trastuzumab deruxtecan (Rx)

Brand and Other Names:Enhertu, fam-trastuzumab deruxtecan-nxki
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Dosing & Uses

AdultPediatric

injection, lyophilized powder for reconstitution

  • 100mg/vial

Breast Cancer

Indicated for unresectable or metastatic HER2-positive breast cancer in adults who have received ≥2 prior anti-HER2-based regimens in the metastatic setting

Do not substitute for or with trastuzumab or ado-trastuzumab emtansine

5.4 mg/kg IV q3Weeks (21-day cycle) until disease progression or unacceptable toxicity

Dosage Modifications

Do not re-escalate dose after a dose reduction is made

Dose reduction schedule

  • First dose reduction: 4.4 mg/kg
  • Second dose reduction: 3.2 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, then maintain dose (if resolved in ≤28 days from date of onset) OR reduce dose 1 level (if resolved in >28 days from date of onset)
  • Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected
  • Symptomatic ILD/pneumonitis (Grade 2 or greater): Permanently discontinue; promptly initiate corticosteroid treatment as soon as ILD/pneumonitis suspected

Neutropenia

  • Grade 3 (<1 to 0.5 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 H4

  • 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): No data are available

Hepatic impairment

  • Mild (total bilirubin ≤ULN and any AST >ULN or total bilirubin >1-1.5x ULN and any AST): No dose adjustment
  • Moderate (total bilirubin >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 (total bilirubin >3 to 10x ULN and any AST): No data are available

Safety and efficacy not established

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Interactions

Interaction Checker

and trastuzumab deruxtecan

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    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            >10%

            WBC decreased (70%)

            Hgb decreased (70%)

            Neutrophil count decreased (62%)

            Fatigue (59%)

            Alopecia (46%)

            AST increased (14-41%)

            ALT increased (10-38%)

            Platelet count decreased (37%)

            Decreased appetite (32%)

            Anemia (31%)

            Neutropenia (28%)

            Hypokalemia (26%)

            Leukopenia (22%)

            Thrombocytopenia (20%)

            Headache (19%)

            Neutropenia (16%)

            Upper respiratory tract infection (15%)

            Dye eye (11%)

            1-10%

            Rash (10%)

            Dizziness (10%)

            Grade (3 or 4)

            • Anemia (7%)
            • WBC decreased (7%)
            • Hgb decreased (7%)
            • Fatigue (6%)
            • Leukopenia (6%)
            • Hypokalemia (3-3.4%)
            • Thrombocytopenia (3.4%)
            • Interstitial lung disease (2.6%)
            • Infusion-related reactions (2.6%)
            • Febrile neutropenia (1.7%)
            • Decreased appetite (1.3%)
            • Dyspnea (1.3%)

            <1%

            Grade (3 or 4)

            • AST increased (0.9%)
            • ALT increased (0.4-0.9%)
            • Dry eye (0.4%)
            • Alopecia (0.4%)
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            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

            Severe neutropenia, including febrile neutropenia, can occur

            Febrile neutropenia was reported; monitor complete blood cell counts before initiating treatment and before each dose, and as clinically indicated

            Left ventricular ejection fraction (LVEF) decrease has been observed; may be at increased risk of developing left ventricular dysfunction

            Based on its mechanism of action, may cause fetal harm when administered to a pregnant woman

            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
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            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.

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            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

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            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

            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

            First infusion: Administer infusion over 90 min

            Subsequent infusions: Administer over 30 min if prior infusions were well tolerated

            Slow or interrupt infusion rate if patient develops infusion-related symptoms

            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 the dose and rate the patient tolerated in the 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

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.