Fam-Trastuzumab Deruxtecan-nxki (Monograph)

Brand name: Enhertu
Drug class: Antineoplastic Agents
Chemical name: Glycinamide, N-[6-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-1-oxohexyl]glycylglycyl-l-phenylalanyl-N-[[2-[[(1S,9S)-9-ethyl-5-fluoro-2,3,9,10,13,15-hexahydro-9-hydroxy-4-methyl-10,13-dioxo-1H,12H-benzo[de]pyrano[3¢,4¢:6,7]indolizino[1,2-b]quinolin-1-yl]amino]-2-oxoethoxy]methyl], disulfide with humanized monoclonal antibody k-chain, anti-(human ERBB2 [epidermal growth factor receptor 2, receptor tyrosine-protein kinase erbB-2, EGFR2, HER2, HER-2, p185c-erbB2, NEU, CD340]), immunoglobulin G1-k dimer
CAS number: 1826843-81-5

Medically reviewed by Drugs.com on Oct 30, 2024. Written by ASHP.

Warning

Serious, sometimes fatal, ILD, including pneumonitis, reported.
Monitor for new or worsening respiratory symptoms indicative of ILD (e.g., dyspnea, cough, fever).
If ILD occurs, temporary interruption, dosage reduction, or permanent discontinuance of therapy may be necessary. (See Dosage Modification for Toxicity under Dosage and Administration and also see ILD under Cautions.)

Risk of embryofetal death or birth defects.
Inform patients of risk to the fetus.
Advise women of childbearing potential to use effective contraception during therapy and for at least 7 months after the last dose. Advise men who are partners of such women to use effective contraception during therapy and for at least 4 months after the last dose. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Introduction

Antineoplastic agent; an anti-human epidermal growth factor receptor type 2 (anti-HER2) antibody-drug conjugate consisting of a humanized IgG₁ monoclonal antibody (trastuzumab) covalently linked to a type I DNA topoisomerase inhibitor DXd (an exatecan derivative).

Uses for Fam-Trastuzumab Deruxtecan-nxki

Breast Cancer

Treatment of unresectable or metastatic breast cancer in patients whose tumors overexpress the HER2 protein and who have received at least 2 prior anti-HER2-based regimens for metastatic disease.

Efficacy determined based on objective response rate and duration of response; clinical benefit not established. Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.

Fam-Trastuzumab Deruxtecan-nxki Dosage and Administration

General

Do not substitute fam-trastuzumab deruxtecan-nxki (Enhertu) for or use with trastuzumab (Herceptin) or ado-trastuzumab emtansine (Kadcyla). Exercise extra care to ensure accuracy of preparation and administration of fam-trastuzumab deruxtecan-nxki.
Consult specialized references for procedures for proper handling and disposal of antineoplastic agents.
If infusion-related reactions occur, slow or interrupt IV infusion. If severe infusion-related reactions occur, permanently discontinue drug.

Restricted Distribution

Obtain through designated specialty pharmacies and specialty distributors.

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion through polyolefin or polybutadiene administration sets with a 0.2 or 0.22-μm polyethersulfone (PES) or polysulfone filter.

Do not administer by rapid IV injection (e.g., IV push or bolus).

Fam-trastuzumab deruxtecan-nxki powder for injection must be reconstituted and diluted prior to administration.

Unopened vials of fam-trastuzumab deruxtecan-nxki injection should be stored at 2–8°C in the original carton for protection from light; vials should not be frozen.

Do not mix or administer through the same IV line with other drugs.

Reconstitution

Reconstitute vial containing 100 mg of fam-trastuzumab deruxtecan-nxki with 5 mL of sterile water for injection to provide a solution containing 20 mg/mL. Gently swirl vial to ensure dissolution. Do not shake reconstituted solution.

Reconstituted solution should be clear and colorless to light yellow, and free of visible particulates.

Dilution

Dilute appropriate dose in a PVC or polyolefin infusion bag containing 100 mL of 5% dextrose injection; do not dilute in 0.9% sodium chloride injection. Mix the diluted solution by gentle inversion; do not shake. Discard any partially used vials.

Rate of Administration

Initial dose: Administer over 90 minutes.

Subsequent doses: Administer over 30 minutes (if first infusion is well tolerated).

Dosage

Adults

Breast Cancer

IV

5.4 mg/kg every 3 weeks. Continue until disease progression or until unacceptable toxicity occurs.

If a dose is missed or delayed, do not wait until the next scheduled dose. Adjust dosage schedule to maintain a 3-week interval between doses.

Dosage Modification for Toxicity

IV

Temporary interruption, dosage reduction, and/or permanent discontinuance may be necessary for adverse reactions.

If dosage reduction is required, reduce dosage as described in Table 1. Do not re-escalate dosage following dosage reduction.

Table 1: Recommended Dosage Reduction for Fam-Trastuzumab Deruxtecan Toxicity1
Dosage Reduction Level	Dosage Reduction after Recovery from Toxicity (Initial Dosage = 5.4 mg/kg every 3 weeks)
First	Resume at 4.4 mg/kg every 3 weeks
Second	Resume at 3.2 mg/kg every 3 weeks
Third	Permanently discontinue drug

If an adverse reaction occurs, modify dosage accordingly (see Table 2).

Table 2. Recommended Dosage Modification for Fam-Trastuzumab Deruxtecan Toxicity1
Adverse Reaction and Severity	Dosage Modification
Pulmonary Toxicity
Grade 1 asymptomatic ILD or pneumonitis	Withhold therapy and consider initiating corticosteroid therapy (see ILD under Cautions) If ILD or pneumonitis resolves in ≤28 days of onset, resume therapy at same dosage If ILD or pneumonitis does not resolve within 28 days of onset, resume therapy at a reduced dosage by one dose level (see Table 1)
Grade 2 or greater symptomatic ILD or pneumonitis	Permanently discontinue therapy and promptly initiate corticosteroid therapy (see ILD under Cautions)
Neutropenia
Grade 3 (absolute neutrophil count [ANC] 500–1000/mm³)	Withhold therapy; when neutropenia improves to grade 2 or less, resume therapy at same dosage
Grade 4 (ANC <500/mm³)	Withhold therapy; when neutropenia improves to grade 2 or less, resume therapy at reduced dosage by one dose level (see Table 1)
Febrile neutropenia (ANC <1000/mm³ with fever >38.3ºC or ≥38ºC for >1 hour)	Withhold therapy; when febrile neutropenia resolves, resume therapy at reduced dosage by one dose level (see Table 1)
Left Ventricular Dysfunction
LVEF >45% with an absolute decrease from baseline of 10–20%	Continue therapy at same dosage
LVEF decreases to 40–45% with an absolute decrease from baseline of <10%	Continue therapy at same dosage and reassess left ventricular function within 3 weeks.
LVEF decreases to 40–45% with an absolute decrease from baseline of 10–20%	Withhold therapy and reassess left ventricular function within 3 weeks If LVEF improves to within 10% of baseline, resume therapy at same dosage If LVEF does not improve to within 10% of baseline, permanently discontinue therapy
LVEF decreases to <40% or absolute decrease from baseline of >20%	Withhold therapy and reassess left ventricular function within 3 weeks If LVEF <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue therapy
Symptomatic CHF	Permanently discontinue therapy

Prescribing Limits

Adults

Breast Cancer

IV

Dosage <3.2 mg/kg every three weeks not recommended.

Special Populations

Hepatic Impairment

Mild (total bilirubin concentration not exceeding upper limit of normal [ULN] with AST concentration exceeding ULN, or total bilirubin concentration exceeding ULN, but ≤1.5 times ULN, with any AST concentration) or moderate (total bilirubin concentration >1.5 times the ULN, but ≤3 times the ULN, with any AST concentration) hepatic impairment: No dosage adjustment required. (See Hepatic Impairment under Cautions.)

Severe hepatic impairment (total bilirubin concentration >3 times ULN, but ≤10 times ULN, with any AST concentration): No specific dosage recommendations.

Renal Impairment

Mild (Cl_cr 60–89 mL/minute) or moderate (Cl_cr 30–59 mL/minute) renal impairment: No dosage adjustment required. (See Renal Impairment under Cautions.)

Severe renal impairment (Cl_cr <30 mL/minute): No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations. (See Geriatric Use under Cautions.)

Cautions for Fam-Trastuzumab Deruxtecan-nxki

Contraindications

Manufacturer states none known.

Warnings/Precautions

Warnings

ILD

Severe, life-threatening, or fatal ILD, including pneumonitis, reported.

Monitor patients for pulmonary symptoms indicative of ILD. If ILD is suspected, evaluate patients using radiographic imaging and consider consultation with a pulmonologist.

If asymptomatic (grade 1) ILD occurs, consider systemic corticosteroid therapy (≥0.5 mg/kg of prednisolone daily [or equivalent]) followed by gradual tapering (e.g., over 4 weeks) of the corticosteroid dosage once symptoms improve. If symptomatic (grade 2 or greater) ILD occurs, initiate systemic corticosteroid therapy (≥1 mg/kg of prednisolone daily [or equivalent]) followed by gradual tapering (e.g., over 4 weeks) of the corticosteroid dosage once symptoms improve. Interruption of therapy, dosage reduction, or permanent discontinuance of therapy may be necessary. (See Dosage Modification for Toxicity under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.

Oligohydramnios, fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death observed following administration of an anti-HER2 antibody to pregnant women in postmarketing experience.

DXd (derivative of exatecan) may cause embryotoxic and fetotoxic effects.

Verify pregnancy status prior to initiation of therapy. Women of reproductive potential should use effective contraceptive methods while receiving the drug and for ≥7 months after the last dose. Men who are partners of such women should use effective contraceptive methods while receiving the drug and for ≥4 months after the last dose.

If used during pregnancy or if patient becomes pregnant during therapy, apprise of potential fetal hazard.

If used during pregnancy or within 7 months prior to conception, monitor for oligohydramnios. If oligohydramnios occurs, perform fetal testing appropriate for gestational age and according to standards of care.

Other Warnings and Precautions

Hematologic Effects

Severe neutropenia, including febrile neutropenia reported.

Monitor CBCs at baseline, prior to each dose, and as clinically indicated. Interruption of therapy or dosage reduction may be necessary. (See Dosage Modification for Toxicity under Dosage and Administration.)

Left Ventricular Dysfunction

Anti-HER2 antibodies, including fam-trastuzumab deruxtecan, are associated with decreases in LVEF.

Not studied in patients with a baseline LVEF <50%, symptomatic CHF, or conditions that could impair left ventricular function (e.g., serious cardiac arrhythmia or unstable angina requiring therapy within 28 days of study enrollment, history of MI within 6 months of study enrollment).

Assess LVEF prior to initiation of therapy, regularly during therapy, and as clinically indicated.

If LVEF occurs, interruption of therapy or discontinuance of therapy may be necessary. Reassessment of LVEF may be needed within 3 weeks. (See Dosage Modification for Toxicity under Dosage and Administration.)

Immunogenicity

Potential for immunogenicity. Data insufficient to determine whether antibody formation affects efficacy or safety. Neutralizing antibodies not assessed.

Infertility

Results of animal studies suggest fam-trastuzumab deruxtecan may impair male fertility.

Specific Populations

Pregnancy

May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether fam-trastuzumab deruxtecan is distributed into milk, affects nursing infants, or affects milk production.

Discontinue nursing during therapy and for 7 months after the last dose.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

In clinical trials, 26% of patients were ≥65 years of age and 5% were ≥75 years of age. No overall differences in efficacy observed between geriatric patients and younger adults. Grade 3 or 4 adverse reactions occurred more frequently in geriatric patients.

Hepatic Impairment

Pharmacokinetics not affected by mild hepatic impairment (total bilirubin concentration not exceeding ULN with AST concentration exceeding ULN, or total bilirubin concentration exceeding ULN, but ≤1.5 times the ULN, with any AST concentration); no dosage adjustment necessary. (See Special Populations under Pharmacokinetics.)

Not studied in patients with moderate or severe (total bilirubin concentration >1.5 times ULN with any AST concentration) hepatic impairment; closely monitor patients with moderate hepatic impairment for signs of toxicity from the type I DNA topoisomerase inhibitor DXd.

Renal Impairment

Pharmacokinetics not affected by mild (Cl_cr 60–89 mL/minute) or moderate (Cl_cr 30–59 mL/minute) renal impairment; no dosage adjustment required. (See Special Populations under Pharmacokinetics.)

Not studied in patients with severe renal impairment (Cl_cr <30 mL/minute).

Common Adverse Effects

Nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, neutropenia, diarrhea, leukopenia, cough, thrombocytopenia.

Drug Interactions

DXd, the type I DNA topoisomerase inhibitor component of the antibody-drug conjugate, primarily metabolized by CYP3A4.

DXd does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A or induce CYP isoenzymes 1A2, 2B6, or 3A.

DXd does not inhibit organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, organic anion transport protein (OATP) 1B1, OATP1B3, multidrug and toxin extrusion (MATE) transporter 1, MATE2K, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), or bile salt export pump (BSEP) at clinically relevant concentrations. DXd is a substrate of OATP1B1, OATP1B3, MATE2K, P-gp, multidrug resistance-associated protein (MRP) 1, and BCRP.

Specific Drugs

Drug	Interaction
Itraconazole	Increased AUC of fam-trastuzumab deruxtecan and DXd by 11 and 18%, respectively; not considered clinically meaningful
Ritonavir	Increased AUC of fam-trastuzumab deruxtecan and DXd by 19 and 22%, respectively; not considered clinically meaningful

Fam-Trastuzumab Deruxtecan-nxki Pharmacokinetics

Absorption

Bioavailability

Systemic exposure of antibody-drug conjugate and free DXd are dose proportional over a dose range of 3.2–8 mg/kg.

Steady-state concentrations achieved after 3 treatment cycles.

Systemic accumulation of antibody-drug conjugate is approximately 35% following repeated administration.

Special Populations

Mild hepatic impairment (total bilirubin concentration not exceeding ULN with AST concentration exceeding ULN, or total bilirubin concentration exceeding ULN, but ≤1.5 times ULN, with any AST concentration): No substantial effects on pharmacokinetics of antibody-drug conjugate or DXd.

Moderate hepatic impairment (total bilirubin concentration >1.5 times ULN, but ≤3 times ULN, with any AST concentration): Pharmacokinetics not studied; increased exposure possible.

Severe hepatic impairment (total bilirubin concentration >3 times ULN, but ≤10 times ULN, with any AST concentration): Pharmacokinetics not studied.

Mild (Cl_cr of 60–89 mL/minute) or moderate (Cl_cr of 30–59 mL/minute) renal impairment: No substantial effects on pharmacokinetics of antibody-drug conjugate or DXd.

Severe renal impairment (Cl_cr <30 mL/minute): Pharmacokinetics not studied.

Age (range: 23–96 years), race, sex, and body weight (range: 35–125 kg) do not have clinically important effects on pharmacokinetics of antibody-drug conjugate or DXd.

Distribution

Extent

Not known whether fam-trastuzumab deruxtecan is distributed into milk.

Plasma Protein Binding

DXd: Approximately 97%.

Elimination

Metabolism

Anti-HER2 antibody: Expected to degrade into small peptides and amino acids via catabolic pathways.

DXd: Metabolized by CYP3A4 in vitro.

Half-life

Antibody-drug conjugate: Approximately 5.7 days.

DXd: Approximately 5.8 days.

Stability

Storage

Parenteral

Powder for Injection

2–8°C in original carton for protection from light. Do not freeze.

May store reconstituted drug in vial at 2–8°C for up to 24 hours after reconstitution. Protect from light; do not freeze.

May store final diluted IV infusion solution at room temperature for ≤4 hours (including preparation and infusion time) or at 2–8°C for ≤24 hours. Allow diluted solutions of the drug to reach room temperature prior to administration. Protect from light. Do not freeze.

Compatibility

Parenteral

Solution Compatibility

Compatible
Dextrose 5% in water
Incompatible
Sodium chloride 0.9%

Actions

An anti-HER2 antibody (trastuzumab; a humanized IgG₁) conjugated via a protease-cleavable maleimide tetrapeptide linker to the type I DNA topoisomerase inhibitor DXd (an exatecan derivative). Resultant complex referred to as deruxtecan.
Antibody portion of fam-trastuzumab deruxtecan binds to extracellular domain of the HER2 receptor on tumor cells; resultant complex internalized by cell and DXd releases following cleavage of the linker by lyososomal enzymes. DXd binds to and stabilizes DNA topoisomerase 1 cleavable complexes, resulting in double-stranded breaks in DNA and apoptosis.
High drug-to-antibody ratio (approximately 8 molecules of deruxtecan are attached to each molecule of antibody) compared with ado-trastuzumab emtansine (approximately 3–4 molecules of emtansine are attached to each molecule of antibody).

Advice to Patients

Importance of instructing patients to read the manufacturer's patient information (medication guide).
Risk of severe or fatal ILD. Importance of immediately informing clinician if new or worsening respiratory symptoms occur (e.g., cough, shortness of breath, wheezing, fever).
Risk of neutropenia. Importance of immediately informing clinician if fever or other signs of infection occur.
Risk of left ventricular dysfunction. Importance of immediately informing clinicians if manifestations of left ventricular dysfunction (e.g., new or worsening shortness of breath, cough, fatigue, swelling of ankles or legs, abnormal heartbeat, dizziness, sudden weight gain, sudden loss of consciousness) occur.
Risk of fetal harm. Necessity of advising women of childbearing potential to avoid pregnancy and to use effective contraceptive methods during and for ≥7 months following the last dose. Importance of advising men who are partners of such women that they should use effective methods of contraception during and for ≥4 months after the last dose. Importance of women informing clinician if they become pregnant during therapy or think they may be pregnant. Advise pregnant women of potential risk to the fetus.
Importance of advising women to avoid breast-feeding during therapy and for 7 months after the last dose.
Risk of impaired male fertility.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.
Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of fam-trastuzumab deruxtecan-nxki is restricted. (See Restricted Distribution under Dosage and Administration.)