ado-trastuzumab emtansine (Rx)

Brand and Other Names:Kadcyla
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injection, lyophilized powder for reconstitution

  • 100mg/vial
  • 160mg/vial
  • 20mg/mL following reconstitution
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Breast Cancer

Early breast cancer

  • Indicated as a single agent for adjuvant treatment of patients with HER2-positive early breast cancer (EBC) who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment
  • 3.6 mg/kg IV q3Weeks
  • Do not administer at doses >3.6 mg/kg
  • Continue treatment for a total of 14 cycles unless there is disease recurrence or unacceptable toxicity

Metastatic breast cancer

  • Indicated as a single agent for treatment of HER2-positive, metastatic breast cancer (MBC) in patients who previously received trastuzumab and a taxane, separately or in combination, and have either received prior therapy for metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy
  • 3.6 mg/kg IV q3Weeks
  • Do not administer at doses >3.6 mg/kg
  • Continue until disease recurrence or unacceptable toxicity

Dosage Modifications

Dose reduction for adverse events

  • Do not re-escalate dose after reduction is made
  • First dose reduction: 3 mg/kg
  • Second dose reduction: 2.4 mg/kg
  • Requirement for further dose reduction: Discontinue treatment

Hepatotoxicity

  • MBC
    • Grade 2 (AST/ALT >2.5 to ≤5x ULN): Maintain same dose level
    • Grade 3 (AST/ALT >5 to ≤20x ULN): Do not administer until AST/ALT recovers to Grade ≤2, and then reduce 1 dose level
    • Grade 4 (AST/ALT >20x ULN): Permanently discontinue
  • EBC
    • Grade 2 (AST >3 to ≤5x ULN on day of treatment): Do not administer until AST recovers to Grade ≤1, and then maintain same dose level
    • Grade 2 or 3 (ALT >3 to ≤20x ULN) or Grade 3 (AST >5 to ≤20x ULN) on day of treatment: Do not administer until ALT/AST recovers to Grade ≤1, and then reduce 1 dose level
    • Grade 4 (AST/ALT >20x ULN at any time): Permanently discontinue

Hyperbilirubinemia

  • MBC
    • Grade 2 (total bilirubin >1.5 to ≤10x ULN): Do not administer until total bilirubin recovers to Grade ≤1, and then maintain same dose level
    • Grade 3 (total bilirubin >3 to ≤10x ULN): Do not administer until total bilirubin recovers to Grade≤1, and then reduce 1 dose level
    • Grade 4 (total bilirubin >10x ULN): Permanently discontinue
  • EBC
    • Total bilirubin >1 to ≤2x ULN on day of treatment: Do not administer until total bilirubin ≤1x ULN, and then reduce 1 dose level
    • Total bilirubin >2x ULN at any time: Permanently discontinue

Left ventricular dysfunction

  • MBC
    • LVEF <40%: Do not administer drug; repeat LVEF assessment within 3 weeks, if <40% confirmed, discontinue drug
    • LVEF 40% to ≤45% and decrease is ≥10% points from baseline: Do not administer drug; repeat LVEF assessment within 3 weeks; if LVEF has not recovered to within 10% points from baseline, discontinue drug
    • LVEF 40% to ≤45% and decrease is <10% points from baseline: Continue drug and repeat LVEF assessment within 3 weeks
    • LVEF >45%: Continue drug
  • EBC
    • LVEF <45%: Do not administer drug; repeat LVEF assessment within 3 weeks, if <45% confirmed, discontinue drug
    • LVEF 45% to <50% and decrease is ≥10% points from baseline: Do not administer drug; repeat LVEF assessment within 3 weeks, if LVEF remains <50% and has not recovered to <10% points from baseline, discontinue drug
    • LVEF 45% to <50% and decrease is <10% points from baseline: Continue drug and repeat LVEF assessment within 3 weeks
    • LVEF >50%: Continue treatment

Heart failure

  • MBC
    • Symptomatic CHF: Discontinue drug
  • EBC
    • Symptomatic CHF, Grade 3-4 LVSD or Grade 3-4 heart failure, or Grade 2 heart failure accompanied by LVEF < 45%: Discontinue treatment

Thrombocytopenia

  • MBC
    • Grade 3 (platelets 25,000/mm³ to ≤50,000/mm³): Do not administer until platelet count recovers to Grade ≤1 (ie, ≥75,000/mm³), and then maintain same dose level
    • Grade 4 (platelets <25,000/mm³): Do not administer until platelet count recovers to Grade ≤1 (ie, ≥75,000/mm³), and then reduce 1 dose level
  • EBC
    • Grade 3 (platelets 25,000/mm³ to ≤75,000/mm³ on day of treatment): Do not administer until platelet count recovers to Grade ≤1 (ie, ≥75,000/mm³), and then maintain same dose level; if patients requires 2 delays, consider reducing dose by 1 level
    • Grade 4 (platelets <25,000/mm³): Do not administer until platelet count recovers to Grade ≤1 (ie, ≥75,000/mm³), and then reduce 1 dose level

Pulmonary toxicity

  • Interstitial lung disease or pneumonitis: Permanently discontinue
  • Radiotherapy-related pneumonitis (EBC only)
    • Grade 2: Discontinue if not resolving with standard treatment
    • Grade 3-4: Discontinue treatment

Peripheral neuropathy

  • Grade 3 or 4: Do not administer until resolution to Grade ≤2

Nodular regenerative hyperplasia

  • All grades: Permanently discontinue

Renal impairment

  • Mild-to-moderate (CrCl ≥30 mL/min): Dose adjustment not necessary (based on population pharmacokinetics)
  • Severe (CrCl <30 mL/min): No dosage adjustment can be recommended owing to limited data

Hepatic impairment

  • Mild or moderate: No adjustment to starting dose required; monitor closely patients with hepatic impairment owing to risk of hepatotoxicity associated with therapy
  • Severe: Not studied

Dosing Considerations

Do not substitute ado-trastuzumab emtansine (Kadcyla) for or with trastuzumab (Herceptin)

Patient Selection

  • Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens
  • Perform assessment of HER2 protein overexpression and/or HER2 gene amplification using FDA-approved tests specific for breast cancers by laboratories with demonstrated proficiency
  • Information on the FDA-approved tests for detection of HER2 protein overexpression and HER2 gene amplification is available at: http://www.fda.gov/CompanionDiagnostics

Safety and efficacy not established

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Interactions

Interaction Checker

and ado-trastuzumab emtansine

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            All grades of severity are listed unless otherwise indicated

            >10% (All Grades for MBC)

            Nausea (40%)

            Fatigue (36%)

            Musculoskeletal pain (36%)

            Hemorrhage (32%)

            Thrombocytopenia (31%)

            AST/ALT increased (29%)

            Constipation (27%)

            Headache (28%)

            Diarrhea (24%)

            Epistaxis (23%)

            Peripheral neuropathy (21%)

            Vomiting (19%)

            Abdominal pain (19%)

            Pyrexia (19%)

            Arthralgia (19%)

            Asthenia (18%)

            Cough (18%)

            Dry mouth (17%)

            Myalgia (14%)

            Anemia (14%)

            Stomatitis (14%)

            Insomnia (12%)

            Dyspnea (12%)

            Rash (12%)

            >10% (All Grades for EBC)

            Fatigue (50%)

            Nausea (42%)

            AST/ALT increased (32%)

            Musculoskeletal pain (30%)

            Thrombocytopenia (29%)

            Hemorrhage (29%)

            Headache (28%)

            Peripheral neuropathy (28%)

            Arthralgia (26%)

            Epistaxis (22%)

            Constipation (17%)

            Myalgia (15%)

            Stomatitis (15%)

            Vomiting (15%)

            Dry Mouth (14%)

            Cough (14%)

            Insomnia (14%)

            Diarrhea (12%)

            Abdominal pain (11%)

            >10% (MBC [Grade 3 or 4])

            Thrombocytopenia (15%)

            1-10% (All Grades)

            MBC

            • Hypokalemia (10%)
            • Dizziness (10%)

            EBC

            • Anemia (10%)
            • Pyrexia (10%)
            • Dizziness (10%)
            • Urinary tract infection (10%)

            1-10% (Grade 3 or 4)

            MBC

            • AST/ALT increased (8%)
            • Anemia (4.1%)
            • Hypokalemia (2.7%)
            • Fatigue (2.5%)
            • Peripheral neuropathy (2.2%)
            • Musculoskeletal pain (1.8%)
            • Hemorrhage (1.8%)
            • Diarrhea (1.6%)

            EBC

            • Thrombocytopenia (6%)
            • Peripheral neuropathy (1.6%)
            • AST/ALT increased (1.5%)

            <1% (Grade 3 or 4)

            Nausea/vomiting (0.8%)

            Headache (0.8%)

            Dyspnea (0.8%)

            Arthralgia/myalgia (0.6%)

            Nausea (0.5%)

            Constipation (0.4%)

            Asthenia (0.4%)

            Dizziness (0.4%)

            Insomnia (0.4%)

            Dry mouth (0.4%)

            Stomatitis (0.2%)

            Pyrexia (0.2%)

            Epistaxis (0.2%)

            Cough (0.2%)

            Postmarketing Reports

            Tumor lysis syndrome (TLS) reported; patients with significant tumor burden (eg, bulky metastases) may be at a higher risk

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            Warnings

            Black Box Warnings

            Hepatotoxicity

            • Serious hepatoxicity reported, including liver failure and death
            • Monitor serum transaminases and bilirubin before initiating and prior to each dose
            • Reduce dose or discontinue as appropriate with elevated transaminases or total bilirubin (see Dosage modifications)

            Cardiac toxicity

            • May decrease LVEF
            • Evaluate LVEF in all patients before and during treatment
            • Withhold treatment for clinically significant decrease in LVEF (see Dosage Modifications)

            Embryofetal toxicity

            • Can result in embryofetal death or birth defects
            • Postmarketing reports of oligohydramnios, some associated with fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death DM1, the cytotoxic component, can be expected to cause embryofetal toxicity based on its mechanism of action
            • Advise patient of risk and the need for effective contraception
            • Verify pregnancy status prior to initiation

            Contraindications

            None

            Cautions

            Hepatotoxicity, predominantly in the form of asymptomatic, transient increases in the concentrations of serum transaminases, reported (see Black Box Warnings and Dosage Modifications)

            Cases of nodular regenerative hyperplasia of the liver reported; upon diagnosis of nodular regenerative hyperplasia of the liver, treatment must be permanently discontinued

            Increased risk of developing left ventricular dysfunction (see Black Box Warnings and Dosage Modifications)

            Discontinue treatment permanently if patient diagnosed with nodular regenerative hyperplasia

            Known to cause fetal harm and death (see Black Box Warnings)

            Pulmonary toxicity may occur; cases of interstitial lung disease, including pneumonitis reported, permanently discontinue drug (see Dosage Modifications)

            For patients with radiation pneumonitis in the adjuvant setting, therapy should be permanently discontinued for grade greater than or equal to 3 or for grade 2 not responding to standard treatment

            Patients with dyspnea at rest due to complications of advanced malignancy, co-morbidities, and receiving concurrent pulmonary radiation therapy may be at increased risk of pulmonary toxicity

            Infusion-related reactions (IRRs) and/or hypersensitivity may occur; temporarily interrupt infusion for severe IRRs and permanently discontinue if life-threatening IRR occurs

            Thrombocytopenia or decreased platelet counts reported (see Dosage Modifications)

            Hemorrhagic events (including CNS, respiratory, and GI hemorrhage) have been reported; although, in some cases patients were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, in others there were no known additional risk factors; use caution with these agents and consider additional monitoring when concomitant use is medically necessary

            Peripheral neuropathy may occur (see Dosage Modifications)

            Extravasation observed during clinical trials; carefully monitor infusion site during infusion and inform patient to report any tenderness/redness

            Drug interactions overview

            • DM1, the cytotoxic component of ado-trastuzumab emtansine, is a CYP3A4 substrate
            • Avoid concomitant use of strong CYP3A4 inhibitors owing to the potential for an increase in DM1 exposure and toxicity; consider an alternative with no or minimal potential to inhibit CYP3A4
            • If concomitant use of strong CYP3A4 inhibitors is unavoidable, consider delaying ado-trastuzumab emtansine until strong CYP3A4 inhibitors have cleared from the circulation (~3 elimination half-lives of the inhibitors) when possible
            • If a strong CYP3A4 inhibitor is coadministered and ado-trastuzumab emtansine cannot be delayed, closely monitor patient for adverse reactions
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            Pregnancy & Lactation

            Pregnancy

            Therapy can cause fetal harm when administered to a pregnant woman

            No data available on use in pregnant women; cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death were observed in postmarketing setting in patients treated with trastuzumab, the antibody component

            Based on mechanism of action, the DM1 component can also cause embryofetal harm when administered to a pregnant woman

            Advise patient of potential risks to a fetus; there are clinical considerations if drug is used in a pregnant woman, or if a patient becomes pregnant within 7 months following last dose

            Pregnancy pharmacovigilance program

            • If administered during pregnancy, or if a patient becomes pregnant while receiving therapy or within 7 months following the last dose, immediately report ado-trastuzumab emtansine exposure to Genentech at 1-888-835-2555

            Reproductive potential

            • Verify pregnancy status of females of reproductive potential prior to initiation of therapy

            Contraception

            • Females: Drug can cause embryofetal harm when administered during pregnancy; advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose
            • Males: Because of potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months following the last dose

            Infertility

            • Based on results from animal toxicity studies, therapy may impair fertility in females and males of reproductive potential; not known if effects are reversible

            Lactation

            There is no information regarding presence of ado-trastuzumab emtansine in human milk, effects on breastfed infant, or on milk production; DM1, the cytotoxic component of the drug, may cause serious adverse reactions in breastfed infants based on its mechanism of action; advise women not to breastfeed during treatment and for 7 months following last dose of the drug

            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 microtubule inhibitory drug DM1 (a maytansine derivative)

            Upon binding to sub-domain IV of the HER2 receptor, ado-trastuzumab emtansine undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in intracellular release of DM1-containing cytotoxic catabolites

            Binding of DM1 to tubulin disrupts microtubule networks in the cell, which results in cell cycle arrest and apoptotic cell death

            In addition, in vitro studies have shown that similar to trastuzumab, ado-trastuzumab emtansine inhibits HER2 receptor signaling, mediates antibody-dependent cell-mediated cytotoxicity and inhibits shedding of the HER2 extracellular domain in human breast cancer cells that overexpress HER2

            Absorption

            Peak plasma time: Near end of infusion

            Peak plasma concentration: 83.4 mcg/mL (ADC); 4.61 ng/mL (DM1)

            Distribution

            Protein bound: 93% (DM1)

            Vd: 3.13 L (ADC)

            DM1 is a P-gp substrate (in vitro)

            Metabolism

            DM1 metabolized by mainly by CYP3A4 and to a lesser degree by CYP3A5

            Elimination

            Half-life: 4 days (ADC)

            Total body clearance: 0.68 L/day (ADC)

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            Administration

            IV Incompatibilities

            Dextrose 5%

            Do not mix or administer as an infusion with other medicinal products

            IV Compatibilities

            0.9% NaCl

            IV Preparation

            Use aseptic technique and procedures for antineoplastic drug preparation

            Reconstitution

            • Reconstitute vial by slowly injecting with sterile water for injection (SWI)
            • Gently swirl vial until completely dissolved; do not shake
            • Inspect reconstituted solution for particulates and discoloration (colorless to pale brown); do not use if particulates are visible or the solution is cloudy or discolored
            • 100-mg vial: Reconstitute with 5 mL SWI
            • 160-mg vial: Reconstitute with 8 mL SWI
            • Resulting concentration is 20mg/mL

            Dilution

            • Calculate volume of reconstituted solution required for individual dose
            • Withdraw this amount from vial and add to 250-mL infusion bag of 0.9% NaCl
            • Gently invert bag to mix solution in order to avoid foaming

            IV Administration

            Administer as IV infusion only with a 0.22 micron in-line nonprotein adsorptive polyethersulfone (PES) filter

            Do NOT give as IV push or bolus

            Do not mix or infuse with other medicinal products

            Closely monitor IV infusion site for possible SC infiltration

            First infusion: Administer over 90 minutes; observe for fever, chills, or other IRRs during infusion and for at least 90 minutes afterwards

            Subsequent infusion: Administer over 90 minutes if prior infusion well tolerated; observe for IRRs during infusion and for at least 30 minutes afterwards

            Slow or interrupt dose if IRR occurs; permanently discontinue for life-threatening related 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 dosing schedule to maintain a 3-week interval between doses
            • Administer infusion at dose and rate the patient tolerated in the most recent infusion

            Storage

            Unused vials: Refrigerate at 2-8ºC (36-46°F)

            Reconstituted vials or diluted solutions

            • Refrigerate at 2-8ºC (36-46°F)
            • Discard after 4 hr
            • Do NOT freeze
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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.
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