Ado-Trastuzumab Emtansine (Monograph)

Brand name: Kadcyla
Drug class: Antineoplastic Agents
Chemical name: Tetraamide with N2′-[3-[[1-[(4-carboxycyclohexyl)methyl]-2,5-dioxo-3-pyrrolidinyl]thio]-1-oxopropyl]-N2′-deacetylmaytansine, disulfide with human-mouse monoclonal rhuMab HER2 light chain, anti-(human p185neu receptor) (human-mouse monoclonal rhuMab HER2 γ1-chain), immunoglobulin G1 dimer
Molecular formula: C₆₄₄₈H₉₉₄₈N₁₇₂₀O₂₀₁₂S₄₄•(C₄₇H₆₂ClN₄O₁₃S)_n
CAS number: 1018448-65-1

Warning

Do not confuse ado-trastuzumab emtansine (Kadcyla) with trastuzumab (Herceptin). Ado-trastuzumab emtansine is an anti-HER2 antibody-drug conjugate; the anti-HER2 antibody trastuzumab, a humanized IgG₁, is conjugated with the microtubule inhibitor DM1 (derivative of maytansine) via the linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate).

Original generic name for Kadcyla was trastuzumab emtansine (established by the US Adopted Name [USAN] Council). Because of similarity between the original generic name for Kadcyla (trastuzumab emtansine) and the generic name for Herceptin (trastuzumab), FDA approved the prefix addition “ado” to the generic name for Kadcyla (i.e., ado-trastuzumab emtansine). However, potential exists for dispensing or prescribing errors involving these drugs.

Exercise extra care to ensure accuracy of prescriptions. Institute for Safe Medication Practices (ISMP), FDA, and the manufacturer of ado-trastuzumab emtansine (Kadcyla) recommend that prescribers communicate both brand and generic names for ado-trastuzumab emtansine (Kadcyla) on prescription order forms. (See Possible Prescribing and Dispensing Errors under Cautions.)

Warning

Hepatotoxicity

Serious, sometimes fatal, hepatotoxicity observed. (See Hepatotoxicity under Cautions.)
Monitor ALT, AST, and bilirubin concentrations prior to each dose of drug.
If elevations in ALT, AST, or bilirubin concentrations occur, interrupt therapy, reduce dosage, or permanently discontinue therapy. (See Dosage Modification for Toxicity under Dosage and Administration.)

Left Ventricular Dysfunction

Risk of cardiotoxicity (e.g., ventricular dysfunction). (See Left Ventricular Dysfunction under Cautions.)
Evaluate left ventricular function prior to and during therapy.
Temporary or permanent discontinuance of therapy may be necessary. (See Dosage Modification for Toxicity under Dosage and Administration.)

Embryofetal Toxicity

Risk of embryofetal death or birth defects.
Inform patients of risk to the fetus. Advise women of childbearing potential to use effective contraception during and for 6 months after discontinuance of drug. (See Advice to Patients.)

Introduction

Antineoplastic agent; an anti-human epidermal growth factor receptor type 2 (anti-HER2) antibody conjugated with the microtubule inhibitor DM1 (a maytansine derivative).

Uses for Ado-Trastuzumab Emtansine

Breast Cancer

Treatment of metastatic breast cancer in patients whose tumors overexpress the HER2 protein and who have received prior therapy with trastuzumab and a taxane, either separately or in combination.

Appropriate patients include those who have received prior therapy for metastatic disease or who experienced disease recurrence during or within 6 months of completing adjuvant therapy.

Efficacy established based on progression-free survival and overall survival.

Ado-Trastuzumab Emtansine Dosage and Administration

General

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

Because of risk of infusion and/or hypersensitivity reactions, closely observe patients during infusion and for 90 minutes after first infusion and for 30 minutes after subsequent infusions. (See Infusion or Hypersensitivity Reactions under Cautions.)

Use of ado-trastuzumab emtansine is not recommended in patients for whom prior therapy with trastuzumab was permanently discontinued because of infusion reactions and/or drug hypersensitivity.

Consult specialized references for procedures for proper handling (e.g., use of gloves) and disposal of antineoplastics.

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion through a 0.22-μm polyethersulfone filter. Do not administer by rapid IV injection (e.g., IV push or bolus).

Ado-trastuzumab emtansine powder for injection must be reconstituted and diluted prior to administration. Use within 24 hours following reconstitution or dilution. (See Storage under Stability.)

Do not mix or administer with any other drug.

Reconstitution

Reconstitute vial containing 100 or 160 mg of ado-trastuzumab emtansine with 5 or 8 mL of sterile water for injection, respectively, to provide a solution containing 20 mg/mL. Gently swirl vial to ensure dissolution. Do not shake reconstituted solution. Discard any unused solution after 24 hours.

Reconstituted solution should be clear to slightly opalescent, colorless to pale brown, and free of visible particulates.

Dilution

Dilute appropriate dose in 250 mL of 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 well tolerated).

Dosage

Adults

Breast Cancer

IV

3.6 mg/kg every 3 weeks. Continue therapy for as long as patient derives clinical benefit 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

When dosage modification is required, reduce dosage by 1 dose level in 0.6-mg/kg decrements (e.g., from 3.6 to 3 mg/kg, from 3 to 2.4 mg/kg).

If a dosage of 2.4 mg/kg requires further reduction, discontinue the drug.

Do not re-escalate dosage following dosage reduction.

Hepatotoxicity

Recommended Dosage Modifications for Hepatotoxicity
Toxicity	Recommended Dosage Modifications
Grade 2 ALT/AST elevation (>2.5 times ULN but ≤5 times ULN)	Continue therapy at the same dosage
Grade 2 or 3 total bilirubin elevation (>1.5 times ULN but ≤10 times ULN)	Interrupt therapy; following recovery to grade 1 or less, reduce dosage by one dose level
Grade 3 ALT/AST elevation (>5 times ULN but ≤20 times ULN)	Interrupt therapy; following recovery to grade 2 or less, reduce dosage by one dose level
Grade 4 ALT/AST elevation (>20 times ULN) or total bilirubin (>10 times ULN)	Permanently discontinue therapy
ALT/AST elevation (>3 times ULN) and total bilirubin >2 times ULN	Permanently discontinue therapy
Nodular regenerative hyperplasia	Permanently discontinue therapy

Infusion or Hypersensitivity Reactions

If infusion reactions occur, reduce infusion rate or interrupt infusion depending on severity of the reaction.

If life-threatening infusion reactions occur, permanently discontinue therapy.

Left Ventricular Dysfunction

Recommended Dosage Modifications for Left Ventricular Dysfunction
Left Ventricular Ejection Fraction (LVEF)	Recommended Dosage Modifications
40–45% with decrease from baseline <10%	Continue therapy
40–45% with decrease from baseline ≥10%	Interrupt therapy for at least 3 weeks. Reassess LVEF within 3 weeks; if LVEF has not improved to within 10% of baseline, discontinue therapy
<40%	Interrupt therapy for at least 3 weeks. Reassess LVEF within 3 weeks; if LVEF has not improved to ≥40%, permanently discontinue therapy
Symptomatic CHF	Discontinue therapy

Thrombocytopenia

If grade 3 thrombocytopenia (platelet counts ≥25,000/mm³ but <50,000/mm³) occurs, interrupt therapy until thrombocytopenia resolves to grade 1 or less (platelet counts ≥75,000/mm³), and then resume therapy at the same dosage.

If grade 4 thrombocytopenia (platelet counts <25,000/mm³) occurs, interrupt therapy until thrombocytopenia resolves to grade 1 or less (platelet counts ≥75,000/mm³), and then resume therapy by reducing dosage one dose level.

Pulmonary Toxicity

If manifestations of interstitial lung disease or pneumonitis develop, permanently discontinue therapy.

Peripheral Neuropathy

If grade 3 or 4 peripheral neuropathy occurs, interrupt dosing until peripheral neuropathy resolves to grade 2 or less.

Prescribing Limits

Adults

Breast Cancer

IV

Do not exceed dose of 3.6 mg/kg.

Special Populations

Dosage adjustment not necessary based on baseline albumin concentrations. (See Special Populations under Pharmacokinetics.)

Hepatic Impairment

No specific dosage recommendations at this time. (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild or moderate renal impairment (Cl_cr 30-89 mL/minute): No dosage adjustment required.

Severe renal impairment (Cl_cr <30 mL/minute): Limited data available; no specific dosage recommendations at this time. (See Renal Impairment under Cautions.)

Geriatric Patients

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

Cautions for Ado-Trastuzumab Emtansine

Contraindications

Manufacturer states none known.

Warnings/Precautions

Warnings

Hepatotoxicity

Hepatotoxicity, mainly manifested by asymptomatic, transient ALT and/or AST elevations, reported. Serious, sometimes fatal, hepatobiliary disorders and nodular regenerative hyperplasia also reported.

Histopathology is necessary to confirm diagnosis of nodular regenerative hyperplasia. Consider this diagnosis in patients presenting with manifestations of portal hypertension without elevations in ALT and/or AST concentrations or manifestations of cirrhosis. If this condition occurs, permanently discontinue therapy.

Not evaluated in patients with active HBV or HCV infection, ALT and/or AST concentrations >2.5 times ULN, or total bilirubin >1.5 times ULN.

Monitor ALT, AST, and bilirubin concentrations prior to each dose of ado-trastuzumab emtansine. If ALT, AST, or bilirubin concentrations increase, interrupt therapy, reduce dosage, or permanently discontinue therapy. (See Dosage Modification for Toxicity under Dosage and Administration.)

Left Ventricular Dysfunction

Decreases in LVEF to <40% reported.

Not evaluated in patients with baseline LVEF <50%, history of symptomatic CHF, serious cardiac arrhythmia, or history of MI or unstable angina within 6 months of initiating therapy.

Assess LVEF prior to initiation of therapy and at regular intervals (e.g., every 3 months) during treatment.

If LVEF decreases to ≤45%, temporarily or permanently discontinue therapy. (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 the anti-HER2 antibody trastuzumab to pregnant women in postmarketing experience. Trastuzumab crossed placental barrier during early and late phases of gestation in monkeys.

DM1 (derivative of maytansine) may cause embryotoxic and fetotoxic effects.

Verify pregnancy status prior to initiation of ado-trastuzumab emtansine. Advise women of childbearing potential to use effective contraception during and for 6 months after discontinuance of drug.

If used during pregnancy or if patient becomes pregnant during therapy, apprise of potential fetal hazard. (See Pregnancy under Cautions.)

Possible Prescribing and Dispensing Errors

Ensure accuracy of prescriptions; similarity in generic name of Kadcyla (ado-trastuzumab emtansine) and Herceptin (trastuzumab) may result in medication errors. Such errors may be associated with severe toxicity or lack of appropriate therapy. (See Special Alerts.)

Sensitivity Reactions

Infusion or Hypersensitivity Reactions

Infusion reactions (e.g, anaphylactoid-like reaction) reported. Infusion reactions characterized by flushing, chills, pyrexia, dyspnea, hypotension, wheezing, bronchospasm, and/or tachycardia. Symptoms generally resolve within several hours to a day following discontinuance of infusion.

Not evaluated in patients for whom prior therapy with trastuzumab was permanently discontinued due to infusion reactions and/or hypersensitivity to the drug. (See Dosage and Administration.)

Closely observe patients for 90 minutes after first infusion and for 30 minutes after subsequent infusions.

If severe or life-threatening infusion reactions occur, may need to reduce infusion rate or temporarily or permanently discontinue therapy. (See Dosage Modification for Toxicity under Dosage and Administration.) Make appropriate medications and emergency equipment available for immediate use.

Other Warnings and Precautions

Pulmonary Effects

Severe, sometimes fatal, adverse pulmonary effects (e.g., interstitial lung disease, pneumonitis, ARDS) reported.

Consider possible pneumonitis in patients presenting with dyspnea, cough, fatigue, and pulmonary infiltrates; symptoms may also occur as sequelae of infusion reactions. Patients with dyspnea at rest resulting from advanced disease or other comorbidities may be at greater risk for pulmonary toxicity.

If interstitial lung disease or pneumonitis occurs, permanently discontinue ado-trastuzumab emtansine.

Thrombocytopenia

Thrombocytopenia occurs frequently; nadir platelet count occurs at approximately day 8 of each 3-week cycle. In clinical trials, incidence and severity of thrombocytopenia higher in Asian patients.

Not evaluated in patients with baseline platelet counts <100,000/mm³.

Monitor platelet counts prior to each dose of ado-trastuzumab emtansine. Closely monitor patients receiving concomitant anticoagulant therapy or those with platelet counts <100,000/mm³.

If thrombocytopenia occurs, interrupt therapy until resolution to grade 1 or less. (See Dosage Modification for Toxicity under Dosage and Administration.)

Peripheral Neuropathy

Peripheral neuropathy (mainly sensory neuropathy) occurs frequently.

Monitor patients for manifestations of neurotoxicity during therapy.

If peripheral neuropathy occurs, temporarily discontinue therapy. (See Dosage Modification for Toxicity under Dosage and Administration.)

Evaluation of HER2

Assess breast tumors for HER2 overexpression prior to initiation of therapy; safety and efficacy of drug established only in patients with HER2-overexpressing tumors.

Immunohistochemistry (IHC) assays (e.g., Dako Herceptest), which measure overexpression of the HER2 protein, and fluorescent in situ hybridization (FISH) (e.g., Dako HER2 FISH PharmDx), which measures amplification of the HER2 oncogene, are tests most commonly used.

In clinical study, patients required to have disease demonstrating an IHC score of 3+ or a FISH amplification ratio of ≥2. Limited data available for patients with FISH-positive tumors that lack HER2 overexpression.

Select laboratories with demonstrated proficiency in the specific technology being used; improper assay performance can lead to unreliable results.

Local Effects

Extravasation resulting in erythema, tenderness, skin irritation, pain, or swelling at the infusion site reported; reactions generally are mild and occur within 24 hours following an infusion. Specific treatment for extravasation following infusion not established.

Closely monitor infusion site for subcutaneous infiltration during administration.

Specific Populations

Pregnancy

Category D. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

If used during pregnancy or if patient becomes pregnant while receiving therapy, apprise of potential fetal hazard. Encourage patient to enroll in the MotHER Pregnancy Registry (800-690-6720), and immediately notify Genentech Adverse Event Line (888-835-2555).

Lactation

Not known whether ado-trastuzumab emtansine is distributed into milk. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No substantial differences in pharmacokinetics relative to younger adults; however, survival benefit not observed in patients ≥65 years of age in a subset analysis.

Hepatic Impairment

Not studied in patients with hepatic impairment. (See Special Populations under Pharmacokinetics.)

Renal Impairment

Pharmacokinetics not altered by mild or moderate renal impairment; no dosage adjustment required. (See Renal Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Limited data available in patients with severe renal impairment.

Common Adverse Effects

Stomatitis, dry mouth, abdominal pain, diarrhea, nausea, vomiting, constipation, pyrexia, asthenia, fatigue, myalgia, arthralgia, musculoskeletal pain, dizziness, peripheral neuropathy, headache, insomnia, dyspnea, cough, epistaxis, rash, pain in extremity, infusion reaction, hypokalemia, liver function test (AST, ALT, alkaline phosphatase) abnormalities, anemia, thrombocytopenia.

Drug Interactions

DM1 component of ado-trastuzumab emtansine metabolized principally by CYP3A4 and, to a lesser extent, by CYP3A5.

DM1 does not inhibit or induce major CYP isoenzymes in vitro.

Substrate of P-glycoprotein (P-gp) in vitro.

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Possible pharmacokinetic interaction (increased systemic exposure of DM1). Avoid concomitant use; select an alternative agent with no or minimal enzyme inhibition potential.

If the potent CYP3A4 inhibitor can be discontinued, delay initiation of ado-trastuzumab emtansine therapy (until after approximately 3 elimination half-lives of the CYP3A4 inhibitor). If concomitant use cannot be avoided, closely monitor patients for adverse effects. (See Specific Drugs under Interactions.)

Specific Drugs

Drug	Interaction	Comments
Antifungals, azoles (e.g., itraconazole, ketoconazole, voriconazole)	Possible increased systemic exposure of DM1	Avoid concomitant use Select alternative antifungal with no or minimal CYP3A4 inhibition potential If concomitant use cannot be avoided, closely monitor patients for adverse effects If CYP3A4 inhibitor is discontinued, delay initiation of ado-trastuzumab emtansine (until after approximately 3 half-lives of CYP3A4 inhibitor)
Antiretrovirals, HIV protease inhibitors (e.g., atazanavir, indinavir, nelfinavir, ritonavir, saquinavir)	Possible increased systemic exposure of DM1	Avoid concomitant use Select alternative antiretroviral with no or minimal CYP3A4 inhibition potential If concomitant use cannot be avoided, closely monitor patients for adverse effects If CYP3A4 inhibitor is discontinued, delay initiation of ado-trastuzumab emtansine (until after approximately 3 half-lives of CYP3A4 inhibitor)
Macrolides (clarithromycin, telithromycin)	Possible increased systemic exposure of DM1	Avoid concomitant use Select alternative anti-infective with no or minimal CYP3A4 inhibition potential If concomitant use cannot be avoided, closely monitor patients for adverse effects If CYP3A4 inhibitor is discontinued, delay initiation of ado-trastuzumab emtansine (until after approximately 3 half-lives of CYP3A4 inhibitor)
Nefazodone	Possible increased systemic exposure of DM1	Avoid concomitant use Select alternative antifungal with no or minimal CYP3A4 inhibition potential If concomitant use cannot be avoided, closely monitor patients for adverse effects If nefazodone is discontinued, delay initiation of ado-trastuzumab emtansine (until after approximately 3 half-lives of nefazodone)

Ado-Trastuzumab Emtansine Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations of the antibody-drug conjugate and DM1 are observed near the end of IV infusion.

Steady-state concentrations achieved after the second cycle of therapy.

Systemic accumulation of the antibody-drug conjugate not observed following repeated doses administered by IV infusion every 3 weeks.

Distribution

Extent

Not known whether ado-trastuzumab emtansine distributes into human milk. (See Lactation under Cautions.)

Trastuzumab (the antibody component of the antibody-drug conjugate) distributes into milk in monkeys.

Plasma Protein Binding

93%.

Elimination

Metabolism

DM1 metabolized by CYP3A4/5 in vitro.

Half-life

Antibody-drug conjugate: approximately 4 days.

Special Populations

Age, race, and serum albumin concentrations do not have clinically important effects on pharmacokinetics of ado-trastuzumab emtansine. (See Special Populations under Dosage and Administration.)

Mild (Cl_cr of 60–89 mL/minute) or moderate (Cl_cr of 30–59 mL/minute) renal impairment: Pharmacokinetics similar to that in patients with normal renal function. (See Renal Impairment under Dosage and Administration.)

Severe renal impairment (Cl_cr <30 mL/minute): Limited data available.

Effect of hepatic impairment on pharmacokinetics not determined.

Stability

Storage

Parenteral

Powder for Injection

2–8°C before reconstitution. Do not freeze or shake.

Use reconstituted solution immediately. If not used immediately, may store reconstituted drug at 2–8°C for up to 24 hours. Do not freeze.

Use diluted solution immediately. If not used immediately, may store diluted infusion solution at 2–8°C for up to 24 hours. Do notfreeze or shake.

Compatibility

Parenteral

Solution Compatibility

Compatible
Sodium chloride 0.9%
Incompatible
Dextrose 5% in water

Actions

An anti-HER2 antibody (trastuzumab; a humanized IgG₁) conjugated via stable thioether linker (MCC) with microtubule inhibitor DM1 (maytansine derivative). Resultant complex, MCC-DM1, referred to as emtansine.
Antibody-drug conjugate binds to extracellular domain (subdomain IV) of HER2 protein; resultant complex internalized by the cell, and DM1 released via lysosomal degradation. DM1 then binds to tubulin, disrupting microtubule activity, and resulting in cell cycle arrest and apoptosis.

Ado-trastuzumab emtansine exhibits similar activity and binding affinity to the HER2 receptor as trastuzumab.

DM1 approximately 2- to 17-fold more potent than paclitaxel on a molar basis in several breast cancer cell lines in vitro.

Advice to Patients

Risk of fetal harm. Necessity of advising women of childbearing potential to use effective contraception during therapy and for 6 months after discontinuance of drug. Encourage women exposed to drug during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 800-690-6720. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Importance of discontinuing breast-feeding during therapy.
Risk of severe hepatotoxicity. Importance of informing clinician if manifestations of acute hepatitis (e.g., nausea, vomiting, abdominal pain [particularly in the right upper quadrant], jaundice, dark urine, generalized pruritus, anorexia) occur.
Importance of informing clinician if new-onset or worsening shortness of breath, cough, swelling of ankles or legs, palpitations, weight gain >5 pounds in 24 hours, dizziness, or loss of consciousness occurs.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, 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.