Ado-trastuzumab emtansine is a HER2-targeted antibody-drug conjugate (ADC) that contains the humanized anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitory drug, DM1 (a derivative of maytansine) by a stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate). Emtansine refers to the MCC-DM1 conjugate. It is indicated for the adjuvant treatment of patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant taxane and trastuzumab-based therapy, as well as for the treatment of patients with HER2-positive, metastatic breast cancer who have previously received trastuzumab and a taxane, either separately or in combination. Before treatment with ado-trastuzumab emtansine, patients should have either received prior therapy for metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy. Do not substitute ado-trastuzumab emtansine for or with other trastuzumab-based products.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-NIOSH (Draft) 2020 List: Table 1
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Emetic Risk
-Low
-Administer routine antiemetic prophylaxis prior to treatment.
Route-Specific 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 other trastuzumab-based 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.
Nausea is the most frequently reported upper gastrointestinal (GI) adverse reaction in breast cancer patients treated with ado-trastuzumab emtansine (n = 1,230), occurring in 40% to 42% (grade 3 or 4, 0.5% to 0.8%) of patients in 2 randomized clinical trials; comparatively, 13% (grade 3 or 4, 0.3%) of early breast cancer patients who received trastuzumab reported nausea in one of these trials (n = 720). Other upper GI adverse reactions occur less frequently with ado-trastuzumab emtansine, but grade 1 or 2 GI adverse reactions are similarly more common in patients treated with ado-trastuzumab emtansine compared to trastuzumab in the clinical trials mentioned above including vomiting (15% to 19% vs. 5%; grade 3 or 4, 0.5% to 0.8% vs. 0.3%), stomatitis (14% to 15% vs. 8%; grade 3 or 4, 0.1% to 0.2% vs. 0.1%), and xerostomia (14% to 17% vs. 1.3%; grade 3 or 4, 0.1% or less vs. 0%). Dyspepsia (4.3% to 9%) and dysgeusia (8%) were also reported in clinical trials.
Constipation (17% vs. 8%; grade 3 or 4, 0.1% vs. 0%) and abdominal pain (11% vs. 7%; grade 3 or 4, 0.4% vs. 0.3%) occurred slightly more often in patients with early breast cancer treated with ado-trastuzumab emtansine (n = 740) compared with trastuzumab (n = 720) in a randomized clinical trial; the incidence of diarrhea was similar between arms (12% vs. 13%; grade 3 or 4, 0.8% vs. 0.3%). In another randomized clinical trial of metastatic breast cancer patients treated with ado-trastuzumab emtansine (n = 490), mostly grade 1 or 2 lower GI adverse reactions occurred with a higher incidence than in the previously mentioned trial of patients with early breast cancer including constipation (27%; grade 3 or 4, 0.4%), diarrhea (24%; grade 3 or 4, 1.6%), and abdominal pain (19%; grade 3 or 4, 0.8%).
Thrombocytopenia has been reported in 29% to 31% (grade 3 or higher, 6% to 15%) of breast cancer patients treated with ado-trastuzumab emtansine in 2 randomized clinical trials (n = 1,230), with a nadir generally occurring by day 8 and improving to grade 1 or less (75,000 cells/mm3 or more) by the next scheduled dose. Comparatively, thrombocytopenia occurred in 2.4% (grade 3 or higher, 0.3%) of patients with early breast cancer treated with trastuzumab in one of these trials (n = 720). The incidence and severity of thrombocytopenia are higher in Asian patients both with early breast cancer (50% or less; grade 3 or higher, 19%) and metastatic breast cancer (grade 3 or higher, 45%; n = 490) who received ado-trastuzumab emtansine. Anemia (10% to 14%; grade 3 or 4, 1.1% to 4.1%) and neutropenia (7% to 8%) have also been reported in breast cancer patients who received ado-trastuzumab emtansine. The incidences of hematologic adverse reactions are higher when reported as selected laboratory abnormalities in these clinical trials. Decreased platelet count (83% vs. 51%; grade 3 or 4, 17% vs. 6%), decreased hemoglobin (60% vs. 31%; grade 3 or 4, 5% vs. 1%), and decreased neutrophils (39% vs. 24%; grade 3 or 4, 3.6% vs. 1%) were reported more often in patients with metastatic breast cancer who received ado-trastuzumab emtansine than in a patients with early breast cancer in separate randomized clinical trials. Monitor platelet counts; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if thrombocytopenia occurs.
Cardiotoxicity, (e.g., a decrease in left ventricular ejection fraction (LVEF) to less than 40%), has been reported in patients treated with ado-trastuzumab in clinical trials; serious cases of heart failure, with no fatal cases, have also been reported. Left ventricular dysfunction occurred in 0.4% to 3% of breast cancer patients treated with ado-trastuzumab emtansine in 2 randomized clinical trials. Based on limited data from a retrospective observational study (n = 32), 22% of patients with HER2-positive metastatic breast cancer with a baseline LVEF of 40% to 49% developed congestive heart failure or more than a 10% decrease in LVEF after treatment with ado-trastuzumab emtansine. Monitor LVEF prior to treatment and at regular intervals during treatment; an interruption or discontinuation of therapy may be necessary. Peripheral edema also occurred in 3.9% to 7% of patients who received ado-trastuzumab in clinical trials.
Hypertension occurred in 5% to 6% of breast cancer patients treated with ado-trastuzumab emtansine (n = 1,230) in 2 randomized clinical trials; grade 3 or higher hypertension was reported in greater than 2% of patients with early breast cancer (n = 740).
Ophthalmic adverse reactions have been reported in breast cancer patients treated with ado-trastuzumab emtansine (n = 1,230) in 2 randomized clinical trials, including increased lacrimation (3.3% to 6%), xerophthalmia (3.9% to 4.5%), blurred vision (3.9% to 4.5%), and conjunctivitis (3.5% to 3.9%).
Hepatotoxicity, primarily as asymptomatic, transiently elevated hepatic enzymes but also as severe as hepatic failure, has been observed in clinical trials with ado-trastuzumab emtansine (n = 1,624); 3 patients with metastatic breast cancer developed fatal hepatotoxicity, including severe drug-induced liver injury and associated hepatic encephalopathy. Increased transaminases (e.g., AST, ALT, GGT, abnormal liver function) were reported as an adverse reaction in 29% to 32% (grade 3 or 4, 1.5% to 8%) and increased alkaline phosphatase in 4.7% to 8% of breast cancer patients treated with ado-trastuzumab emtansine in clinical trials; hyperbilirubinemia was also reported in 7% of patients with early breast cancer who received ado-trastuzumab emtansine (n = 740). The incidence of increased AST (79% vs. 21%; grade 3, 0.8% vs. 0.1%), increased ALT (55% vs. 21%; grade 3, 0.7% vs. 0.1%), and hyperbilirubinemia (12% vs. 4%; grade 3, 0% vs. 0.7%) were higher in patients with early breast cancer treated with ado-trastuzumab emtansine (n = 740) compared with trastuzumab (n = 720) in a randomized clinical trial. These occurrences were slightly higher in patients with metastatic breast cancer who received ado-trastuzumab emtansine in another clinical trial, including increased AST (98%; grade 3 or 4, 7.5%), increased ALT (82%; grade 3 or 4, 5.2%), and hyperbilirubinemia (17%; grade 3, 0.6%). Monitor liver function tests; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for hepatotoxicity.
Nodular regenerative hyperplasia (NRH), characterized by a widespread benign transformation of hepatic parenchyma into small regenerative nodules, was identified from liver biopsies of 5 patients (0.3%) treated with ado-trastuzumab emtansine in clinical trials (n = 1,684), one of whom died. Of the 4 patients who survived, 2 had early breast cancer and 2 had metastatic breast cancer. Nodular regenerative hyperplasia may lead to non-cirrhotic portal hypertension; portal hypertension was reported in 0.4% of patients with metastatic breast cancer who received ado-trastuzumab emtansine (n = 490) in one clinical trial. Consider a diagnosis of NRH in all patients with clinical symptoms of portal hypertension and/or a cirrhosis-like pattern seen on a CT scan of the liver, but with normal transaminases and no other manifestations of cirrhosis. Permanently discontinue ado-trastuzumab emtansine if NRH is diagnosed.
Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratory distress syndrome (ARDS) or fatal outcome have been reported with ado-trastuzumab emtansine treatment in clinical trials; signs and symptoms include dyspnea, cough, fatigue, and pulmonary infiltrates. Pneumonitis occurred in 0.8% to 1.2% (grade 3 or 4, 0.1%) of breast cancer patients treated with ado-trastuzumab in 2 randomized clinical trials. In patients with early breast cancer, radiation pneumonitis was reported in 1.5% to 1.8% (grade 3 or 4, 0.3%) of patients treated with ado-trastuzumab emtansine. An interruption or discontinuation of therapy may be necessary for ILD/pneumonitis. Cough (14% to 18%; grade 3 or 4, 0.1% to 0.2%) and dyspnea (8% to 12%; grade 3 or 4, 0.8% or less) have also been reported.
Fever was reported in 10% to 19% of breast cancer patients treated with ado-trastuzumab emtansine (n = 1,230) in 2 randomized clinical trials). Additionally, 9% to 10% (grade 3 or 4, 0.3% or less) of patients reported a urinary tract infection or cystitis, and 5% to 8% reported chills.
Infusion-related reactions, characterized by flushing, chills, fever, dyspnea, hypotension, wheezing, bronchospasm, and/or sinus tachycardia, have been reported in 1.4% to 1.6% of breast cancer patients treated with ado-trastuzumab emtansine in 2 randomized clinical trials. These reactions resolved over the course of several hours to a day after the infusion was terminated in most patients, although there was one case of serious hypersensitivity/anaphylactoid reactions reported. Slow or interrupt the infusion rate of ado-trastuzumab emtansine if an infusion-related reaction occurs; permanently discontinue therapy if the reaction is life-threatening. Ado-trastuzumab hypersensitivity was reported in 2.2% to 2.7% of patients.
Antibody formation has been reported after ado-trastuzumab therapy. Following ado-trastuzumab emtansine administration in several clinical trials (n = 1,243), 3.7% to 6.4% of patients tested positive for anti-drug antibodies. Neutralizing antibodies have been identified in 1.2% to 2.8% of patients in two randomized clinical trials. 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.
Musculoskeletal pain, including muscle spasms (muscle cramps), musculoskeletal chest pain, back pain, pain in extremities, and bone pain, was reported in 30% to 36% (grade 3 or 4, 0.7% to 1.8%) of breast cancer patients treated with ado-trastuzumab emtansine (n = 1,230) in 2 randomized clinical trials. Additionally, myalgia (14% to 15%; grade 3 or 4, 0.4% to 0.6%) and arthralgia (19% to 26%; grade 3 or 4, 0.1% to 0.6%) have been reported.
Peripheral neuropathy, predominantly sensory but including peripheral motor neuropathy and paresthesias, has been reported in 26.7% (grade 3 or higher, 1.6%) of patients treated with ado-trastuzumab emtansine in clinical trials (n = 1,624). The incidence was similar in patients with early breast cancer (n = 740) compared to those with metastatic breast cancer (n = 490) in separate randomized clinical trials (32% vs. 21%; grade 3 or higher, 1.6% vs. 2.2%). Comparatively, 17% (grade 3 or higher, 0.1%) of patients with early breast cancer who received trastuzumab (n = 720) reported peripheral neuropathy in one of these 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.
Hypokalemia was reported in 7% to 10% (grade 3 or 4, 2.7%) of breast cancer patients treated with ado-trastuzumab emtansine (n = 1,230) in 2 randomized clinical trials. As an abnormal laboratory parameter, decreased potassium was reported in 26% to 33% (grade 3 or 4, 2.5% to 3%) of patients who received ado-trastuzumab emtansine. Comparatively, decreased potassium occurred in 9% (grade 3 or 4, 0.8%) of early breast cancer patients who received trastuzumab (n = 720) in one of these trials.
A mild rash (1.1% to 12%) and pruritus (6% to 7%) have been reported in breast cancer patients treated with ado-trastuzumab emtansine (n = 1,230) in 2 randomized clinical trials.
An injection site reaction secondary to extravasation has 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; skin necrosis/tissue necrosis after extravasation has been reported in postmarketing experience. Specific treatment for an extravasation of ado-trastuzumab is unknown. Closely monitor the infusion site for possible subcutaneous infiltration during administration.
Cases of bleeding and serious hemorrhagic events including intracranial bleeding, pulmonary hemorrhage, and GI bleeding, have been reported with ado-trastuzumab emtansine treatment in clinical trials; some events have had fatal outcomes. Hemorrhage occurred in 29% to 32% (grade 3 or higher, 0.4% to 1.8%) of breast cancer patients treated with ado-trastuzumab emtansine in 2 randomized clinical trials (n = 1,230); in one of these trials, hemorrhage occurred in 10% (grade 3 or higher, 0.3%) of patients with early breast cancer who received trastuzumab (n = 720). Epistaxis has additionally occurred in 22% to 23% (grade 3 or 4, 0.2% or less) of breast cancer patients treated with ado-trastuzumab emtansine.
Cases of oligohydramnios and oligohydramnios sequence resulting in teratogenesis (e.g., pulmonary hypoplasia and skeletal abnormalities) and neonatal death has been reported in postmarketing surveillance of trastuzumab, either alone or in combination with chemotherapy. In some case reports, the amniotic fluid index increased after trastuzumab was stopped; in one case, trastuzumab therapy resumed after amniotic index improved, and oligohydramnios recurred. Additionally, DM1, the cytotoxic component of ado-trastuzumab emtansine, can cause embryo-fetal toxicity based on its mechanism of action. If oligohydramnios occurs, perform fetal testing appropriate for gestational age and consistent with community standards of care.
Tumor lysis syndrome (TLS) has been reported in postmarketing experience with ado-trastuzumab emtansine.
Headache (28%; grade 3 or 4, 0.8% or less), dizziness (10%; grade 3 or 4, 0.1% to 0.4%), and insomnia (12% to 14%; grade 3 or 4, 0.4% or less) have been reported in breast cancer patients treated with ado-trastuzumab emtansine (n = 1,230) in 2 randomized clinical trials.
Fatigue was reported more often in patients with early breast cancer who received ado-trastuzumab emtansine (n = 740) compared with trastuzumab (n = 720) in a randomized clinical trial (50% vs. 34%; grade 3 or 4, 1.1% vs. 0.1%); asthenia was additionally reported in 0.4% of patients who received ado-trastuzumab emtansine. In a separate randomized clinical trial of patients with metastatic breast cancer, fatigue was reported in 36% (grade 3 or 4, 2.5%) and asthenia in 18% (grade 3 or 4, 0.4%) those who received ado-trastuzumab emtansine (n = 490).
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; the use of ado-trastuzumab emtansine has not been studied in an adequately controlled study in patients with LVEF less than 50%. 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%.
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.
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, 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.
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.
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.
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.
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.
Ado-trastuzumab emtansine has different dosage and administration recommendations than other trastuzumab-based products. Ensure correct formulation selection and dose before preparation and administration.
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.
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.
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.
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.
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 www.fda.gov/CompanionDiagnostics.
-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-based 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.
-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 other trastuzumab-based products. 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.
-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 other trastuzumab-based products. 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.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities:
Interrupt ado-trastuzumab emtansine therapy per specific instructions below. Restart ado-trastuzumab emtansine as appropriate at the following reduced doses:
Starting dose: 3.6 mg/kg IV.
First dose reduction: 3 mg/kg IV.
Second dose reduction: 2.4 mg/kg IV.
Left Ventricular Dysfunction
Early Breast Cancer
-Left ventricular ejection fraction (LVEF) 50% or more: Continue treatment with ado-trastuzumab emtansine.
-LVEF 45% to 49% and decrease is LESS THAN 10% from baseline: Continue treatment with ado-trastuzumab emtansine. Repeat LVEF within 3 weeks.
-LVEF 45% to 49% and decrease is 10% OR MORE from baseline: Do not administer ado-trastuzumab emtansine. Repeat LVEF within 3 weeks. If LVEF remains below 50% and has not recovered to less than 10% from baseline, discontinue ado-trastuzumab emtansine.
-LVEF less than 45%: Do not administer ado-trastuzumab emtansine. Repeat LVEF within 3 weeks. If LVEF below 45% is confirmed, discontinue ado-trastuzumab emtansine.
Metastatic Breast Cancer
-LVEF greater than 45%: Continue treatment with ado-trastuzumab emtansine.
-LVEF 40% to 45%, and decrease is LESS THAN 10% from baseline: Continue treatment with ado-trastuzumab emtansine. Repeat LVEF within 3 weeks.
-LVEF 40% to 45% and decrease is 10% OR MORE from baseline: Do not administer ado-trastuzumab emtansine. Repeat LVEF within 3 weeks. If LVEF has not recovered to within 10% from baseline, discontinue ado-trastuzumab emtansine.
-LVEF less than 40%: Do not administer ado-trastuzumab emtansine. Repeat LVEF within 3 weeks. If LVEF below 40% is confirmed, discontinue ado-trastuzumab emtansine.
Heart Failure
Early Breast Cancer
-Symptomatic congestive heart failure (CHF), grade 3 or 4 left ventricular systolic dysfunction, grade 3 or 4 CHF, or grade 2 heart failure with LVEF less than 45%: Discontinue ado-trastuzumab emtansine.
Metastatic Breast Cancer
-Symptomatic CHF: Discontinue ado-trastuzumab emtansine.
Infusion-Related Reactions
-Slow or interrupt the infusion rate of ado-trastuzumab emtansine if an infusion-related reaction occurs; treat with supportive care as necessary. Permanently discontinue treatment if the reaction is life-threatening.
Peripheral Neuropathy
-Grade 3 to 4: Do not administer ado-trastuzumab emtansine. When peripheral neuropathy resolves to grade 2 or less, resume therapy.
Pulmonary Toxicity
-Interstitial lung disease(ILD)/pneumonitis (any grade): Permanently discontinue ado-trastuzumab emtansine.
-Grade 2 radiation-related pneumonitis in patients with early breast cancer: Treat according to standard medical therapy. Discontinue ado-trastuzumab emtansine if pneumonitis does not resolve with standard treatment.
-Grade 3 to 4 radiation-related pneumonitis in patients with early breast cancer: Discontinue ado-trastuzumab emtansine.
Thrombocytopenia
Early Breast Cancer
-Grade 2 to 3 (platelets 25,000 to 74,999 cells/mm3) on day of scheduled treatment: Do not administer ado-trastuzumab emtansine. When platelet count recovers to grade 1 or less (75,000 cells/mm3 or more), resume treatment at the same dose level. If a patient requires 2 delays due to thrombocytopenia, consider reducing the dose by one level as specified above. Do not re-escalate the dose of ado-trastuzumab emtansine after a dose reduction is made.
-Grade 4 (platelets less than 25,000 cells/mm3): Do not administer ado-trastuzumab emtansine. When platelet count recovers to grade 1 or less (75,000 cells/mm3 or more), reduce the dose of ado-trastuzumab emtansine by one dose level as specified above and resume treatment. Do not re-escalate the dose of ado-trastuzumab emtansine after a dose reduction is made.
Metastatic Breast Cancer
-Grade 3 (25,000 to 49,999 cells/mm3): Do not administer ado-trastuzumab emtansine. When platelet count recovers to grade 1 or less (75,000 cells/mm3 or more), resume therapy at the same dose level. Do not re-escalate the dose of ado-trastuzumab emtansine after a dose reduction is made.
-Grade 4 (less than 25,000 cells/mm3): Do not administer ado-trastuzumab emtansine. When platelet count recovers to grade 1 or less (75,000 cells/mm3 or more), reduce the dose of ado-trastuzumab emtansine by one dose level as specified above and resume treatment.
Maximum Dosage Limits:
-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.
Patients with Hepatic Impairment Dosing
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.
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.
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.
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).
Patients with Renal Impairment Dosing
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.
*non-FDA-approved indication
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.
Acetaminophen; Aspirin: (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.
Acetaminophen; Aspirin; Diphenhydramine: (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.
Adagrasib: (Major) Avoid coadministration of adagrasib 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 adagrasib has cleared from the circulation (approximately 3 half-lives of adagrasib) 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 CYP3A and to a lesser extent by CYP3A5; adagrasib is a strong CYP3A 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; 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; 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; 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.
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.
Butalbital; Aspirin; 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.
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.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
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.
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.
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.
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.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
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.
Lansoprazole; Amoxicillin; 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.
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.
Levoketoconazole: (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.
Lonafarnib: (Major) Avoid coadministration of lonafarnib 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 lonafarnib has cleared from the circulation (approximately 3 half-lives of lonafarnib) 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; lonafarnib is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
Lopinavir; 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.
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.
Nirmatrelvir; 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.
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.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
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.
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.
Tucatinib: (Major) Avoid coadministration of tucatinib 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 tucatinib has cleared from the circulation (approximately 3 half-lives of tucatinib) 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; tucatinib is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
Vonoprazan; Amoxicillin; 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.
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.
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.
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.
-Route-Specific Pharmacokinetics
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).
-Special Populations
Hepatic Impairment
Plasma concentrations of the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, and DM1-containing catabolites (Lys-MCC-DM1 and MCC-DM1) were low and comparable between patients with (Child-Pugh class A, n = 10; Child-Pugh class B, n = 8) and without (n = 10) hepatic impairment after a single dose of ado-trastuzumab emtansine administered to patients with metastatic HER2-positive breast cancer. The AUC of ado-trastuzumab emtansine in cycle 1 is approximately 38% lower in patients with mild (Child-Pugh class A) hepatic impairment compared with patients with normal hepatic function, and 67% lower in patients with moderate (Child-Pugh class B) hepatic impairment. At cycle 3 after repeated dosing, AUCs were similar between groups. Ado-trastuzumab emtansine has not been studied in patients with severe (Child-Pugh class C) hepatic impairment. Based on a population pharmacokinetic analysis, AST levels had a statistically significant effect on the clearance of ado-trastuzumab emtansine; however, the magnitude of effect was unlikely to be clinically meaningful.
Renal Impairment
Based on a population analysis, the pharmacokinetics of ado-trastuzumab emtansine are not affected by mild to moderate renal impairment (CrCl 30 to 89 mL/min, n = 307) as compared to normal renal function (CrCL 90 mL/min or more, n = 361). Data from only one patient with severe renal impairment (CrCl less than 30 mL/min) is available.
Geriatric
Based on population pharmacokinetic analysis, age (less than 65 years, n = 577; 65 to 75 years, n = 78; greater than 75 years, n = 16) does not have a clinically meaningful effect on the pharmacokinetics of ado-trastuzumab emtansine.
Ethnic Differences
Based on population pharmacokinetic analysis, race (Asian patients (n = 73); non-Asian patients (n = 598)) does not have a clinically meaningful effect on the pharmacokinetics of ado-trastuzumab emtansine.
Obesity
Based on a population pharmacokinetic analysis, body weight was the only covariate to likely to have a statistically significant and clinically meaningful effect on the exposure of ado-trastuzumab emtansine.
Other
Based on a population pharmacokinetic analysis, the sum of longest diameter of target lesions by RECIST, HER2 extracellular domain (ECD) concentrations, albumin, and baseline trastuzumab concentrations were identified as having a statistically significant effect on the clearance of ado-trastuzumab emtansine; however, the magnitude of effect on ado-trastuzumab exposure was unlikely to be clinically meaningful.