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  • CLASSES

    Antineoplastic Monoclonal Antibodies

    BOXED WARNING

    Heart failure, ventricular dysfunction

    Patients treated with ado-trastuzumab emtansine are at increased risk of developing left ventricular dysfunction. Assess left ventricular ejection fraction (LVEF) prior to initiation of therapy and every 3 months during treatment. A reduction in LVEF may require a delay in dosage, dose reduction, or permanent discontinuation of therapy. In a randomized trial, a decrease of LVEF to less than 40% occurred in 1.8% of patients receiving ado-trastuzumab emtansine (n = 495) and 3.3% of patients receiving lapatinib plus capecitabine (n = 496). Patients with a baseline LVEF less than 50%, a history of symptomatic congestive heart failure, serious cardiac arrhythmia, or history of myocardial infarction or unstable angina were excluded from the clinical trial.

    Ensure correct formulation selection

    The ado-trastuzumab emtansine label contains a warning to ensure correct formulation selection for the patient. Practitioners must not prescribe or substitute trastuzumab in place of ado-trastuzumab emtansine.

    Pregnancy

    Fetal harm may occur if ado-trastuzumab emtansine is administered during pregnancy or within 7 months of conception; monitoring for oligohydramnios is recommended. If oligohydramnios occurs, fetal testing should be done that is appropriate for gestational age and consistent with community standards of care. Pregnancy should be avoided by females taking ado-trastuzumab emtansine during therapy and for 7 months after the last dose; male patients with female partners should use effective contraception during treatment and for 4 months after the last dose. Women who become pregnant during this time frame should be apprised of the potential hazard to the fetus. Encourage these women to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 or visiting http://www.motherpregnancyregistry.com. Healthcare professionals and patients should additionally report the pregnancy to the pregnancy pharmacovigilance program at Genentech (1-888-835-2555). Post-marketing, oligohydramnios and oligohydramnios sequence (manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death) occurred in pregnant women who received trastuzumab alone or in combination with chemotherapy. DM1, the cytotoxic component of ado-trastuzumab emtansine, can cause embryo-fetal toxicity based on its mechanism of action.

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during ado-trastuzumab emtansine treatment. Ado-trastuzumab emtansine can be teratogenic if taken by the mother during pregnancy or within 7 months prior to conception. Females should avoid pregnancy and use effective contraception during and for at least 7 months after treatment; male patients with female partners should use effective contraception during therapy and for 4 months after the last dose. Females of reproductive potential should undergo pregnancy testing prior to initiation of therapy. Women who become pregnant while receiving ado-trastuzumab emtansine or within 7 months of the last dose should be apprised of the potential hazard to the fetus and encouraged to enroll in the MotHER Pregnancy Registry (1-800-690-6720 or www.motherpregnancyregistry.com); additionally, healthcare providers and patients should report ado-trastuzumab emtansine exposure to the pregnancy pharmacovigilance program at Genentech (1-888-835-2555). Because of the potential for genotoxicity or male-mediated teratogenicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment with ado-trastuzumab emtansine and for 4 months following the last dose. Additionally, ado-trastuzumab emtansine may cause impaired fertility or infertility in both males and females; it is unknown whether the effects on fertility are reversible.

    DEA CLASS

    Rx

    DESCRIPTION

    Antibody-drug conjugate that targets HER2-positive cells.
    FDA-approved for HER2-positive, metastatic breast cancer in patients who have previously received trastuzumab and a taxane, either separately or in combination.
    Should not be substituted for trastuzumab.
    Carries black box warnings for reduced left ventricular ejection fraction (LVEF)and hepatotoxicity. Assess LVEF and hepatic function prior to initiation and during treatment.
    Can cause fetal harm. Advise women of potential risk to the fetus.

    COMMON BRAND NAMES

    Kadcyla

    HOW SUPPLIED

    Kadcyla Intravenous Inj Pwd F/Sol: 100mg, 160mg

    DOSAGE & INDICATIONS

    For the treatment of patients with HER2-positive breast cancer.
    For the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, either separately or in combination.
    Intravenous dosage
    Adults

    3.6 mg/kg IV every 3 weeks until disease progression or unacceptable toxicity. Infuse the first infusion over 90 minutes; if tolerated, subsequent infusions may be administered over 30 minutes. Do not substitute ado-trastuzumab emtansine for or with trastuzumab. In a randomized, multicenter, open-label clinical trial of patients with metastatic breast cancer, treatment with ado-trastuzumab emtansine (n = 495) improved progression-free survival (PFS) (9.6 months vs. 6.4 months; HR 0.650; p < 0.0001), overall survival (30.9 months vs. 25.1 months; HR 0.682; p = 0.0006), objective response rate (43.6% vs. 30.8%), and duration of response (12.6 months vs. 6.5 months) compared with a combination of lapatinib plus capecitabine (n = 496).

    For the first-line treatment of HER2-positive advanced breast cancer†.
    Intravenous dosage
    Adults

    3.6 mg/kg IV every 3 weeks. In a multicenter, randomized, open-label, phase III clinical trial, ado-trastuzumab emtansine (T-DM1) was non-inferior to trastuzumab plus taxane therapy (TH) in terms of progression-free survival (PFS) in the first-line treatment of HER2-positive advanced breast cancer; however, standard of care today is TH plus pertuzumab. Median overall survival was not reached in any group. The addition of pertuzumab did not improve outcomes when added to T-DM1. The median time to decrease in health-related QOL was significantly longer in patients treated with T-DM1 compared with TH.

    MAXIMUM DOSAGE

    Adults

    3.6 mg/kg IV every 3 weeks.

    Geriatric

    3.6 mg/kg IV every 3 weeks.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment: Ado-trastuzumab emtansine has not been studied in patients with baseline serum transaminases greater than 2.5 times the upper limit of normal (ULN), total bilirubin greater than 1.5 times ULN, or known active hepatitis B or hepatitis C.
    Mild to moderate hepatic impairment (Child-Pugh class A and B): No adjustment to the starting dose is necessary. Use caution due to the risk of hepatotoxicity with ado-trastuzumab emtansine therapy.
    Severe hepatic impairment (Child-Pugh class C): Ado-trastuzumab emtansine has not been studied in patients with severe hepatic impairment.
    Treatment-Related Hepatotoxicity
    Nodular Regenerative Hyperplasia (NRH): Permanently discontinue ado-trastuzumab emtansine therapy.
    AST/ALT less than or equal to 3 times the upper limit of normal (ULN):
    Total bilirubin less than or equal to 1.5 times ULN: No dosage adjustment necessary.
    Total bilirubin greater than 1.5 to 3 times ULN: Hold ado-trastuzumab emtansine therapy. When total bilirubin recovers to 1.5 times ULN or less, restart therapy at the original dose.
    Total bilirubin greater than 3 to 10 times ULN: Hold ado-trastuzumab emtansine therapy. When total bilirubin recovers to 1.5 times ULN or less, restart therapy at a reduced dose (e.g., 3.6 mg/kg to 3 mg/kg; 3 mg/kg to 2.4 mg/kg). If hepatotoxicity occurs at a dose of 2.4 mg/kg, discontinue therapy.
    Total bilirubin greater than 10 times ULN: Permanently discontinue ado-trastuzumab emtansine therapy.
    AST/ALT greater than 3 to 5 times ULN:
    Total bilirubin less than or equal to 1.5 times ULN: No dosage adjustment necessary:
    Total bilirubin greater than 1.5 to 2 times ULN: Hold ado-trastuzumab emtansine therapy. When total bilirubin recovers to 1.5 times ULN or less, resume therapy at the original dose.
    Total bilirubin greater than 2 times ULN: Permanently discontinue ado-trastuzumab emtansine therapy.
    AST/ALT greater than 5 to 20 times ULN:
    Total bilirubin less than or equal to 1.5 times ULN: Hold ado-trastuzumab emtansine therapy. When AST/ALT recover to 5 times the ULN or less, resume therapy at a reduced dose (e.g., 3.6 mg/kg to 3 mg/kg; 3 mg/kg to 2.4 mg/kg). If hepatotoxicity occurs at a dose of 2.4 mg/kg, discontinue therapy.
    Total bilirubin greater than 1.5 to 2 times ULN: Hold ado-trastuzumab emtansine therapy. When AST/ALT recover to 5 times the ULN or less and bilirubin is 1.5 times ULN or less, resume therapy at a reduced dose (e.g., 3.6 mg/kg to 3 mg/kg; 3 mg/kg to 2.4 mg/kg). If hepatotoxicity occurs at a dose of 2.4 mg/kg, discontinue therapy.
    Total bilirubin greater than 2 times ULN: Permanently discontinue ado-trastuzumab emtansine therapy.
    AST/ALT greater than 20 times ULN:
    Any bilirubin: Permanently discontinue ado-trastuzumab emtansine therapy.

    Renal Impairment

    Based on population pharmacokinetics and analysis of Grade 3 or higher adverse events and dose modifications, dose adjustments of ado-trastuzumab emtansine are not required in patients with mild to moderate renal impairment (CrCl 30—90 mL/min). No dose adjustment can be recommended for patients with CrCl < 30 mL/min due to limited data available.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Document the trade name and batch number in the patient file to improve ability to trace the product.
    Do not mix with, or administer as an infusion with, other IV products.
    Administer as an intravenous (IV) infusion with a 0.2 or 0.22 micron in-line polyethersulfone (PES) filter. Do not administer as an IV push or bolus.
    If a dose is delayed or missed, administer as soon as possible; do not wait until the next planned cycle. Adjust the schedule of administration to maintain a 3-week interval between doses. Administer the infusion at the dose and rate tolerated in the most recent infusion.
    Reconstitution:
    100 mg vial: Slowly inject 5 mL of sterile water for injection into the vial; direct the stream toward the wall of the vial and not directly at the cake or powder. 
    160 mg vial: Slowly inject 8 mL of sterile water for injection into the vial; direct the stream toward the wall of the vial and not directly at the cake or powder. 
    Gently swirl to aid in dissolution; do not shake. The final concentration of both the 100-mg and 160-mg vial is 20 mg/mL.
    Reconstituted vials should be used immediately as they do not contain preservatives; however, they may be stored under refrigeration (2 to 8 degrees C, or 36 to 46 degrees F) for up to 24 hours. Do not freeze.
    Dilute reconstituted ado-trastuzumab emtansine in 250 mL of 0.9% Sodium Chloride Injection; do not use 5% Dextrose solution. Gently invert the bag to mix; do not shake.
    Diluted bags may be refrigerated (2 to 8 degrees C, or 36 to 46 degrees F) for up to 24 hours in addition to storage time allowed for reconstituted vials. Do not freeze.
    Intravenous Infusion:
    Closely monitor the infusion site for possible subcutaneous infiltration during drug administration.
    First infusion: Administer over 90 minutes; slow or interrupt the infusion if the patient develops an infusion-related reaction. Patients should be observed for at least 90 minutes following the initial dose for fever, chills, or other infusion related reactions. Permanently discontinue ado-trastuzumab emtansine for life-threatening infusion-related reactions.
    Subsequent infusions: Administer over 30 minutes if prior infusions were well tolerated; slow or interrupt the infusion if the patient develops an infusion-related reaction. Patients should be observed for at least 30 minutes after the infusion. Permanently discontinue ado-trastuzumab emtansine for life-threatening infusion-related reactions.

    STORAGE

    Kadcyla:
    - Diluted product if not used immediately can be stored at 36 to 46 degrees F for up to 24 hours
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Reconstituted product may be stored refrigerated in its carton at 36 to 46 degrees F for up to 24 hours if not used immediately
    - Store unreconstituted product in refrigerator (36 to 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Do not substitute ado-trastuzumab emtansine for or with other trastuzumab formulations.

    Heart failure, ventricular dysfunction

    Patients treated with ado-trastuzumab emtansine are at increased risk of developing left ventricular dysfunction. Assess left ventricular ejection fraction (LVEF) prior to initiation of therapy and every 3 months during treatment. A reduction in LVEF may require a delay in dosage, dose reduction, or permanent discontinuation of therapy. In a randomized trial, a decrease of LVEF to less than 40% occurred in 1.8% of patients receiving ado-trastuzumab emtansine (n = 495) and 3.3% of patients receiving lapatinib plus capecitabine (n = 496). Patients with a baseline LVEF less than 50%, a history of symptomatic congestive heart failure, serious cardiac arrhythmia, or history of myocardial infarction or unstable angina were excluded from the clinical trial.

    Hepatic disease, hepatic encephalopathy, hepatitis, hepatotoxicity

    Hepatotoxicity, usually in the form of asymptomatic, transient increases in serum transaminases, has been observed in clinical trials with ado-trastuzumab emtansine. Serious hepatobiliary disorders, including at least 2 fatal cases of severe drug-induced hepatic disease and associated hepatic encephalopathy, have also been reported; some of the observed cases may have been confounded by co-morbidities and/or concomitant medications with known hepatotoxic potential. Serum transaminases and bilirubin should be monitored prior to initiation of ado-trastuzumab emtansine and before each dose. An increase in hepatic enzymes or bilirubin may require a delay in dosage, dose reduction, or permanent discontinuation of therapy. Ado-trastuzumab emtansine has not been studied in patients with known active hepatitis B, hepatitis C, baseline AST/ALT > 2.5 times the upper limit of normal (ULN) or baseline total bilirubin > 1.5 times ULN.

    Asthma, chronic obstructive pulmonary disease (COPD), pneumonitis, pulmonary disease, respiratory distress syndrome, respiratory insufficiency

    Cases of interstitial lung disease (ILD), including pneumonitis (n = 7), have been reported in clinical trials (n = 884). Some cases of pulmonary disease have lead to acute respiratory distress syndrome or death. Signs and symptoms include dyspnea, cough, fatigue, and pulmonary infiltrates. These events may or may not occur as sequelae of infusion reactions. Permanently discontinue treatment with ado-trastuzumab emtansine in patients with ILD or pneumonitis. Patients with dyspnea at rest due to complications of advanced malignancy and co-morbidities (e.g., asthma, chronic obstructive pulmonary disease (COPD), or respiratory insufficiency) may be at increased risk of pulmonary toxicity.

    Acute bronchospasm, fever, hamster protein hypersensitivity, hypotension, infusion-related reactions, tachycardia

    Ado-trastuzumab emtansine should be used cautiously in patients with hamster protein hypersensitivity (i.e., Chinese hamster ovary cell hypersensitivity), trastuzumab hypersensitivity, or hypersensitivity to other components of the product due to increased risk of severe allergic reactions. Ado-trastuzumab emtansine has not been studied in patients who had trastuzumab permanently discontinued due to infusion-related reactions and/or hypersensitivity; treatment with ado-trastuzumab emtansine is not recommended for these patients. Patients should be observed closely for infusion-related reactions, especially during the first infusion. Ado-trastuzumab emtansine infusion should be interrupted for patients experiencing infusion-related reactions, characterized by flushing, chills, fever, dyspnea, hypotension, wheezing, acute bronchospasm, and tachycardia, which have been reported in clinical trials with an overall frequency of 1.4%. In most patients, these reactions resolved over the course of several hours to a day after the infusion was terminated. One case of a serious, allergic/anaphylactic-like reaction has been observed in clinical trials. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. Ado-trastuzumab emtansine should be permanently discontinued in the event of a life-threatening infusion-related reaction.

    Human anti-human antibody (HAHA)

    Of 836 patients evaluated, human anti-human antibody (HAHA) was detected in 5.3% of patients (n = 44). Data may not accurately reflect the true incidence of antibody development because the presence of ado-trastuzumab emtansine in patient serum at the time of HAHA sampling may interfere with the ability of this assay to detect antibodies. In addition, neutralizing activity of anti-ado-trastuzumab antibodies has not been assessed. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Results may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Comparison of the incidence of antibodies to ado-trastuzumab emtansine with the incidence of antibodies to other products may be misleading.

    Anticoagulant therapy, Asian patients, bleeding, GI bleeding, intracranial bleeding, pulmonary bleeding, thrombocytopenia

    In clinical trials (n = 884), thrombocytopenia of any grade was reported in 283 patients, with 103 patients experiencing >= grade 3 thrombocytopenia. The incidence and severity of thrombocytopenia were higher in Asian patients (>= grade 3, 45.1%) compared with non-Asian patients (>= grade 3, 14.5%). Severe hemorrhages (including intracranial bleeding, GI bleeding, and pulmonary bleeding), some fatal, have been reported in 1.8% of patients treated with ado-trastuzumab emtansine compared with 0.8% of patients who received lapatinib plus capecitabine in a randomized, clinical trial. Bleeding occurred in patients receiving anticoagulant therapy, antiplatelet therapy, and in those who had thrombocytopenia; however, in some patients there were no known risk factors. Monitor platelet counts prior to initiation of ado-trastuzumab therapy and before each dose. Ado-trastuzumab emtansine has not been studied in patients with a baseline platelet count < 100,000 /mm3. A reduction in platelet count may require a delay in dosage, dose reduction, or permanent discontinuation of therapy. Use ado-trastuzumab with caution in patients with thrombocytopenia (less than 100,000 /mm3) and closely monitor for signs of bleeding. If the use of anticoagulant therapy or antiplatelet therapy cannot be avoided, additional monitoring may be needed.

    Peripheral neuropathy

    Patients receiving ado-trastuzumab emtansine have developed peripheral neuropathy in clinical trials. Grade 3 or 4 peripheral neuropathy requires temporary discontinuation of ado-trastuzumab emtansine therapy until recovery to <= grade 2. Patients should be clinically monitored on an ongoing basis for signs or symptoms of neurotoxicity.

    Ensure correct formulation selection

    The ado-trastuzumab emtansine label contains a warning to ensure correct formulation selection for the patient. Practitioners must not prescribe or substitute trastuzumab in place of ado-trastuzumab emtansine.

    Pregnancy

    Fetal harm may occur if ado-trastuzumab emtansine is administered during pregnancy or within 7 months of conception; monitoring for oligohydramnios is recommended. If oligohydramnios occurs, fetal testing should be done that is appropriate for gestational age and consistent with community standards of care. Pregnancy should be avoided by females taking ado-trastuzumab emtansine during therapy and for 7 months after the last dose; male patients with female partners should use effective contraception during treatment and for 4 months after the last dose. Women who become pregnant during this time frame should be apprised of the potential hazard to the fetus. Encourage these women to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 or visiting http://www.motherpregnancyregistry.com. Healthcare professionals and patients should additionally report the pregnancy to the pregnancy pharmacovigilance program at Genentech (1-888-835-2555). Post-marketing, oligohydramnios and oligohydramnios sequence (manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death) occurred in pregnant women who received trastuzumab alone or in combination with chemotherapy. DM1, the cytotoxic component of ado-trastuzumab emtansine, can cause embryo-fetal toxicity based on its mechanism of action.

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during ado-trastuzumab emtansine treatment. Ado-trastuzumab emtansine can be teratogenic if taken by the mother during pregnancy or within 7 months prior to conception. Females should avoid pregnancy and use effective contraception during and for at least 7 months after treatment; male patients with female partners should use effective contraception during therapy and for 4 months after the last dose. Females of reproductive potential should undergo pregnancy testing prior to initiation of therapy. Women who become pregnant while receiving ado-trastuzumab emtansine or within 7 months of the last dose should be apprised of the potential hazard to the fetus and encouraged to enroll in the MotHER Pregnancy Registry (1-800-690-6720 or www.motherpregnancyregistry.com); additionally, healthcare providers and patients should report ado-trastuzumab emtansine exposure to the pregnancy pharmacovigilance program at Genentech (1-888-835-2555). Because of the potential for genotoxicity or male-mediated teratogenicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment with ado-trastuzumab emtansine and for 4 months following the last dose. Additionally, ado-trastuzumab emtansine may cause impaired fertility or infertility in both males and females; it is unknown whether the effects on fertility are reversible.

    Breast-feeding

    It is not known whether ado-trastuzumab emtansine is excreted into human milk. Published data suggest human IgG is present in human milk, but does not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in a nursing infant, advise women to discontinue breast-feeding during treatment with ado-trastuzumab emtansine and for 7 months after the last dose.

    ADVERSE REACTIONS

    Severe

    thrombocytopenia / Delayed / 11.9-17.0
    elevated hepatic enzymes / Delayed / 3.1-8.0
    anemia / Delayed / 2.9-5.0
    neutropenia / Delayed / 2.0-4.0
    hypokalemia / Delayed / 2.7-3.3
    fatigue / Early / 2.5-3.2
    peripheral neuropathy / Delayed / 2.2-2.4
    musculoskeletal pain / Early / 1.8-1.8
    diarrhea / Early / 1.0-1.6
    nausea / Early / 0.8-1.1
    hepatic encephalopathy / Delayed / 0-1.0
    hyperbilirubinemia / Delayed / 0-1.0
    acute respiratory distress syndrome (ARDS) / Early / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    vomiting / Early / 0.8-0.9
    arthralgia / Delayed / 0.6-0.9
    abdominal pain / Early / 0.8-0.8
    dyspnea / Early / 0.8-0.8
    headache / Early / 0.6-0.8
    anorexia / Delayed / 0.7-0.7
    constipation / Delayed / 0.4-0.6
    infection / Delayed / 0.6-0.6
    myalgia / Early / 0.6-0.6
    epistaxis / Delayed / 0.2-0.5
    heart failure / Delayed / 0.4-0.4
    asthenia / Delayed / 0.4-0.4
    insomnia / Early / 0.4-0.4
    dizziness / Early / 0.4-0.4
    fever / Early / 0.2-0.3
    stomatitis / Delayed / 0.2-0.2
    hepatic failure / Delayed / 0.2-0.2
    cough / Delayed / 0.1-0.2
    pruritus / Rapid / 0.2-0.2
    visual impairment / Early / Incidence not known
    bronchospasm / Rapid / Incidence not known

    Moderate

    peripheral edema / Delayed / 7.1-7.1
    blurred vision / Early / 4.5-4.5
    hypertension / Early / 3.9-3.9
    conjunctivitis / Delayed / 3.9-3.9
    infusion-related reactions / Rapid / 1.4-1.4
    pneumonitis / Delayed / 1.2-1.2
    sinus tachycardia / Rapid / Incidence not known
    wheezing / Rapid / Incidence not known
    hypotension / Rapid / Incidence not known

    Mild

    xerostomia / Early / 16.7-16.7
    rash (unspecified) / Early / 11.6-11.6
    dyspepsia / Early / 9.2-9.2
    dysgeusia / Early / 8.0-8.0
    chills / Rapid / 7.6-7.6
    xerophthalmia / Early / 3.9-3.9
    lacrimation / Early / 3.3-3.3
    flushing / Rapid / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Major) Use caution if coadministration of platelet inhibitors such as abciximab with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anti-platelet therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Acetaminophen; Aspirin, ASA; Caffeine: (Major) Use caution if coadministration of platelet inhibitors such as aspirin, ASA with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. Per the manufacturer of ado-trastuzumab emtansine, if anti-platelet therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid concomitant use of ado-trastuzumab emtansine with clarithromycin, as plasma exposure to the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, may be increased. Treatment with ado-trastuzumab emtansine should be delayed until clarithromycin is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered. If co-administration is necessary, monitor for an increase in ado-trastuzumab emtansine-related adverse events. Clarithromycin is a strong CYP3A4 inhibitor. When a single dose of another CYP3A4 substrate, midazolam, was coadministered with 7 days of clarithromycin, the AUC of IV midazolam increased by 174% and PO midazolam by 600%. While formal drug interaction studies have not been conducted, DM1 is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of ado-trastuzumab emtansine with clarithromycin, as plasma exposure to the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, may be increased. Treatment with ado-trastuzumab emtansine should be delayed until clarithromycin is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered. If co-administration is necessary, monitor for an increase in ado-trastuzumab emtansine-related adverse events. Clarithromycin is a strong CYP3A4 inhibitor. When a single dose of another CYP3A4 substrate, midazolam, was coadministered with 7 days of clarithromycin, the AUC of IV midazolam increased by 174% and PO midazolam by 600%. While formal drug interaction studies have not been conducted, DM1 is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Anagrelide: (Major) Use caution if coadministration of platelet inhibitors such as anagrelide with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anti-platelet therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Anticoagulants: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Antithrombin III: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Apixaban: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Argatroban: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Aspirin, ASA: (Major) Use caution if coadministration of platelet inhibitors such as aspirin, ASA with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. Per the manufacturer of ado-trastuzumab emtansine, if anti-platelet therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Use caution if coadministration of platelet inhibitors such as aspirin, ASA with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. Per the manufacturer of ado-trastuzumab emtansine, if anti-platelet therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Use caution if coadministration of platelet inhibitors such as aspirin, ASA with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. Per the manufacturer of ado-trastuzumab emtansine, if anti-platelet therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Use caution if coadministration of platelet inhibitors such as aspirin, ASA with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. Per the manufacturer of ado-trastuzumab emtansine, if anti-platelet therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Aspirin, ASA; Carisoprodol: (Major) Use caution if coadministration of platelet inhibitors such as aspirin, ASA with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. Per the manufacturer of ado-trastuzumab emtansine, if anti-platelet therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Use caution if coadministration of platelet inhibitors such as aspirin, ASA with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. Per the manufacturer of ado-trastuzumab emtansine, if anti-platelet therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Aspirin, ASA; Dipyridamole: (Major) Use caution if coadministration of anticoagulants such as dipyridamole with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors. (Major) Use caution if coadministration of platelet inhibitors such as aspirin, ASA with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. Per the manufacturer of ado-trastuzumab emtansine, if anti-platelet therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Aspirin, ASA; Omeprazole: (Major) Use caution if coadministration of platelet inhibitors such as aspirin, ASA with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. Per the manufacturer of ado-trastuzumab emtansine, if anti-platelet therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Aspirin, ASA; Oxycodone: (Major) Use caution if coadministration of platelet inhibitors such as aspirin, ASA with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. Per the manufacturer of ado-trastuzumab emtansine, if anti-platelet therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Aspirin, ASA; Pravastatin: (Major) Use caution if coadministration of platelet inhibitors such as aspirin, ASA with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. Per the manufacturer of ado-trastuzumab emtansine, if anti-platelet therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Atazanavir: (Severe) Atazanavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use atazanavir concomitantly with ado-trastuzumab emtansine. Atazanavir is a strong CYP3A4 inhibitor. Although formal drug interactions have not been completed, the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, is primarily metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro, and has been associated with hepatotoxicity, interstitial lung disease (ILD) / pneumonitis, and severe bleeding events. Treatment with ado-trastuzumab emtansine should be delayed until atazanavir is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered.
    Atazanavir; Cobicistat: (Severe) Atazanavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use atazanavir concomitantly with ado-trastuzumab emtansine. Atazanavir is a strong CYP3A4 inhibitor. Although formal drug interactions have not been completed, the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, is primarily metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro, and has been associated with hepatotoxicity, interstitial lung disease (ILD) / pneumonitis, and severe bleeding events. Treatment with ado-trastuzumab emtansine should be delayed until atazanavir is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered.
    Betrixaban: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Bivalirudin: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Boceprevir: (Severe) Boceprevir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use boceprevir concomitantly with ado-trastuzumab emtansine. Boceprevir is a strong CYP3A4 inhibitor. Although formal drug interactions have not been completed, the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, is primarily metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro, and has been associated with hepatotoxicity, interstitial lung disease (ILD) / pneumonitis, and severe bleeding events. Treatment with ado-trastuzumab emtansine should be delayed until boceprevir is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered.
    Ceritinib: (Major) Avoid coadministration of ceritinib with ado-trastuzumab emtansine due to increased ado-trastuzumab emtansine exposure. If coadministration is unavoidable, monitor for ado-trastuzumab emtansine-related adverse reactions. Ceritinib is a CYP3A4 inhibitor; the extent of inhibition is unknown. The cytotoxic component of ado-trastuzumab emtansine, DM-1, is primarily metabolized by CYP3A4. Formal drug-drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Chloramphenicol: (Major) Avoid concomitant use of ado-trastuzumab emtansine with chloramphenicol, as plasma exposure to the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, may be increased. Treatment with ado-trastuzumab emtansine should be delayed until chloramphenicol is cleared from the circulation (approximately 3 elimination half-lives), or an alternate medication with less potential to inhibit CYP3A4 should be considered. If co-administration is necessary, monitor for an increase in ado-trastuzumab emtansine-related adverse events. Chloramphenicol is a moderate-to-strong CYP3A4 inhibitor. While formal drug interaction studies have not been conducted, DM1 is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Cilostazol: (Major) Use caution if coadministration of platelet inhibitors such as cilostazol with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anti-platelet therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Ciprofloxacin: (Major) Avoid concomitant use of ado-trastuzumab emtansine with ciprofloxacin, as plasma exposure to the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, may be increased. Treatment with ado-trastuzumab emtansine should be delayed until ciprofloxacin is cleared from the circulation (approximately 3 elimination half-lives), or an alternate medication with less potential to inhibit CYP3A4 should be considered. If co-administration is necessary, monitor for an increase in ado-trastuzumab emtansine-related adverse events. Ciprofloxacin is a moderate CYP3A4 inhibitor. While formal drug interaction studies have not been conducted, DM1 is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Clarithromycin: (Major) Avoid concomitant use of ado-trastuzumab emtansine with clarithromycin, as plasma exposure to the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, may be increased. Treatment with ado-trastuzumab emtansine should be delayed until clarithromycin is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered. If co-administration is necessary, monitor for an increase in ado-trastuzumab emtansine-related adverse events. Clarithromycin is a strong CYP3A4 inhibitor. When a single dose of another CYP3A4 substrate, midazolam, was coadministered with 7 days of clarithromycin, the AUC of IV midazolam increased by 174% and PO midazolam by 600%. While formal drug interaction studies have not been conducted, DM1 is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Clopidogrel: (Major) Use caution if coadministration of platelet inhibitors such as clopidogrel with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anti-platelet therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Conivaptan: (Major) Avoid concomitant use of ado-trastuzumab emtansine with conivaptan, as plasma exposure to the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, may be increased. Treatment with ado-trastuzumab emtansine should be delayed until no sooner than 1 week after the infusion of conivaptan is complete, or an alternate medication with less potential to inhibit CYP3A4 should be considered. If co-administration is necessary, monitor for an increase in ado-trastuzumab emtansine-related adverse events. Conivaptan is a strong CYP3A4 inhibitor; conivaptan (40 mg/day IV) increases the mean AUC values of midazolam by approximately 2-fold and 3-fold when coadministered with midazolam 1 mg IV or 2 mg PO, respectively.. While formal drug interaction studies have not been conducted, DM1 is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Dabigatran: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Dalfopristin; Quinupristin: (Major) Avoid concomitant use of ado-trastuzumab emtansine with dalfopristin; quinupristin, as plasma exposure to the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, may be increased. Treatment with ado-trastuzumab emtansine should be delayed until dalfopristin; quinupristin is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered. If co-administration is necessary, monitor for an increase in ado-trastuzumab emtansine-related adverse events. Quinupristin is a strong CYP3A4 inhibitor; the AUC of another CYP3A4 substrate, midazolam, was increased by 33% when coadministered with dalfopristin; quinupristin). While formal drug interaction studies have not been conducted, DM1 is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Dalteparin: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Danaparoid: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Darunavir: (Severe) Darunavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use darunavir concomitantly with ado-trastuzumab emtansine. Darunavir is a strong CYP3A4 inhibitor. Although formal drug interactions have not been completed, the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, is primarily metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro, and has been associated with hepatotoxicity, interstitial lung disease (ILD) / pneumonitis, and severe bleeding events. Treatment with ado-trastuzumab emtansine should be delayed until darunavir is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered.
    Darunavir; Cobicistat: (Severe) Darunavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use darunavir concomitantly with ado-trastuzumab emtansine. Darunavir is a strong CYP3A4 inhibitor. Although formal drug interactions have not been completed, the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, is primarily metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro, and has been associated with hepatotoxicity, interstitial lung disease (ILD) / pneumonitis, and severe bleeding events. Treatment with ado-trastuzumab emtansine should be delayed until darunavir is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Severe) Ritonavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use ritonavir concomitantly with ado-trastuzumab emtansine. Ritonavir is a strong CYP3A4 inhibitor. Although formal drug interactions have not been completed, the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, is primarily metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro, and has been associated with hepatotoxicity, interstitial lung disease (ILD) / pneumonitis, and severe bleeding events. Treatment with ado-trastuzumab emtansine should be delayed until ritonavir is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered.
    Delavirdine: (Severe) Delavirdine is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use delavirdine concomitantly with ado-trastuzumab emtansine. Delavirdine is a strong CYP3A4 inhibitor. Although formal drug interactions have not been completed, the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, is primarily metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro, and has been associated with hepatotoxicity, interstitial lung disease (ILD) / pneumonitis, and severe bleeding events. Treatment with ado-trastuzumab emtansine should be delayed until delavirdine is cleared from the circulation (approximately 1 week) or an alternate medication with less potential to inhibit CYP3A4 should be considered.
    Desirudin: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Dipyridamole: (Major) Use caution if coadministration of anticoagulants such as dipyridamole with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Edoxaban: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Enoxaparin: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Eptifibatide: (Major) Use caution if coadministration of platelet inhibitors such as eptifibatide with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anti-platelet therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Fluvoxamine: (Moderate) If coadministration is necessary, monitor for an increase in ado-trastuzumab emtansine-related adverse events. Fluvoxamine is a moderate CYP3A4 inhibitor and plasma exposure to DM1, the cytotoxic small molecule of ado-trastuzumab emtansine, may be increased. While formal drug interaction studies have not been conducted, DM1 is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Fondaparinux: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Fosamprenavir: (Severe) Fosamprenavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use fosamprenavir concomitantly with ado-trastuzumab emtansine. Fosamprenavir is a strong CYP3A4 inhibitor. Although formal drug interactions have not been completed, the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, is primarily metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro, and has been associated with hepatotoxicity, interstitial lung disease (ILD) / pneumonitis, and severe bleeding events. Treatment with ado-trastuzumab emtansine should be delayed until fosamprenavir is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered.
    Grapefruit juice: (Major) Avoid concomitant use of ado-trastuzumab emtansine with grapefruit juice, as plasma exposure to the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, may be increased. Treatment with ado-trastuzumab emtansine should be delayed until grapefruit juice is cleared from the circulation (approximately 3 elimination half-lives), or an alternate medication with less potential to inhibit CYP3A4 should be considered. If co-administration is necessary, monitor for an increase in ado-trastuzumab emtansine-related adverse events. Grapefruit juice is a moderate-to-strong CYP3A4 inhibitor. While formal drug interaction studies have not been conducted, DM1 is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Heparin: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Idelalisib: (Major) Avoid concomitant use of ado-trastuzumab emtansine with idelalisib, as plasma exposure to the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, may be increased. Treatment with ado-trastuzumab emtansine should be delayed until idelalisib is cleared from the circulation (approximately 3 elimination half-lives), or an alternate medication with less potential to inhibit CYP3A4 should be considered. If co-administration is necessary, monitor for an increase in ado-trastuzumab emtansine-related adverse events. Idelalisib is a strong CYP3A4 inhibitor; the Cmax of another sensitive CYP3A4 substrate, midazolam, was increased by 2.4-fold and the AUC by 5.4-fold when coadministered with idelalisib. While formal drug interaction studies have not been conducted, DM1 is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Indinavir: (Major) Avoid concomitant use of ado-trastuzumab emtansine with indinavir, as plasma exposure to the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, may be increased. Treatment with ado-trastuzumab emtansine should be delayed until indinavir is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered. If co-administration is necessary, monitor for an increase in ado-trastuzumab emtansine-related adverse events. Indinavir is a strong CYP3A4 inhibitor. While formal drug interaction studies have not been conducted, DM1 is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Isoniazid, INH: (Moderate) Use caution if isoniazid, INH is coadministered with ado-trastuzumab emtansine, and monitor for an increase in ado-trastuzumab emtansine-related adverse events. Isoniazid is a CYP3A4 inhibitor in vitro. While formal drug interaction studies have not been conducted, the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Use caution if isoniazid, INH is coadministered with ado-trastuzumab emtansine, and monitor for an increase in ado-trastuzumab emtansine-related adverse events. Isoniazid is a CYP3A4 inhibitor in vitro. While formal drug interaction studies have not been conducted, the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Isoniazid, INH; Rifampin: (Moderate) Use caution if isoniazid, INH is coadministered with ado-trastuzumab emtansine, and monitor for an increase in ado-trastuzumab emtansine-related adverse events. Isoniazid is a CYP3A4 inhibitor in vitro. While formal drug interaction studies have not been conducted, the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Itraconazole: (Major) Avoid concomitant use of ado-trastuzumab emtansine with itraconazole, as plasma exposure to the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, may be increased. Treatment with ado-trastuzumab emtansine should be delayed until itraconazole is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered. If co-administration is necessary, monitor for an increase in ado-trastuzumab emtansine-related adverse events. Itraconazole is a strong CYP3A4 inhibitor. While formal drug interaction studies have not been conducted, DM1 is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Ketoconazole: (Major) Avoid concomitant use of ado-trastuzumab emtansine with ketoconazole, as plasma exposure to the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, may be increased. Treatment with ado-trastuzumab emtansine should be delayed until ketoconazole is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered. If co-administration is necessary, monitor for an increase in ado-trastuzumab emtansine-related adverse events. Ketoconazole is a strong CYP3A4 inhibitor. While formal drug interaction studies have not been conducted, DM1 is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Lepirudin: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Lopinavir; Ritonavir: (Severe) Lopinavir; ritonavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use lopinavir; ritonavir concomitantly with ado-trastuzumab emtansine. Lopinavir and ritonavir are both strong CYP3A4 inhibitors. Although formal drug interactions have not been completed, the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, is primarily metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro, and has been associated with hepatotoxicity, interstitial lung disease (ILD) / pneumonitis, and severe bleeding events. Treatment with ado-trastuzumab emtansine should be delayed until lopinavir; ritonavir is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered. (Severe) Ritonavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use ritonavir concomitantly with ado-trastuzumab emtansine. Ritonavir is a strong CYP3A4 inhibitor. Although formal drug interactions have not been completed, the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, is primarily metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro, and has been associated with hepatotoxicity, interstitial lung disease (ILD) / pneumonitis, and severe bleeding events. Treatment with ado-trastuzumab emtansine should be delayed until ritonavir is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered.
    Nefazodone: (Major) Avoid concomitant use of ado-trastuzumab emtansine, a CYP3A4 substrate, and nefazodone, a strong CYP3A4 inhibitor, as ado-trastuzumab emtansine plasma exposure may be increased.
    Nelfinavir: (Severe) Nelfinavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use nelfinavir concomitantly with ado-trastuzumab emtansine. Nelfinavir is a strong CYP3A4 inhibitor. Although formal drug interactions have not been completed, the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, is primarily metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro, and has been associated with hepatotoxicity, interstitial lung disease (ILD) / pneumonitis, and severe bleeding events. Treatment with ado-trastuzumab emtansine should be delayed until nelfinavir is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered.
    Ombitasvir; Paritaprevir; Ritonavir: (Severe) Ritonavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use ritonavir concomitantly with ado-trastuzumab emtansine. Ritonavir is a strong CYP3A4 inhibitor. Although formal drug interactions have not been completed, the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, is primarily metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro, and has been associated with hepatotoxicity, interstitial lung disease (ILD) / pneumonitis, and severe bleeding events. Treatment with ado-trastuzumab emtansine should be delayed until ritonavir is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered.
    Pentosan: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Posaconazole: (Major) Avoid concomitant use of ado-trastuzumab emtansine with posaconazole, as plasma exposure to the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, may be increased. Treatment with ado-trastuzumab emtansine should be delayed until posaconazole is cleared from the circulation (approximately 3 elimination half-lives), or an alternate medication with less potential to inhibit CYP3A4 should be considered. If co-administration is necessary, monitor for an increase in ado-trastuzumab emtansine-related adverse events. Posaconazole is a strong CYP3A4 inhibitor; coadministration with another CYP3A substrate, midazolam, increased midazolam plasma concentrations by approximately 5-fold. In one study, posaconazole (200 mg and 400 mg PO twice daily for 7 days) coadministered with midazolam (single oral dose) resulted in significant increases in the midazolam Cmax (169% and 138% increase, respectively) and AUC (470% and 397% increase, respectively). In addition, the mean terminal half-life of midazolam was increased from 3 hours to 7 to 11 hours when coadministered with posaconazole. While formal drug interaction studies have not been conducted, DM1 is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Prasugrel: (Major) Use caution if coadministration of platelet inhibitors such as prasugrel with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anti-platelet therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with ado-trastuzumab emtansine is necessary, as the systemic exposure of DM1, the cytotoxic component of ado-trastuzumab emtansine may be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor. While no formal drug-drug interaction studies with ado-trastuzumab emtansine have been conducted, in vitro studies indicate that DM1 is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with ado-trastuzumab emtansine is necessary, as the systemic exposure of DM1, the cytotoxic component of ado-trastuzumab emtansine may be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor. While no formal drug-drug interaction studies with ado-trastuzumab emtansine have been conducted, in vitro studies indicate that DM1 is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5.
    Ritonavir: (Severe) Ritonavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use ritonavir concomitantly with ado-trastuzumab emtansine. Ritonavir is a strong CYP3A4 inhibitor. Although formal drug interactions have not been completed, the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, is primarily metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro, and has been associated with hepatotoxicity, interstitial lung disease (ILD) / pneumonitis, and severe bleeding events. Treatment with ado-trastuzumab emtansine should be delayed until ritonavir is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered.
    Rivaroxaban: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Saquinavir: (Major) Avoid concomitant use of ado-trastuzumab emtansine with saquinavir, as plasma exposure to the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, may be increased. Treatment with ado-trastuzumab emtansine should be delayed until saquinavir is cleared from the circulation (approximately 3 elimination half-lives), or an alternate medication with less potential to inhibit CYP3A4 should be considered. If co-administration is necessary, monitor for an increase in ado-trastuzumab emtansine-related adverse events. Saquinavir is a strong CYP3A4 inhibitor. While formal drug interaction studies have not been conducted, DM1 is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Streptogramins: (Major) Avoid concomitant use of ado-trastuzumab emtansine with dalfopristin; quinupristin, as plasma exposure to the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, may be increased. Treatment with ado-trastuzumab emtansine should be delayed until dalfopristin; quinupristin is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered. If co-administration is necessary, monitor for an increase in ado-trastuzumab emtansine-related adverse events. Quinupristin is a strong CYP3A4 inhibitor; the AUC of another CYP3A4 substrate, midazolam, was increased by 33% when coadministered with dalfopristin; quinupristin). While formal drug interaction studies have not been conducted, DM1 is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Telaprevir: (Major) Avoid concomitant use of ado-trastuzumab emtansine, a CYP3A4 substrate, and telaprevir, a strong CYP3A4 inhibitor, as ado-trastuzumab emtansine plasma exposure may be increased.
    Telithromycin: (Major) Avoid concomitant use of ado-trastuzumab emtansine with telithromycin, as plasma exposure to the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, may be increased. Treatment with ado-trastuzumab emtansine should be delayed until telithromycin is cleared from the circulation (approximately 3 elimination half-lives), or an alternate medication with less potential to inhibit CYP3A4 should be considered. If co-administration is necessary, monitor for an increase in ado-trastuzumab emtansine-related adverse events. Telithromycin is a strong CYP3A4 inhibitor; concomitant administration of telithromycin with another CYP3A substrate, midazolam (IV or oral), resulted in 2- and 6-fold increases, respectively, in the AUC of midazolam. While formal drug interaction studies have not been conducted, DM1 is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and ado-trastuzumab is necessary, as the systemic exposure of ado-trastuzumab may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of ado-trastuzumab. DM-1, the cytotoxic component of ado-trastuzumab, is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Ticagrelor: (Major) Use caution if coadministration of platelet inhibitors such as ticagrelor with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anti-platelet therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Ticlopidine: (Major) Use caution if coadministration of platelet inhibitors such as ticlopidine with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anti-platelet therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Tinzaparin: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Tipranavir: (Severe) Tipranavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use tipranavir concomitantly with ado-trastuzumab emtansine. Tipranavir is a strong CYP3A4 inhibitor. Although formal drug interactions have not been completed, the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, is primarily metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro, and has been associated with hepatotoxicity, interstitial lung disease (ILD) / pneumonitis, and severe bleeding events. Treatment with ado-trastuzumab emtansine should be delayed until tipranavir is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered.
    Tirofiban: (Major) Use caution if coadministration of platelet inhibitors such as tirofiban with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anti-platelet therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Vorapaxar: (Major) Use caution if coadministration of platelet inhibitors such as vorapaxar with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anti-platelet therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Voriconazole: (Major) Avoid concomitant use of ado-trastuzumab emtansine with voriconazole, as plasma exposure to the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, may be increased. Voriconazole and its major metabolite, voriconazole N-oxide, are CYP3A4 inhibitors; however, the inhibitory potential is less with voriconazole than with ketoconazole and itraconazole. While formal drug interaction studies have not been conducted, the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. In healthy male volunteers, voriconazole reduced the clearance of another CYP3A substrate, midazolam (IV) by 72% and prolonged the elimination half-life to about 8 hours in a randomized, crossover study. Voriconazole also increased the Cmax and AUC of oral midazolam by 3.8-fold and 10.3-fold, respectively. There was an increase in the bioavailability of oral midazolam from 31% to 84%. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Warfarin: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.

    PREGNANCY AND LACTATION

    Pregnancy

    Fetal harm may occur if ado-trastuzumab emtansine is administered during pregnancy or within 7 months of conception; monitoring for oligohydramnios is recommended. If oligohydramnios occurs, fetal testing should be done that is appropriate for gestational age and consistent with community standards of care. Pregnancy should be avoided by females taking ado-trastuzumab emtansine during therapy and for 7 months after the last dose; male patients with female partners should use effective contraception during treatment and for 4 months after the last dose. Women who become pregnant during this time frame should be apprised of the potential hazard to the fetus. Encourage these women to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 or visiting http://www.motherpregnancyregistry.com. Healthcare professionals and patients should additionally report the pregnancy to the pregnancy pharmacovigilance program at Genentech (1-888-835-2555). Post-marketing, oligohydramnios and oligohydramnios sequence (manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death) occurred in pregnant women who received trastuzumab alone or in combination with chemotherapy. DM1, the cytotoxic component of ado-trastuzumab emtansine, can cause embryo-fetal toxicity based on its mechanism of action.

    Counsel patients about the reproductive risk and contraception requirements during ado-trastuzumab emtansine treatment. Ado-trastuzumab emtansine can be teratogenic if taken by the mother during pregnancy or within 7 months prior to conception. Females should avoid pregnancy and use effective contraception during and for at least 7 months after treatment; male patients with female partners should use effective contraception during therapy and for 4 months after the last dose. Females of reproductive potential should undergo pregnancy testing prior to initiation of therapy. Women who become pregnant while receiving ado-trastuzumab emtansine or within 7 months of the last dose should be apprised of the potential hazard to the fetus and encouraged to enroll in the MotHER Pregnancy Registry (1-800-690-6720 or www.motherpregnancyregistry.com); additionally, healthcare providers and patients should report ado-trastuzumab emtansine exposure to the pregnancy pharmacovigilance program at Genentech (1-888-835-2555). Because of the potential for genotoxicity or male-mediated teratogenicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment with ado-trastuzumab emtansine and for 4 months following the last dose. Additionally, ado-trastuzumab emtansine may cause impaired fertility or infertility in both males and females; it is unknown whether the effects on fertility are reversible.

    MECHANISM OF ACTION

    Ado-trastuzumab emtansine is a HER2-targeted antibody-drug conjugate. Trastuzumab, a humanized anti-HER2 IgG1 antibody, is joined by a stable linker to DM1, a small molecule microtubule inhibitor. The stable linker is designed to keep DM1 attached to trastuzumab until taken up by a HER2-positive cell. 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. Once inside the cell, DM1 binds to tubulin, disrupting the microtubule networks in the cell and resulting in apoptosis. 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.

    PHARMACOKINETICS

    Ado-trastuzumab emtansine is administered by intravenous (IV) injection. In data from a phase 1 study and a population pharmacokinetic analysis using pooled data from 5 trials in patients with breast cancer, ado-trastuzumab emtansine exhibited a linear two-compartment model with first-order elimination from the central compartment. The volume of distribution (Vd) was 3.13 liters.
    In vitro studies indicate that DM1 is 93% bound to plasma proteins. Ado-trastuzumab emtansine catabolites have been detected at low levels in human plasma, including MCC-DM1, Lys-MCC-DM1, and DM1. Ado-trastuzumab emtansine clearance is 0.68 L/day, with an elimination half-life of approximately 4 days. There was no accumulation after repeated dosing every 3 weeks.
    Clearance of ado-trastuzumab emtansine is affected by body weight, sum of longest diameter of target lesions by RECIST, HER2 extracellular domain concentrations, AST, albumin, and baseline trastuzumab concentrations. However, only body weight is likely to have a clinically meaningful effect on ado-trastuzumab emtansine exposure.
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4/5, P-glycoprotein (P-gp)
    Formal drug interaction studies have not been conducted with ado-trastuzumab emtansine. However, in vitro, the cytotoxic small molecule component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; DM1 is also a substrate of P-gp in vitro. DM1 does not inhibit or induce major CYP450 enzymes in vitro.

    Intravenous Route

    After IV administration, maximum concentrations (Cmax) of the ado-trastuzumab emtansine antibody-drug conjugate (ADC) are typically observed close to the end of the infusion. The mean (standard deviation) Cmax of the ADC during cycle 1 was 83.4 (16.5) micrograms/mL, and for DM1 was 4.61 (1.61) ng/mL.