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  • CLASSES

    Monoclonal Antibodies that Target HER2/neu

    BOXED WARNING

    Angina, cardiac arrhythmias, cardiotoxicity, heart failure, myocardial infarction, ventricular dysfunction

    Patients treated with ado-trastuzumab emtansine are at increased risk of developing cardiotoxicity (i.e., left ventricular dysfunction). Assess left ventricular ejection fraction (LVEF) prior to initiation of therapy and at regular intervals (e.g., every 3 months) during treatment. A reduction in LVEF may require a delay in dosage, dose reduction, or permanent discontinuation of therapy. Use ado-trastuzumab emtansine with caution in patients with a history of symptomatic congestive heart failure (CHF), serious cardiac arrhythmias, or a history of myocardial infarction or unstable angina within 6 months of treatment, as these patients were excluded from clinical trials. Ado-trastuzumab emtansine has not been studied in patients with a baseline left ventricular ejection fraction of less than 50%.

    Hepatic disease, hepatitis, hepatotoxicity

    Use ado-trastuzumab emtansine with caution in patients with hepatic disease. Monitor transaminases and bilirubin prior to initiation of therapy and before each dose; an interruption of therapy, dose adjustment, or discontinuation of therapy may be necessary for hepatotoxicity. Patients with known active liver disease (e.g., hepatitis B or hepatitis C) were excluded from clinical trials. Ado-trastuzumab emtansine has not been studied in patients with transaminases greater than 2.5 times the upper limit of normal (ULN) or bilirubin greater than 1.5 times ULN at baseline. Hepatotoxicity (usually in the form of asymptomatic, transient increases in serum transaminases) has been observed in clinical trials with ado-trastuzumab emtansine (n = 1,624); three fatal cases, including severe drug-induced liver injury and associated hepatic encephalopathy, occurred in patients with metastatic breast cancer. Some patients experiencing hepatotoxicity had comorbidities or concomitant medications that also carry a risk of hepatotoxicity. Cases of nodular regenerative hyperplasia (NRH) have also been reported; consider a diagnosis of NRH in all patients with symptoms of portal hypertension and/or a cirrhosis-like pattern seen on CT scan of the liver, but with normal transaminases and no other manifestations of cirrhosis. Permanently discontinue ado-trastuzumab emtansine if a diagnosis of NRH is confirmed.[53295]

    Pregnancy

    Serious fetal harm can occur if ado-trastuzumab emtansine is administered during pregnancy or within 7 months prior to conception. 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. If a woman becomes pregnant during this time frame, inform her of the fetal risks, monitor for oligohydramnios, and immediately report exposure to the pregnancy pharmacovigilance program at Genentech (1-888-835-2555). If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. 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. In addition, DM1, the cytotoxic component of ado-trastuzumab emtansine, can cause embryo-fetal toxicity based on its mechanism of action.[53295]

    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. 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. 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; healthcare providers and patients should report ado-trastuzumab emtansine exposure to the pregnancy pharmacovigilance program at Genentech (1-888-835-2555). 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
    Used for HER2-positive early breast cancer with residual disease after neoadjuvant taxane/trastuzumab, and metastatic breast cancer in patients who have previously received taxane/trastuzumab, either separately or in combination
    Do not substitute for trastuzumab or trastuzumab; hyaluronidase; assess LVEF and hepatic function prior to initiation of therapy and during treatment

    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.
    NOTE: Patients should be selected based on the presence of HER2 protein overexpression or HER2 gene amplification in tumor specimens. Tests should be specific for breast cancers due to differences in breast vs. gastric histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers. Improper assay performance, including use of sub-optimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Information on FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at http://www.fda.gov/CompanionDiagnostics.
    For the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, either separately or in combination.
    NOTE: Patients should have either received prior therapy for metastatic disease, or developed recurrent disease during or within 6 months of completing adjuvant therapy.
    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. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a randomized, multicenter, open-label clinical trial of patients with metastatic breast cancer, treatment with ado-trastuzumab emtansine (n = 495) significantly improved progression-free survival (PFS) (9.6 months vs. 6.4 months) and overall survival (30.9 months vs. 25.1 months) compared with a combination of lapatinib plus capecitabine (n = 496); objective response rate (43.6% vs. 30.8%) and duration of response (12.6 months vs. 6.5 months) were also improved.

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

    3.6 mg/kg IV every 3 weeks. Give the first infusion over 90 minutes; if tolerated, give subsequent infusions over 30 minutes. Do not substitute ado-trastuzumab emtansine for or with trastuzumab. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, open-label, phase 3 clinical trial, ado-trastuzumab emtansine (T-DM1) was non-inferior to trastuzumab plus taxane therapy (TH) in terms of progression-free survival (PFS) for the first-line treatment of HER2-positive advanced breast cancer. Median overall survival was not reached in any group. The median time to decrease in health-related QOL was significantly longer in patients treated with T-DM1 compared with TH. The addition of pertuzumab did not improve outcomes when added to T-DM1.[61497]

    For the adjuvant treatment of HER2-positive early breast cancer in patients with residual invasive disease after neoadjuvant chemotherapy containing a taxane and trastuzumab.
    Intravenous dosage
    Adults

    3.6 mg/kg IV every 3 weeks for 14 cycles, unless there is disease recurrence or unacceptable toxicity. Give the first infusion over 90 minutes; if tolerated, give subsequent infusions over 30 minutes. Do not substitute ado-trastuzumab emtansine for or with other trastuzumab products. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. An open-label, phase 3 clinical trial (KATHERINE trial) was terminated early after showing a significant benefit on invasive disease-free survival with adjuvant treatment with T-DM1 to complete 52 weeks of therapy compared with trastuzumab in patients with early HER2-positive breast cancer and residual disease at the time of surgery after neoadjuvant chemotherapy.[63814]

    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
    Mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment: No dosage adjustment is necessary.
    Severe (Child-Pugh C) hepatic impairment: Ado-trastuzumab emtansine has not been studied in this patient population.
     
    Treatment-Related Hepatotoxicity
     
    Nodular Regenerative Hyperplasia (NRH)
    Permanently discontinue ado-trastuzumab emtansine.[53295]
     
    Hyperbilirubinemia, Early Breast Cancer
    Total bilirubin 1.1 to 2 times the upper limit of normal (ULN) on the day of scheduled treatment: Do not administer ado-trastuzumab emtansine. When total bilirubin recovers to 1 times ULN or less, reduce the dose of ado-trastuzumab emtansine by one dose level (3.6 mg/kg; 3 mg/kg; 2.4 mg/kg) and resume treatment. Do not re-escalate the dose of ado-trastuzumab emtansine after a dose reduction is made.
    Total bilirubin greater than 2 times ULN at any time: Discontinue ado-trastuzumab emtansine.
    Hyperbilirubinemia, Metastatic Breast Cancer
    Grade 2 (total bilirubin 1.6 to 3 times ULN): Do not administer ado-trastuzumab emtansine. When total bilirubin recovers to grade 1 or less, resume treatment at the same dose level.
    Grade 3 (total bilirubin 3.1 to 10 times ULN): Do not administer ado-trastuzumab emtansine. When total bilirubin recovers to grade 1 or less, reduce the dose of ado-trastuzumab emtansine by one dose level (3.6 mg/kg; 3 mg/kg; 2.4 mg/kg) and resume treatment. Do not re-escalate the dose of ado-trastuzumab emtansine after a dose reduction is made.
    Grade 4 (total bilirubin 10.1 or more times ULN): Discontinue ado-trastuzumab emtansine.[53295]
     
    Increased Transaminases, Early Breast Cancer
    Grade 2 increases in AST (3.1 to 5 times ULN) on the scheduled day of treatment: Do not administer ado-trastuzumab emtansine. When AST recovers to grade 1 or less, resume treatment at the same dose.
    Grade 2 increases in ALT (3.1 to 5 times ULN) on the scheduled day of treatment: Do not administer ado-trastuzumab emtansine. When ALT recovers to grade 1 or less, reduce the dose of ado-trastuzumab by one dose level (3.6 mg/kg; 3 mg/kg; 2.4 mg/kg) and resume treatment. Do not re-escalate the dose of ado-trastuzumab emtansine after a dose reduction is made.
    Grade 3 increases in ALT/AST (5.1 to 20 times ULN) on the scheduled day of treatment: Do not administer ado-trastuzumab emtansine. When ALT/AST recovers to grade 1 or less, reduce the dose of ado-trastuzumab by one dose level (3.6 mg/kg; 3 mg/kg; 2.4 mg/kg) and resume treatment. Do not re-escalate the dose of ado-trastuzumab emtansine after a dose reduction is made.
    Grade 4 increases in ALT/AST at any time (greater than 20 times ULN): Discontinue ado-trastuzumab emtansine.
    Increased Transaminases, Metastatic Breast Cancer
    Grade 2 increases in AST/ALT: Continue treatment at the same dose level.
    Grade 3 increases in ALT/AST: Do not administer ado-trastuzumab emtansine. When ALT/AST recovers to grade 2 or less, reduce the dose of ado-trastuzumab by one dose level (3.6 mg/kg; 3 mg/kg; 2.4 mg/kg) and resume treatment. Do not re-escalate the dose of ado-trastuzumab emtansine after a dose reduction is made.
    Grade 4 increases in ALT/AST: Discontinue ado-trastuzumab emtansine.[53295]
     
    Drug-Induced Liver Injury (DILI), Metastatic Breast Cancer
    ALT/AST greater than 3 times ULN and concomitant total bilirubin greater than 2 times ULN: Permanently discontinue ado-trastuzumab emtansine in the absence of another likely cause for the elevation of liver enzymes and bilirubin (e.g., liver metastasis or concomitant medication).[53295]

    Renal Impairment

    Baseline Renal Impairment
    Mild to moderate renal impairment (CrCL 30 to 90 mL/min): No dosage adjustment is necessary.
    Severe renal impairment (CrCL less than 30 mL/min): No dose adjustment can be recommended due to limited data available.[53295]

    ADMINISTRATION

    Injectable Administration

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

    Intravenous Administration

    Do not mix with or administer as an infusion with other IV products.
    Do not substitute ado-trastuzumab emtansine for or with trastuzumab or trastuzumab; hyaluronidase.
    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.[53295]

    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

    Angina, cardiac arrhythmias, cardiotoxicity, heart failure, myocardial infarction, ventricular dysfunction

    Patients treated with ado-trastuzumab emtansine are at increased risk of developing cardiotoxicity (i.e., left ventricular dysfunction). Assess left ventricular ejection fraction (LVEF) prior to initiation of therapy and at regular intervals (e.g., every 3 months) during treatment. A reduction in LVEF may require a delay in dosage, dose reduction, or permanent discontinuation of therapy. Use ado-trastuzumab emtansine with caution in patients with a history of symptomatic congestive heart failure (CHF), serious cardiac arrhythmias, or a history of myocardial infarction or unstable angina within 6 months of treatment, as these patients were excluded from clinical trials. Ado-trastuzumab emtansine has not been studied in patients with a baseline left ventricular ejection fraction of less than 50%.

    Hepatic disease, hepatitis, hepatotoxicity

    Use ado-trastuzumab emtansine with caution in patients with hepatic disease. Monitor transaminases and bilirubin prior to initiation of therapy and before each dose; an interruption of therapy, dose adjustment, or discontinuation of therapy may be necessary for hepatotoxicity. Patients with known active liver disease (e.g., hepatitis B or hepatitis C) were excluded from clinical trials. Ado-trastuzumab emtansine has not been studied in patients with transaminases greater than 2.5 times the upper limit of normal (ULN) or bilirubin greater than 1.5 times ULN at baseline. Hepatotoxicity (usually in the form of asymptomatic, transient increases in serum transaminases) has been observed in clinical trials with ado-trastuzumab emtansine (n = 1,624); three fatal cases, including severe drug-induced liver injury and associated hepatic encephalopathy, occurred in patients with metastatic breast cancer. Some patients experiencing hepatotoxicity had comorbidities or concomitant medications that also carry a risk of hepatotoxicity. Cases of nodular regenerative hyperplasia (NRH) have also been reported; consider a diagnosis of NRH in all patients with symptoms of portal hypertension and/or a cirrhosis-like pattern seen on CT scan of the liver, but with normal transaminases and no other manifestations of cirrhosis. Permanently discontinue ado-trastuzumab emtansine if a diagnosis of NRH is confirmed.[53295]

    Pneumonitis, pulmonary disease, radiation therapy, respiratory distress syndrome, respiratory insufficiency

    Cases of interstitial lung disease (ILD) including pneumonitis, some leading to acute respiratory distress syndrome or death, have been reported with ado-trastuzumab use in clinical trials; signs and symptoms include dyspnea, cough, fatigue, and pulmonary infiltrates. Use ado-trastuzumab emtansine with caution in patients with pulmonary disease at baseline, respiratory insufficiency or dyspnea at rest, and in patients receiving concomitant pulmonary radiation therapy as they may be at increased risk for ILD/pneumonitis. Permanently discontinue treatment with ado-trastuzumab emtansine in patients with ILD or pneumonitis. For patients with radiation pneumonitis in the adjuvant setting, permanently discontinue ado-trastuzumab emtansine if pneumonitis is grade 3 or higher, or grade 2 that is unresponsive to standard treatment.

    Infusion-related reactions

    Infusion-related reactions, characterized by flushing, chills, fever, dyspnea, hypotension, wheezing, bronchospasm, and/or tachycardia, have been reported in patients treated with trastuzumab in clinical trials. Treatment with ado-trastuzumab emtansine is not recommended in patients who had trastuzumab permanently discontinued due to infusion-related reactions and/or hypersensitivity, as it has not been studied in these patients. Closely observe patients for infusion-related reactions, especially during the first infusion; ensure that emergency equipment and medications to treat infusion-related reactions are available for immediate use. Slow or interrupt the infusion rate of ado-trastuzumab emtansine if an infusion-related reaction occurs; permanently discontinue treatment if the reaction is life-threatening.

    Human anti-human antibody (HAHA)

    Antibody formation including human anti-human antibody (HAHA) and neutralizing antibodies have been reported after ado-trastuzumab emtansine therapy. Due to the low incidence of anti-drug antibodies, conclusions cannot be made on the impact of these antibodies on the pharmacokinetics, safety, and efficacy of ado-trastuzumab emtansine. The presence of ado-trastuzumab emtansine in patient serum at the time of sampling may interfere with the ability of this assay to detect anti-ado-trastuzumab emtansine antibodies; as a result, data may not accurately reflect the true incidence.[53295]

    Anticoagulant therapy, bleeding

    Bleeding and serious hemorrhagic events have been reported with ado-trastuzumab treatment in clinical trials, including some that have resulted in death. In some but not all cases, patients were receiving concomitant anticoagulant therapy, antiplatelet therapy, or had low platelet counts; there were no known additional risk factors in other patients. Use ado-trastuzumab emtansine with caution and consider additional monitoring if concomitant anticoagulant therapy or antiplatelet therapy is medically necessary.

    Asian patients, thrombocytopenia

    Thrombocytopenia, usually grade 1 or 2 and recovering before the next scheduled dose, has been reported in patients treated with ado-trastuzumab emtansine in clinical trials; the incidence and severity are higher in Asian patients. Ado-trastuzumab emtansine has not been studied in patients with baseline platelet counts less than 100,000 cells/mm3. Monitor platelet counts at baseline and prior to each dose of ado-trastuzumab emtansine; closely monitor patients with thrombocytopenia (platelets less than 100,000 cells/mm3). An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if thrombocytopenia occurs.[53295]

    Peripheral neuropathy

    Use ado-trastuzumab emtansine with caution in patients with baseline peripheral neuropathy. Peripheral neuropathy, mainly grade 1 and predominantly sensory, has been reported in patients treated with ado-trastuzumab emtansine in clinical trials. Clinically monitor patients on an ongoing basis for signs or symptoms of neurotoxicity. An interruption of therapy is necessary for grade 3 or higher peripheral neuropathy.

    Ensure correct formulation selection

    Ado-trastuzumab emtansine has different dosage and administration recommendations than trastuzumab or trastuzumab; hyaluronidase. Ensure correct formulation selection and dose before preparation and administration.

    Tumor lysis syndrome (TLS)

    Cases of tumor lysis syndrome (TLS) have been reported in patients treated with ado-trastuzumab emtansine. Patients with significant tumor burden (e.g., bulky metastases) may be at higher risk. Patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure (unspecified); consider additional monitoring and/or treatment as clinically indicated.

    Extravasation

    Skin reactions secondary to ado-trastuzumab emtansine extravasation have been observed in clinical trials. These reactions, including erythema, tenderness, skin irritation, pain, or swelling at the infusion site, are typically observed within 24 hours of infusion and are usually mild. Specific treatment for an extravasation of ado-trastuzumab is unknown. Closely monitor the infusion site for possible subcutaneous infiltration during administration.[53295]

    Pregnancy

    Serious fetal harm can occur if ado-trastuzumab emtansine is administered during pregnancy or within 7 months prior to conception. 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. If a woman becomes pregnant during this time frame, inform her of the fetal risks, monitor for oligohydramnios, and immediately report exposure to the pregnancy pharmacovigilance program at Genentech (1-888-835-2555). If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. 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. In addition, DM1, the cytotoxic component of ado-trastuzumab emtansine, can cause embryo-fetal toxicity based on its mechanism of action.[53295]

    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. 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. 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; healthcare providers and patients should report ado-trastuzumab emtansine exposure to the pregnancy pharmacovigilance program at Genentech (1-888-835-2555). 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 / 6.0-45.0
    elevated hepatic enzymes / Delayed / 0.7-8.0
    hypertension / Early / 2.0-6.0
    anemia / Delayed / 1.1-4.1
    hypokalemia / Delayed / 0-2.7
    fatigue / Early / 1.1-2.5
    peripheral neuropathy / Delayed / 1.6-2.2
    musculoskeletal pain / Early / 0.7-1.8
    diarrhea / Early / 0.8-1.6
    anaphylactoid reactions / Rapid / 0-1.0
    abdominal pain / Early / 0.4-0.8
    dyspnea / Early / 0-0.8
    headache / Early / 0-0.8
    hyperbilirubinemia / Delayed / 0-0.6
    myalgia / Early / 0.4-0.6
    arthralgia / Delayed / 0.1-0.6
    constipation / Delayed / 0.1-0.4
    heart failure / Delayed / 0-0.4
    insomnia / Early / 0-0.4
    dizziness / Early / 0.1-0.4
    pneumonitis / Delayed / 0.1-0.3
    infection / Delayed / 0-0.3
    cough / Delayed / 0.1-0.2
    fever / Early / 0-0.2
    pruritus / Rapid / 0.2-0.2
    epistaxis / Delayed / 0-0.2
    xerostomia / Early / 0-0.1
    cardiotoxicity / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    hepatic encephalopathy / Delayed / Incidence not known
    cirrhosis / Delayed / Incidence not known
    acute respiratory distress syndrome (ARDS) / Early / Incidence not known
    bronchospasm / Rapid / Incidence not known
    teratogenesis / Delayed / Incidence not known

    Moderate

    peripheral edema / Delayed / 3.9-7.1
    antibody formation / Delayed / 3.7-6.4
    blurred vision / Early / 3.9-4.5
    conjunctivitis / Delayed / 3.5-3.9
    infusion-related reactions / Rapid / 1.4-1.6
    interstitial lung disease / Delayed / Incidence not known
    cystitis / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    wheezing / Rapid / Incidence not known
    bone pain / Delayed / Incidence not known
    erythema / Early / Incidence not known

    Mild

    asthenia / Delayed / 0.4-17.6
    rash / Early / 1.1-12.0
    chills / Rapid / 5.0-8.0
    lacrimation / Early / 3.3-6.0
    xerophthalmia / Early / 3.9-4.5
    flushing / Rapid / Incidence not known
    back pain / Delayed / Incidence not known
    muscle cramps / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    skin irritation / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) Use caution if coadministration of platelet inhibitors with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Use caution if coadministration of aspirin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of clarithromycin with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until clarithromycin has cleared from the circulation (approximately 3 half-lives of clarithromycin) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; clarithromycin is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of clarithromycin with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until clarithromycin has cleared from the circulation (approximately 3 half-lives of clarithromycin) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; clarithromycin is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Anagrelide: (Moderate) Use caution if coadministration of platelet inhibitors with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Anticoagulants: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Antithrombin III: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Apixaban: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Argatroban: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Aspirin, ASA: (Moderate) Use caution if coadministration of aspirin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Use caution if coadministration of aspirin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Use caution if coadministration of aspirin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Use caution if coadministration of aspirin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Use caution if coadministration of aspirin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors
    Aspirin, ASA; Carisoprodol: (Moderate) Use caution if coadministration of aspirin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Use caution if coadministration of aspirin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Use caution if coadministration of aspirin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors
    Aspirin, ASA; Dipyridamole: (Moderate) Use caution if coadministration of aspirin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors (Moderate) Use caution if coadministration of platelet inhibitors with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Aspirin, ASA; Omeprazole: (Moderate) Use caution if coadministration of aspirin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors
    Aspirin, ASA; Oxycodone: (Moderate) Use caution if coadministration of aspirin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors
    Aspirin, ASA; Pravastatin: (Moderate) Use caution if coadministration of aspirin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors
    Atazanavir: (Major) Avoid coadministration of atazanavir with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until atazanavir has cleared from the circulation (approximately 3 half-lives of atazanavir) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; atazanavir is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of atazanavir with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until atazanavir has cleared from the circulation (approximately 3 half-lives of atazanavir) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; atazanavir is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted. (Major) Avoid coadministration of cobicistat with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until cobicistat has cleared from the circulation (approximately 3 half-lives of cobicistat) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; cobicistat is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Betrixaban: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Bivalirudin: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, 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 if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until ceritinib has cleared from the circulation (approximately 3 half-lives of ceritinib) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; ceritinib is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Chloramphenicol: (Major) Avoid coadministration of chloramphenicol with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until chloramphenicol has cleared from the circulation (approximately 3 half-lives of chloramphenicol) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; chloramphenicol is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Cilostazol: (Moderate) Use caution if coadministration of platelet inhibitors with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, 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 coadministration of clarithromycin with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until clarithromycin has cleared from the circulation (approximately 3 half-lives of clarithromycin) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; clarithromycin is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Clopidogrel: (Moderate) Use caution if coadministration of platelet inhibitors with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, 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.
    Cobicistat: (Major) Avoid coadministration of cobicistat with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until cobicistat has cleared from the circulation (approximately 3 half-lives of cobicistat) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; cobicistat is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Conivaptan: (Major) Avoid coadministration of conivaptan with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until conivaptan has cleared from the circulation (approximately 3 half-lives of conivaptan) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; conivaptan is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Dabigatran: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Dalteparin: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Danaparoid: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Darunavir: (Major) Avoid coadministration of darunavir with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until darunavir has cleared from the circulation (approximately 3 half-lives of darunavir) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; darunavir is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Darunavir; Cobicistat: (Major) Avoid coadministration of cobicistat with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until cobicistat has cleared from the circulation (approximately 3 half-lives of cobicistat) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; cobicistat is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted. (Major) Avoid coadministration of darunavir with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until darunavir has cleared from the circulation (approximately 3 half-lives of darunavir) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; darunavir is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of cobicistat with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until cobicistat has cleared from the circulation (approximately 3 half-lives of cobicistat) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; cobicistat is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted. (Major) Avoid coadministration of darunavir with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until darunavir has cleared from the circulation (approximately 3 half-lives of darunavir) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; darunavir is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of ritonavir with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until ritonavir has cleared from the circulation (approximately 3 half-lives of ritonavir) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; ritonavir is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Delavirdine: (Major) Avoid coadministration of delavirdine with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until delavirdine has cleared from the circulation (approximately 3 half-lives of delavirdine) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; delavirdine is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Desirudin: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Dipyridamole: (Moderate) Use caution if coadministration of platelet inhibitors with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Edoxaban: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of cobicistat with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until cobicistat has cleared from the circulation (approximately 3 half-lives of cobicistat) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; cobicistat is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of cobicistat with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until cobicistat has cleared from the circulation (approximately 3 half-lives of cobicistat) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; cobicistat is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Enoxaparin: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Eptifibatide: (Moderate) Use caution if coadministration of platelet inhibitors with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, 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: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Fosamprenavir: (Major) Avoid coadministration of fosamprenavir with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until fosamprenavir has cleared from the circulation (approximately 3 half-lives of fosamprenavir) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; fosamprenavir is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Grapefruit juice: (Major) Avoid administration of ado-trastuzumab emtansine with grapefruit juice due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; grapefruit juice is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Heparin: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Idelalisib: (Major) Avoid coadministration of idelalisib with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until idelalisib has cleared from the circulation (approximately 3 half-lives of idelalisib) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; idelalisib is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Indinavir: (Major) Avoid coadministration of indinavir with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until indinavir has cleared from the circulation (approximately 3 half-lives of indinavir) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; indinavir is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Itraconazole: (Major) Avoid coadministration of itraconazole with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until itraconazole has cleared from the circulation (approximately 3 half-lives of itraconazole) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; itraconazole is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Ketoconazole: (Major) Avoid coadministration of ketoconazole with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until ketoconazole has cleared from the circulation (approximately 3 half-lives of ketoconazole) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; ketoconazole is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Lepirudin: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Letermovir: (Moderate) Caution is advised when administering ado-trastuzumab with letermovir. If the patient is also receiving cyclosporine, use of ado-trastuzumab should be avoided for 3 half-lives after discontinuation of letermovir and cyclosporine. If these drugs must be administered concurrently, closely monitor for adverse drug reactions. Administering letermovir with ado-trastuzumab may increase ado-trastuzumab concentration and risk for adverse events. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Ado-trastuzumab is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir; ritonavir with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until lopinavir; ritonavir has cleared from the circulation (approximately 3 half-lives of lopinavir; ritonavir) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; lopinavir; ritonavir is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted. (Major) Avoid coadministration of ritonavir with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until ritonavir has cleared from the circulation (approximately 3 half-lives of ritonavir) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; ritonavir is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Mifepristone: (Major) Avoid coadministration of mifepristone with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until mifepristone has cleared from the circulation (approximately 3 half-lives of mifepristone) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; mifepristone is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
    Nefazodone: (Major) Avoid coadministration of nefazodone with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until nefazodone has cleared from the circulation (approximately 3 half-lives of nefazodone) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; nefazodone is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Nelfinavir: (Major) Avoid coadministration of nelfinavir with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until nelfinavir has cleared from the circulation (approximately 3 half-lives of nelfinavir) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; nelfinavir is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of ritonavir with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until ritonavir has cleared from the circulation (approximately 3 half-lives of ritonavir) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; ritonavir is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentosan: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Platelet Inhibitors: (Moderate) Use caution if coadministration of platelet inhibitors with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Posaconazole: (Major) Avoid coadministration of posaconazole with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until posaconazole has cleared from the circulation (approximately 3 half-lives of posaconazole) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; posaconazole is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Prasugrel: (Moderate) Use caution if coadministration of platelet inhibitors with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Ribociclib: (Major) Avoid coadministration of ribociclib with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until ribociclib has cleared from the circulation (approximately 3 half-lives of ribociclib) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; ribociclib is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until ribociclib has cleared from the circulation (approximately 3 half-lives of ribociclib) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; ribociclib is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Ritonavir: (Major) Avoid coadministration of ritonavir with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until ritonavir has cleared from the circulation (approximately 3 half-lives of ritonavir) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; ritonavir is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Rivaroxaban: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Saquinavir: (Major) Avoid coadministration of saquinavir with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until saquinavir has cleared from the circulation (approximately 3 half-lives of saquinavir) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; saquinavir is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    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 coadministration of telithromycin with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until telithromycin has cleared from the circulation (approximately 3 half-lives of telithromycin) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; telithromycin is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    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: (Moderate) Use caution if coadministration of platelet inhibitors with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Ticlopidine: (Moderate) Use caution if coadministration of platelet inhibitors with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Tinzaparin: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Tipranavir: (Major) Avoid coadministration of tipranavir with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until tipranavir has cleared from the circulation (approximately 3 half-lives of tipranavir) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; tipranavir is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Tirofiban: (Moderate) Use caution if coadministration of platelet inhibitors with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Vorapaxar: (Moderate) Use caution if coadministration of platelet inhibitors with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Voriconazole: (Major) Avoid coadministration of voriconazole with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until voriconazole has cleared from the circulation (approximately 3 half-lives of voriconazole) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; voriconazole is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Warfarin: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.

    PREGNANCY AND LACTATION

    Pregnancy

    Serious fetal harm can occur if ado-trastuzumab emtansine is administered during pregnancy or within 7 months prior to conception. 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. If a woman becomes pregnant during this time frame, inform her of the fetal risks, monitor for oligohydramnios, and immediately report exposure to the pregnancy pharmacovigilance program at Genentech (1-888-835-2555). If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. 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. In addition, DM1, the cytotoxic component of ado-trastuzumab emtansine, can cause embryo-fetal toxicity based on its mechanism of action.[53295]

    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.

    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 vitro studies indicate that DM1 is 93% bound to plasma proteins. 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 central volume of distribution (Vd) was 3.13 liters. 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.
     
    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 CYP3A4/5; DM1 is also a substrate of P-gp in vitro. Ado-trastuzumab emtansine catabolites have been detected at low levels in human plasma, including MCC-DM1, Lys-MCC-DM1, and DM1. DM1 does not inhibit or induce major CYP450 enzymes in vitro.[53295]

    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. In patients with metastatic breast cancer, the mean (standard deviation) Cmax of the ADC during cycle 1 was 83.4 (16.5) mcg/mL, and for DM1 was 4.61 (1.61) ng/mL. In patients with early breast cancer, the cycle 1 Cmax of the ADC was 72.6 (24.3) mcg/mL and for DM1 was 4.71 (2.25) mcg/mL. A population pharmacokinetic analysis suggested no difference in ado-trastuzumab emtansine exposure based on disease status (adjuvant vs. metastatic setting).