Ado-trastuzumab emtansine (Kadcyla®) should not be confused with trastuzumab (Herceptin®).1001, 1005, 1006 Ado-trastuzumab emtansine is an anti-human epidermal growth factor receptor type 2 (anti- HER2 ) antibody-drug conjugate; the anti- HER2 antibody trastuzumab, a humanized immunoglobulin (IgG1), is conjugated with the microtubule inhibitor DM1 (derivative of maytansine) via the linker MCC (4-[ N -maleimidomethyl] cyclohexane-1-carboxylate).1, 1004 The original generic name for Kadcyla®, as established by the US Adopted Name (USAN) Council in 2009, was trastuzumab emtansine.1003, 1005, 1006 Because of the similarity between the original generic name (trastuzumab emtansine) and the generic name for Herceptin® (trastuzumab), the US Food and Drug Administration (FDA) approved the addition of the prefix “ado” to the generic name for Kadcyla® (i.e., ado-trastuzumab emtansine);1004, 1005 however, the potential exists for dispensing or prescribing errors involving these drugs.1001, 1004, 1005, 1006 The manufacturer of ado-trastuzumab emtansine (Kadcyla®) states that this drug should not be substituted for or used with trastuzumab (Herceptin®).1 Therefore, extra care should be exercised to ensure the accuracy of prescriptions for ado-trastuzumab emtansine (Kadcyla®) or trastuzumab (Herceptin®).1, 1001, 1005, 1006 To avoid medication errors, the Institute for Safe Medication Practices (ISMP), the FDA, and the manufacturer of ado-trastuzumab emtansine (Kadcyla®) recommend that prescribers communicate both the brand and generic names for ado-trastuzumab emtansine (Kadcyla®) on the prescription order form.1, 1001, 1005, 1006 (See Dispensing and Administration Precautions under Dosage and Administration: Administration and also under Warnings/Precautions: Warnings, in Cautions.) |
Ado-trastuzumab emtansine, an anti-human epidermal growth factor receptor type 2 (anti- HER2 ) antibody conjugated with the microtubule inhibitor DM1 (a maytansine derivative), is an antineoplastic agent.1, 2, 3, 4, 8, 9, 10, 11
Ado-trastuzumab emtansine is used for the treatment of metastatic breast cancer in patients whose tumors overexpress the human epidermal growth factor receptor type 2 ( HER2 ) protein and who have received prior therapy with trastuzumab and a taxane, either separately or in combination.1, 2, 3, 4 Appropriate candidates for ado-trastuzumab emtansine therapy include those who have received prior therapy for metastatic disease or who developed disease recurrence during or within 6 months of completing adjuvant therapy.1
The current indication for ado-trastuzumab emtansine is based principally on the results of a randomized, open-label phase 3 study (EMILIA) in patients with HER2 -overexpressing metastatic breast cancer.1, 2 Patients were eligible for enrollment in the study if they had disease demonstrating an immunohistochemistry (IHC) assay score of 3+ or a fluorescent in situ hybridization (FISH) amplification ratio of 2 or higher.1, 2 In this study, 991 patients were randomized in a 1:1 ratio to receive either ado-trastuzumab emtansine alone (3.6 mg/kg IV every 21 days) or combined therapy with lapatinib (1.25 g once daily, continuously) and capecitabine (2 g/m2 daily on days 1-14 every 21 days).1, 2 Treatment was continued until disease progression or unacceptable toxicity occurred, or the patient withdrew from the study.1, 2 The primary end points of this study were progression-free survival as assessed by an independent review facility (IRF-assessed progression-free survival) and overall survival.2 The median age of patients enrolled in the study was 53 years; all except 5 of the enrolled patients were women.1, 2 The majority (88%) of patients had received prior systemic therapy in the metastatic setting and 12% of patients had experienced disease relapse within 6 months of receiving prior adjuvant or neoadjuvant chemotherapy.1 All except 1 of the enrolled patients had received prior trastuzumab therapy and over 99 or 61% of patients had received prior therapy with a taxane or anthracycline, respectively.1 Among patients with hormone receptor-positive tumors, approximately 44% of these patients had received prior adjuvant hormonal therapy and approximately 45% had received hormonal therapy for locally advanced or metastatic disease.1
At the time of the primary analysis, patients receiving ado-trastuzumab emtansine alone had longer median IRF-assessed progression-free survival compared with patients receiving combined therapy with lapatinib and capecitabine (9.6 versus 6.4 months, respectively).1, 2 Effects of ado-trastuzumab emtansine on investigator-assessed progression-free survival and IRF-assessed progression-free survival were comparable.1 A subset analysis of progression-free survival based on clinically relevant baseline patient and disease characteristics consistently showed treatment benefit with ado-trastuzumab emtansine alone compared with combined therapy with lapatinib and capecitabine;1, 2 however, this benefit was not observed in patients 65 years of age or older and in those with nonmeasurable disease.1 At the first interim analysis, overall survival did not cross the predefined stopping boundary for significance; however, results of a second interim analysis indicated that median overall survival was prolonged in patients receiving ado-trastuzumab emtansine compared with those receiving combined therapy with lapatinib and capecitabine (30.9 versus 25.1 months, respectively).1, 2 In addition, patients receiving ado-trastuzumab emtansine appeared to have a higher objective response rate (43.6 versus 30.8%, respectively) and a longer median duration of response (12.6 versus 6.5 months, respectively) compared with those receiving lapatinib and capecitabine.1, 2 The median follow-up period at the time of the primary analysis for progression-free survival and at the second interim analysis for overall survival was 13 and 19 months, respectively.2
Ado-trastuzumab emtansine (Kadcyla®) should not be substituted for or used with trastuzumab (Herceptin®).1
Because infusion or hypersensitivity reactions may occur, patients should be closely observed during infusions and for 90 minutes following the first infusion of ado-trastuzumab emtansine; following subsequent infusions, patients should be observed for 30 minutes.1 (See Infusion or Hypersensitivity Reactions under Warnings/Precautions: Sensitivity Reactions, in Cautions.)
Ado-trastuzumab emtansine is not recommended for use in patients for whom prior therapy with trastuzumab was permanently discontinued because of infusion reactions and/or hypersensitivity to the drug.1 (See Infusion or Hypersensitivity Reactions under Warnings/Precautions: Sensitivity Reactions, in Cautions.)
Procedures for proper handling (e.g., use of gloves) and disposal of antineoplastic drugs should be followed when preparing or administering ado-trastuzumab emtansine.1
Ado-trastuzumab emtansine is administered by IV infusion through a 0.22- µ m polyethersulfone filter.1 The initial dose of ado-trastuzumab emtansine should be administered as an IV infusion over 90 minutes; if the first infusion is well tolerated, subsequent doses may be administered by IV infusion over 30 minutes.1 (See Dosage and Administration: General.) Ado-trastuzumab emtansine solutions should not be administered by rapid IV injection, such as IV push or bolus. 1
Unreconstituted vials of ado-trastuzumab emtansine injection should be stored at 2-8°C until use; vials should not be frozen or shaken.1
Prior to administration, commercially available ado-trastuzumab emtansine powder for injection must be reconstituted and diluted using proper aseptic technique.1 The powder for injection is reconstituted by adding 5 or 8 mL of sterile water for injection to a vial labeled as containing 100 or 160 mg, respectively, of the drug to provide a solution containing 20 mg/mL.1 The vial should be gently swirled and inspected visually for particulate matter and discoloration prior to dilution and administration.1 The resulting solution should not be shaken.1 The solution should be clear to slightly opalescent, colorless to pale brown, and free of visible particulates.1 The reconstituted ado-trastuzumab emtansine solution may be diluted immediately or stored at 2-8°C for use within 24 hours.1 The reconstituted solution should not be frozen.1 Any unused solution should be discarded after 24 hours.1
For preparation of the final diluted ado-trastuzumab emtansine solution for infusion, the appropriate volume of reconstituted solution should be withdrawn from the vial and further diluted in 250 mL of 0.9% sodium chloride injection.1 The final diluted ado-trastuzumab emtansine solution for infusion should be mixed by gentle inversion and should not be shaken.1 The solution may be infused immediately or stored at 2-8°C and used within 24 hours following dilution; the solution for infusion should not be frozen.1 Any partially used vials should be discarded.1 Ado-trastuzumab emtansine solutions for infusion should not be diluted in or administered through an IV line containing 5% dextrose injection, and ado-trastuzumab emtansine should not be mixed or administered with other drugs.1
Dispensing and Administration Precautions
Ado-trastuzumab emtansine (Kadcyla®) should not be confused with trastuzumab (Herceptin®).1001, 1005, 1006 Because of the similarity between the original generic name of Kadcyla® (trastuzumab emtansine) and the generic name for Herceptin® (trastuzumab), the US Food and Drug Administration (FDA) approved the addition of the prefix “ado” to the generic name for Kadcyla® (i.e., ado-trastuzumab emtansine).1004, 1005 However, the potential exists for dispensing or prescribing errors involving these drugs.1001, 1004, 1005, 1006 Extra care should be exercised to ensure the accuracy of prescriptions for ado-trastuzumab emtansine (Kadcyla®) or trastuzumab (Herceptin®).1001, 1005, 1006 To avoid medication errors, the Institute for Safe Medication Practices (ISMP), the FDA, and the manufacturer of ado-trastuzumab emtansine (Kadcyla®) recommend that prescribers communicate both the brand and generic names for ado-trastuzumab emtansine (Kadcyla®) on the prescription order form.1, 1001, 1005, 1006 (See Special Alerts.)
For the treatment of metastatic breast cancer that overexpresses the human epidermal growth factor receptor type 2 ( HER2 ) protein in patients who have received prior therapy including trastuzumab and a taxane, either separately or in combination, the recommended adult dosage of ado-trastuzumab emtansine is 3.6 mg/kg administered as an IV infusion every 3 weeks.1 Ado-trastuzumab emtansine should not be administered at doses exceeding 3.6 mg/kg.1 Treatment should be continued until disease progression or unacceptable toxicity occurs.1
If a dose is missed or delayed, the dose of ado-trastuzumab emtansine should be administered as soon as possible; waiting until the next scheduled dose is not recommended.1 The schedule of administration should be adjusted to maintain a 3-week interval between doses.1
Dosage Modification for Toxicity
When dosage modification is necessary, dosage of ado-trastuzumab emtansine should be reduced by 1 dose level in decrements of 0.6 mg/kg (e.g., from 3.6 to 3 mg/kg, from 3 to 2.4 mg/kg); however, if a dose of 2.4 mg/kg requires further reduction, ado-trastuzumab emtansine should be discontinued.1
Dosage of ado-trastuzumab emtansine should not be re-escalated following a dosage reduction.1
In patients who exhibit grade 2 serum aminotransferase (ALT and/or AST) elevations (i.e., exceeding 2.5 times the upper limit of normal [ULN], but not more than 5 times the ULN), ado-trastuzumab emtansine therapy may be continued at the same dosage.1 (See Hepatotoxicity under Warnings/Precautions: Warnings, in Cautions.)
In patients who exhibit grade 2 or 3 elevations in total bilirubin concentrations (i.e., exceeding 1.5 times the ULN, but not more than 10 times the ULN), ado-trastuzumab therapy should be interrupted.1 If elevations in total bilirubin concentrations decrease to no more than grade 1, therapy with ado-trastuzumab emtansine may be resumed at 1 dose level lower than the previous dosage.1
In patients who exhibit grade 3 serum aminotransferase elevations (i.e., exceeding 5 times the ULN, but not more than 20 times the ULN), ado-trastuzumab emtansine therapy should be interrupted.1 If elevations in ALT and/or AST concentrations decrease to no more than grade 2, therapy with ado-trastuzumab emtansine may be resumed at 1 dose level lower than the previous dosage.1
In patients who exhibit grade 4 serum aminotransferase elevations (i.e., exceeding 20 times the ULN) or increased total bilirubin concentrations (i.e., exceeding 10 times the ULN), treatment with ado-trastuzumab emtansine should be permanently discontinued.1
In patients who exhibit concurrent increases in serum aminotransferase (exceeding 3 times the ULN) and total bilirubin concentrations (exceeding 2 times the ULN), treatment with ado-trastuzumab emtansine should be permanently discontinued.1
If manifestations of nodular regenerative hyperplasia occur, treatment with ado-trastuzumab emtansine should be permanently discontinued.1
Infusion or Hypersensitivity Reactions
If infusion reactions occur, the infusion rate should be reduced or ado-trastuzumab emtansine therapy interrupted depending on the severity of the reaction.1 If life-threatening infusion reactions occur, ado-trastuzumab emtansine should be permanently discontinued.1 (See Infusion or Hypersensitivity Reactions under Warnings/Precautions: Sensitivity Reactions, in Cautions.)
If left ventricular ejection fraction (LVEF) decreases to 45% or less, left ventricular function should be reassessed within 3 weeks.1 (See Left Ventricular Dysfunction under Warnings/Precautions: Warnings, in Cautions.)
If LVEF decreases to 40-45% with a decrease from baseline of less than 10%, therapy with ado-trastuzumab emtansine may be continued.1
If LVEF decreases to 40-45% with a decrease from baseline of 10% or more, ado-trastuzumab emtansine should be withheld for at least 3 weeks.1 If LVEF has not improved to within 10% of baseline, ado-trastuzumab emtansine should be discontinued.1
If LVEF decreases to less than 40%, ado-trastuzumab emtansine should be withheld for at least 3 weeks.1 If LVEF has not improved or has declined further, ado-trastuzumab emtansine should be permanently discontinued.1
If manifestations of congestive heart failure develop, the drug should be discontinued.1
If grade 3 thrombocytopenia (platelet counts of 25,000/mm3 to less than 50,000/mm3) occurs, ado-trastuzumab emtansine therapy should be interrupted.1 Treatment may be resumed at the same dosage if thrombocytopenia resolves to no more than grade 1 (platelet counts reach or exceed 75,000/mm3).1 (See Thrombocytopenia under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
If grade 4 thrombocytopenia (platelet counts less than 25,000/mm3) occurs, ado-trastuzumab emtansine therapy should be interrupted.1 If thrombocytopenia resolves to no more than grade 1 (platelet counts of 75,000/mm3 or more), therapy with ado-trastuzumab emtansine may be resumed at 1 one dose level lower than the previous dosage.1
If manifestations of interstitial lung disease or pneumonitis develop, ado-trastuzumab emtansine therapy should be permanently discontinued.1 (See Pulmonary Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
If grade 3 or 4 peripheral neuropathy occurs, ado-trastuzumab emtansine therapy should be interrupted until the toxicity resolves to no more than grade 2.1 (See Peripheral Neuropathy under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Dosage adjustment is not necessary based on baseline albumin concentrations.1 (See Description.)
Dosage adjustment is not necessary in patients with mild (creatinine clearance of 60-89 mL/minute) or moderate (creatinine clearance of 30-59 mL/minute) renal impairment.1 The manufacturer makes no specific dosage recommendations for patients with severe renal impairment (creatinine clearance less than 30 mL/minute) because data are limited in this population.1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
The manufacturer makes no specific dosage recommendations for geriatric patients or patients with hepatic impairment.1 (See Geriatric Use and also Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
The manufacturer states that there are no known contraindications to the use of ado-trastuzumab emtansine.1
Hepatotoxicity has been reported in patients receiving ado-trastuzumab emtansine.1 Hepatotoxicity was mainly manifested by asymptomatic, transient elevations in serum aminotransferase (ALT and/or AST) concentrations.1 Serious hepatobiliary disorders, including 2 fatal cases of severe drug-induced liver injury and associated hepatic encephalopathy, have been reported in clinical studies.1 Reported cases of serious hepatobiliary disorders may have been confounded by comorbidities and/or concomitant use of drugs with known hepatotoxic potential.1
Nodular regenerative hyperplasia also has been reported and was identified in liver biopsies in 3 of 884 patients receiving ado-trastuzumab emtansine in clinical studies.1 Nodular regenerative hyperplasia is a rare liver condition that may result in non-cirrhotic portal hypertension; the disease is characterized by widespread benign transformation of hepatic parenchyma into small regenerative nodules.1 Diagnosis of nodular regenerative hyperplasia must be confirmed by histopathology.1 Nodular regenerative hyperplasia should be considered in any patient presenting with manifestations of portal hypertension without elevations in serum aminotransferase concentrations or manifestations of cirrhosis.1 If nodular regenerative hyperplasia occurs, ado-trastuzumab emtansine should be permanently discontinued.1
Ado-trastuzumab emtansine has not been studied in patients with active hepatitis B virus or hepatitis C virus infection or in patients with serum aminotransferase concentrations exceeding 2.5 times the upper limit of normal (ULN) or total bilirubin concentrations exceeding 1.5 times the ULN.1
Serum aminotransferase and total bilirubin concentrations should be evaluated prior to each dose of ado-trastuzumab emtansine.1 If serum aminotransferase and/or total bilirubin concentrations are elevated, interruption of ado-trastuzumab emtansine therapy, dosage reduction, or discontinuation of therapy may be necessary.1 (See Hepatotoxicity under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Patients receiving ado-trastuzumab emtansine are at increased risk of developing left ventricular dysfunction.1 Decreases in left ventricular ejection fraction (LVEF) to less than 40% have been reported in patients receiving ado-trastuzumab emtansine.1, 2 In the EMILIA study, left ventricular dysfunction occurred in 1.8% of patients receiving ado-trastuzumab emtansine alone and in 3.3% of patients receiving combined therapy with lapatinib and capecitabine.1, 2, 7
Ado-trastuzumab emtansine has not been studied in patients with a baseline LVEF less than 50%, history of symptomatic congestive heart failure, or conditions that could impair left ventricular function (e.g., serious cardiac arrhythmia, history of myocardial infarction or unstable angina within 6 months prior to therapy initiation).1
LVEF should be assessed prior to initiation of ado-trastuzumab emtansine and at regular intervals (e.g., every 3 months) during treatment.1 If left ventricular dysfunction occurs, interruption of ado-trastuzumab emtansine therapy and reassessment of left ventricular function within 3 weeks may be necessary; if LVEF has not improved or has declined further, ado-trastuzumab emtansine should be permanently discontinued.1 (See Left Ventricular Dysfunction under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Fetal/Neonatal Morbidity and Mortality
Ado-trastuzumab emtansine may cause fetal harm if administered to pregnant women.1 There are no adequate and well-controlled studies to date in pregnant women; however, oligohydramnios, fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death have been reported in women receiving the anti-human epidermal growth factor receptor type 2 (anti- HER2 ) antibody trastuzumab during pregnancy in postmarketing experience.1 Based on the mechanism of action of the microtubule inhibitor DM1 (derivative of maytansine), embryotoxic and fetotoxic effects may occur.1 When trastuzumab was administered to pregnant monkeys at dosages 7 times the human clinical dosage, the drug crossed the placental barrier during early and late phases of gestation.1 (See Cautions: Pregnancy, Fertility, and Lactation, in Trastuzumab 10:00.)
Pregnancy status should be verified prior to initiation of ado-trastuzumab emtansine, and women of childbearing potential should be advised to use effective contraception during and for 6 months after discontinuance of the drug.1 If ado-trastuzumab emtansine is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1 (See Advice to Patients and also see Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)
Dispensing and Administration Precautions
Ado-trastuzumab emtansine (Kadcyla®) should not be confused with trastuzumab (Herceptin®).1001, 1005, 1006 Because of the similarity between the original generic name of Kadcyla® (trastuzumab emtansine) and the generic name for Herceptin® (trastuzumab), the US Food and Drug Administration (FDA) approved the addition of the prefix “ado” to the generic name for Kadcyla® (i.e., ado-trastuzumab emtansine).1004, 1005 However, the potential exists for dispensing or prescribing errors involving these drugs.1001, 1004, 1005, 1006 Such medication errors may be associated with severe toxicity or lack of appropriate therapy in patients who did not receive the intended drug.1001, 1004, 1005 The manufacturer of ado-trastuzumab emtansine (Kadcyla®) states that this drug should not be substituted for or used with trastuzumab (Herceptin®).1 Therefore, extra care should be exercised to ensure the accuracy of prescriptions for ado-trastuzumab emtansine (Kadcyla®) and trastuzumab (Herceptin®).1, 1001, 1005, 1006 (See Special Alerts.)
Infusion or Hypersensitivity Reactions
Infusion reactions have been reported in patients receiving ado-trastuzumab emtansine.1 Infusion reactions were characterized by the presence of 1 or more of the following manifestations: flushing, chills, pyrexia, dyspnea, hypotension, wheezing, bronchospasm, and tachycardia.1 In the EMILIA study, infusion reactions were reported in 1.4% of patients receiving ado-trastuzumab emtansine; symptoms resolved within several hours to a day following discontinuance of the infusion in most patients.1 In another clinical study, a serious, allergic anaphylactoid-like reaction was reported in 1 patient.1
Ado-trastuzumab emtansine has not been studied in patients for whom prior therapy with trastuzumab was permanently discontinued due to infusion reactions and/or hypersensitivity to the drug; ado-trastuzumab emtansine is not recommended for use in such patients.1
Patients should be observed closely for 90 minutes after the first infusion of ado-trastuzumab emtansine and for 30 minutes after subsequent infusions of the drug.1 If severe or life-threatening infusion reactions occur, temporary or permanent discontinuance of ado-trastuzumab emtansine may be required.1 (See Infusion or Hypersensitivity Reactions under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.) Appropriate equipment and agents for the treatment of allergic or anaphylactoid-like reactions should be available for immediate use in patients receiving the drug.1
Other Warnings and Precautions
Severe, and sometimes fatal, adverse pulmonary effects, including interstitial lung disease, pneumonitis, and acute respiratory distress syndrome (ARDS), have been reported.1 In clinical studies, pneumonitis has been reported in 0.8% of patients; grade 3 pneumonitis occurred in 1 of 884 patients receiving ado-trastuzumab emtansine.1 Patients who have dyspnea at rest resulting from complications of advanced disease or other comorbidities may be at greater risk for pulmonary toxicity.1 Manifestations of pneumonitis include dyspnea, cough, fatigue, and pulmonary infiltrates; however, these manifestations may also occur as sequelae of infusion reactions.1
Ado-trastuzumab emtansine should be permanently discontinued in patients diagnosed with interstitial lung disease or pneumonitis.1 (See Pulmonary Toxicity under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Thrombocytopenia is a common dose-limiting adverse effect of ado-trastuzumab emtansine.1, 9, 11 Thrombocytopenia of any grade was reported in 32% of patients receiving ado-trastuzumab emtansine in clinical trials; grade 3 or greater thrombocytopenia was reported in 11.7% of patients.1 The incidence of severe hemorrhagic events in patients receiving ado-trastuzumab emtansine was low.1, 2, 4 In patients with grade 1 or 2 thrombocytopenia, the nadir platelet count occurred around day 8 of each 3-week cycle; thrombocytopenia generally improved to grade 0 or 1 (i.e., platelet counts reach or exceed 75,000/mm3) by the next scheduled dose.1, 3, 8, 11 In the EMILIA study, thrombocytopenia occurred in 31.2% of patients receiving ado-trastuzumab emtansine alone and in 3.3% of patients receiving combined therapy with lapatinib and capecitabine.1 The incidence of grade 3 or greater thrombocytopenia was higher in patients receiving ado-trastuzumab emtansine alone compared with those receiving combined therapy with lapatinib and capecitabine (14.5 versus 0.4%, respectively).1 The first occurrence of grade 3 or 4 thrombocytopenia was reported during the first 2 cycles of therapy with ado-trastuzumab emtansine in most patients enrolled in the EMILIA study; the majority of patients continued treatment following dosage modifications.2 In the EMILIA study, the incidence and severity of thrombocytopenia was higher in Asian patients; the incidence of grade 3 or greater thrombocytopenia was substantially higher in Asian patients receiving ado-trastuzumab emtansine alone compared with those receiving combined therapy with lapatinib and capecitabine (45.1 versus 1.3%, respectively).1
Ado-trastuzumab emtansine has not been studied in patients with baseline platelet counts less than 100,000/mm3.1
Platelet counts should be monitored prior to each dose of ado-trastuzumab emtansine.1 Patients receiving concomitant anticoagulant therapy or those with platelet counts less than 100,000/mm3 should be closely monitored during therapy.1 Therapy with the drug should be interrupted in patients who experience grade 3 or greater thrombocytopenia until resolution to grade 1 or less.1 (See Thrombocytopenia under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Peripheral neuropathy of any grade (mainly sensory neuropathy) was reported in 22% of patients receiving ado-trastuzumab emtansine in clinical trials; grade 3 or greater peripheral neuropathy was reported in 1.6% of patients.1 In the EMILIA study, peripheral neuropathy occurred in 21.2% of patients receiving ado-trastuzumab emtansine alone and in 13.5% of patients receiving combined therapy with lapatinib and capecitabine.1 The incidence of grade 3 or greater peripheral neuropathy was higher in patients receiving ado-trastuzumab emtansine alone compared with those receiving combined therapy with lapatinib and capecitabine (2.2 versus 0.2%, respectively).1 Peripheral neuropathy generally was managed with treatment interruption and/or dosage reduction in clinical trials.1
Patients receiving ado-trastuzumab emtansine should be monitored for manifestations of neurotoxicity during therapy.1 The drug should be withheld in patients who experience grade 3 or 4 peripheral neuropathy until it resolves to grade 2 or less.1 (See Peripheral Neuropathy under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Detection of HER2 overexpression is necessary prior to initiating therapy because safety and efficacy of ado-trastuzumab emtansine have been established only in patients with HER2 -overexpressing tumors.1 In clinical practice and clinical research studies, the methods of HER2 evaluation most commonly used are immunohistochemistry (IHC) assays, which directly measure overexpression of the HER2 protein, and fluorescent in situ hybridization (FISH), which measures amplification of the HER2 oncogene.5 (See Evaluation of HER2/neu in Breast Cancer under Uses: Breast Cancer, in Trastuzumab 10:00.) In the EMILIA study, patients with breast cancer were required to have disease demonstrating an IHC score of 3+ (as determined by the Dako Herceptest®) or a FISH amplification ratio of 2 or higher (as determined by the Dako HER2 FISH PharmDx® test kit).1, 2 Limited data are available for patients whose breast tumors are FISH-positive but lack HER2 overexpression.1
Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being used.1 Improper assay performance, including use of suboptimally fixed tissue, failure to use specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.1
Extravasation of ado-trastuzumab emtansine has resulted in reactions including erythema, tenderness, skin irritation, pain, or swelling at the infusion site; these effects were generally mild and observed more frequently within 24 hours following an infusion.1 Specific treatment for extravasation following an infusion of ado-trastuzumab emtansine has not been established.1 The infusion site should be closely monitored for subcutaneous infiltration during administration.1
As with all therapeutic proteins, there is a potential for immunogenicity.1 In clinical studies, anti-ado-trastuzumab emtansine antibodies were detected in 44 of 836 patients (5.3%) receiving ado-trastuzumab emtansine.1, 3, 4, 8, 9 No clinically important effects on safety, efficacy, or pharmacokinetics of the drug were observed in patients who tested positive for anti-ado-trastuzumab emtansine antibodies.3, 4, 8, 9 Neutralizing antibodies have not been assessed.1
The presence of ado-trastuzumab emtansine in the serum sample may interfere with assays used to measure antibodies to the drug.1 Therefore, data may not accurately reflect the true incidence of anti-ado-trastuzumab emtansine antibody formation.1
Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)
If ado-trastuzumab emtansine is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard; the patient should be encouraged to enroll in the MotHER Pregnancy Registry (800-690-6720), and clinicians should immediately notify the Genentech Adverse Event Line (888-835-2555).1
It is not known whether ado-trastuzumab emtansine is distributed into human milk.1 Trastuzumab is distributed into milk in monkeys; it is not known whether trastuzumab is distributed into milk in humans.1, 14 (See Cautions: Pregnancy, Fertility, and Lactation, in Trastuzumab 10:00.) Because human immunoglobulin G (IgG) is distributed into milk in humans, and because of the potential for serious adverse reactions to ado-trastuzumab emtansine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1
Safety and efficacy of ado-trastuzumab emtansine have not been established in pediatric patients.1
In the EMILIA study, 13% of patients were 65 years of age or older, and 2% were 75 years of age or older.1 In a subset analysis, survival benefit (i.e., progression-free survival and overall survival) was not observed in patients 65 years of age or older (hazard ratio 1.06 and 1.05, respectively).1 In a population pharmacokinetic analysis, no substantial differences in pharmacokinetics were observed between geriatric and younger adults.1
Pharmacokinetic studies have not been conducted in patients with hepatic impairment; however, the microtubule inhibitor DM1 is metabolized by cytochrome P-450 (CYP) isoenzymes 3A4/5.1
Ado-trastuzumab emtansine has not been studied in patients with serum aminotransferase concentrations exceeding 2.5 times the upper limit of normal (ULN) or total bilirubin concentrations exceeding 1.5 times the ULN.1
Formal pharmacokinetic studies have not been conducted in patients with renal impairment.1 In a population pharmacokinetic analysis, the pharmacokinetics of ado-trastuzumab emtansine were similar between patients with mild (creatinine clearance of 60-89 mL/minute) or moderate (creatinine clearance of 30-59 mL/minute) renal impairment and those with normal renal function.1 Pharmacokinetic data in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) are limited.1 (See Dosage and Administration: Special Populations.)
Adverse effects reported in 10% or more of patients receiving ado-trastuzumab emtansine include stomatitis,1 dry mouth,1, 3 abdominal pain,1 diarrhea,1, 2, 3, 4 nausea,1, 2, 3, 4 vomiting,1, 2, 3, 4 constipation,1, 3, 4 pyrexia,1, 3, 4 asthenia,1 fatigue,1, 2, 3, 4 myalgia,1, 3 arthralgia,1, 3, 4 musculoskeletal pain,1 dizziness,1 peripheral neuropathy,1, 3 headache,1, 3, 4 insomnia,1 dyspnea,1, 3, 4 cough,1, 3, 4 epistaxis,1, 3, 4 rash,1 pain in extremity,3, 4 infusion reaction,3 hypokalemia,1, 3, 4 liver function test (AST, ALT, alkaline phosphatase) abnormalities,1, 2, 3 anemia,1, 2, 3, 4 and thrombocytopenia.1, 2, 3
In vitro studies indicate that DM1, the microtubule-disrupting component of ado-trastuzumab emtansine, is primarily metabolized by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by CYP3A5.1, 6 (See Description.) In vitro studies also indicate that DM1 does not inhibit or induce major CYP isoenzymes.1
DM1 is a substrate for the efflux transporter P-glycoprotein (P-gp) in vitro.1
Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of ado-trastuzumab emtansine with potent inhibitors of CYP3A4 may result in increased systemic exposure of DM1.1 Concomitant use with potent CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) should be avoided, and selection of an alternative drug with no or minimal CYP3A4 inhibition potential is recommended.1 If concomitant use of the potent CYP3A4 inhibitor is unavoidable, delaying initiation of ado-trastuzumab emtansine therapy until after approximately 3 elimination half-lives of the CYP3A4 inhibitor should be considered.1 If concomitant use cannot be delayed, patients should be closely monitored for adverse effects.1
Ado-trastuzumab emtansine, an anti-human epidermal growth factor receptor type 2 (anti- HER2 ) antibody-drug conjugate, is an antineoplastic agent.1, 2, 3, 4, 8, 9, 10, 11 The anti- HER2 antibody, a humanized immunoglobulin (IgG1), is conjugated with the microtubule inhibitor DM1 (a maytansine derivative).1, 12 A stable thioether linker (MCC) covalently binds DM1 to the antibody component; the resultant complex, MCC-DM1, is referred to as emtansine.1, 12 The antibody portion of ado-trastuzumab emtansine binds specifically to the extracellular domain of the HER2 receptor.1, 8 Following binding of the antibody portion of ado-trastuzumab emtansine to sub-domain IV of the HER2 receptor, the resultant complex is internalized by the cell.1 DM1 is released via lysosomal degradation and binds to tubulin, resulting in cell cycle arrest and apoptosis.1, 9 In addition, ado-trastuzumab emtansine has been shown to exhibit similar activity (i.e., inhibit HER2 signaling, mediate antibody-dependent cell-mediated cytotoxicity [ADCC], and inhibit shedding of the HER2 extracellular domain in breast cancer cells that overexpress the HER2 protein) and binding affinity to the HER2 receptor as trastuzumab.1, 9, 10, 12
In one in vitro study comparing the relative potency of DM1 and paclitaxel in 6 cell lines in breast cancer, DM1 was approximately 2- to 17-fold more potent than paclitaxel on a molar basis.12
The pharmacokinetics of the antibody-drug conjugate following IV administration is characterized by a 2-compartment model with first-order elimination.1 Peak plasma concentrations of the antibody-drug conjugate and DM1 were observed near the end of IV infusion.1 Following repeated doses of ado-trastuzumab emtansine administered IV every 3 weeks, systemic accumulation of the antibody-drug conjugate was not observed.1, 13 Steady-state concentrations are reached by the second cycle of therapy.13 In vitro studies indicate that DM1 is metabolized by cytochrome P-450 (CYP) 3A4/5 isoenzymes.1 In vitro, DM1 is 93% bound to plasma proteins.1 The terminal half-life of the antibody-drug conjugate is approximately 4 days.1, 8, 13
Population pharmacokinetic analyses indicate that age, race, and serum albumin concentrations do not have clinically important effects on the pharmacokinetics of the antibody-drug conjugate.1
Risk of fetal harm (e.g., embryofetal death, birth defects).1 Necessity of advising women of childbearing potential to use effective contraception during therapy and for 6 months after discontinuance of ado-trastuzumab emtansine.1 Encourage women who have been exposed to the drug during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 800-690-6720.1 (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)
Importance of discontinuing breast-feeding during therapy.1
Risk of severe hepatotoxicity.1 Importance of contacting clinician promptly if manifestations of acute hepatitis occur (e.g., nausea, vomiting, abdominal pain [particularly in the right upper quadrant], jaundice, dark urine, generalized pruritus, anorexia).1
Importance of contacting clinician promptly if new-onset or worsening shortness of breath, cough, swelling of ankles or legs, palpitations, weight gain exceeding 5 pounds in 24 hours, dizziness, or loss of consciousness occurs.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
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.
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions April 6, 2016. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Genentech, Inc. Kadcyla® (ado-trastuzumab emtansine) injection for intravenous use prescribing information. South San Francisco, CA; 2013 May.
2. Verma S, Miles D, Gianni L et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med . 2012; 367:1783-91. [PubMedCentral][PubMed 23020162]
3. Krop IE, LoRusso P, Miller KD et al. A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J Clin Oncol . 2012; 30:3234-41. [PubMed 22649126]
4. Burris HA, Rugo HS, Vukelja SJ et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol . 2011; 29:398-405. [PubMed 21172893]
5. Jacobs TW, Gown AM, Yaziji H et al. Comparison of fluorescense in situ hybridization and immunohistochemistry for the evaluation of HER-2/neu in breast cancer. J Clin Oncol . 1999; 17:1974-82. [PubMed 10561247]
6. Boyraz B, Sendur MA, Aksoy S et al. Trastuzumab emtansine (T-DM1) for HER2-positive breast cancer. Curr Med Res Opin . 2013; 29:405-14. [PubMed 23402224]
7. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 125427Orig1s000: Summary review. 2013 Feb 21. From FDA website. [Web]
8. Krop IE, Beeram M, Modi S et al. Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol . 2010; 28:2698-704. [PubMed 20421541]
9. Girish S, Gupta M, Wang B et al. Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody-drug conjugate in development for the treatment of HER2-positive cancer. Cancer Chemother Pharmacol . 2012; 69:1229-40. [PubMedCentral][PubMed 22271209]
10. Barok M, Tanner M, Köninki K et al. Trastuzumab-DM1 causes tumour growth inhibition by mitotic catastrophe in trastuzumab-resistant breast cancer cells in vivo. Breast Cancer Res . 2011; 13:R46.
11. Bender BC, Schaedeli-Stark F, Koch R et al. A population pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancer. Cancer Chemother Pharmacol . 2012; 70:591-601. [PubMed 22886072]
12. Junttila TT, Li G, Parsons K et al. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat . 2011; 128:347-56. [PubMed 20730488]
13. Gupta M, Lorusso PM, Wang B et al. Clinical implications of pathophysiological and demographic covariates on the population pharmacokinetics of trastuzumab emtansine, a HER2-targeted antibody-drug conjugate, in patients with HER2-positive metastatic breast cancer. J Clin Pharmacol . 2012; 52:691-703. [PubMed 21953571]
14. Genentecc, Inc. Herceptin® (trastuzumab) prescribing information. South San Francisco, CA; 2010 Oct.
1001. Institute for Safe Medication Practices. Confusion between two HER2-targeted monoclonal antibodies. ISMP Medication Safety Alert! Horsham, PA; 2013 Mar 7.
1003. US Adopted Name (USAN) Council. Trastuzumab emtansine. From USAN website. Accessed 2013 Apr 12 [Web]
1004. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125427Orig1s000: Proprietary name review(s). From FDA website. Accessed 2013 Apr 22. [Web]
1005. National Alert Network (NAN). Confusion regarding the generic name of the HER2-targeted drug KADCYLA (ado-trastuzumab emtansine). NAN Alert. Horsham, PA; 2013 Apr 17.
1006. US Food and Drug Administration. FDA Drug Safety Communication: Kadcyla (ado-trastuzumab emtansine) potential medication errors resulting from name confusion. Rockville, MD; 2013 May 6. From FDA website. Accessed 2013 Jun 17. [Web]