4 hr including preparation and infusion, or refrigerate 2-8ºC (36-46ºF) for up to 24 hr
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Formulary
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