Version May 2024
Serious hepatotoxicity has been reported, including liver failure and death in patients treated with ado-trastuzumab emtansine. Monitor serum transaminases and bilirubin prior to initiation of ado-trastuzumab emtansine treatment and prior to each ado-trastuzumab emtansine dose. Reduce the dose or discontinue ado-trastuzumab emtansine as appropriate in cases of increased serum transaminases or total bilirubin.
Ado-trastuzumab emtansine administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with ado-trastuzumab emtansine. Withhold treatment for a clinically significant decrease in left ventricular function.
Exposure to ado-trastuzumab emtansine during pregnancy can result in embryo-fetal harm. Advise patients of these risks and the need for effective contraception.
Note: Actively manage modifiable cardiac risk factors (smoking, hypertension, diabetes, dyslipidemia, obesity) before initiating treatment (Ref). Do not substitute ado-trastuzumab emtansine (United States) or trastuzumab emtansine (Canada) for or with fam-trastuzumab deruxtecan, conventional trastuzumab, trastuzumab/hyaluronidase, or pertuzumab/trastuzumab/hyaluronidase; products are different and are NOT interchangeable.
Breast cancer, early, HER2+, adjuvant therapy for residual disease: IV: 3.6 mg/kg every 3 weeks for a total of 14 cycles in the absence of disease recurrence or unacceptable toxicity (Ref); Maximum dose: 3.6 mg/kg.
Breast cancer, metastatic, HER2+: IV: 3.6 mg/kg every 3 weeks until disease progression or unacceptable toxicity (Ref); Maximum dose: 3.6 mg/kg.
Missed or delayed doses: If a planned dose is missed or delayed, administer as soon as possible (at the dose and rate most recently tolerated), do not wait until the next planned cycle. Then adjust schedule to maintain a 3-week interval between doses.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
CrCl ≥30 mL/minute: No dosage adjustment necessary.
CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Hepatic impairment prior to treatment initiation:
Mild to moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary; use with caution.
Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Hepatotoxicity during treatment: Refer to dosage adjustment for toxicity for dose level reductions:
Early breast cancer:
Grades 2 to 3 ALT elevations (>3 to ≤20 times ULN on the day of scheduled treatment): Withhold until ALT recovers to ≤ grade 1, then resume with one dose level reduction.
Grade 2 AST elevations (>3 to ≤5 times ULN on the day of scheduled treatment): Withhold until AST recovers to ≤ grade 1, then resume at the same dose level.
Grade 3 AST elevations (>5 to ≤20 times ULN on the day of scheduled treatment): Withhold until AST recovers to ≤ grade 1, then resume with one dose level reduction.
Grade 4 ALT or AST elevations (>20 times ULN at any time): Discontinue treatment.
Hyperbilirubinemia:
Total bilirubin >1 to ≤2 times ULN on the day of scheduled treatment: Withhold until bilirubin recovers to ≤1 times ULN, then resume with one dose level reduction.
Total bilirubin >2 times ULN at any time: Discontinue treatment.
Metastatic breast cancer:
Grade 2 ALT, AST elevations (>2.5 to ≤5 times ULN): Continue at same dose level.
Grade 3 ALT, AST elevations (>5 to ≤20 times ULN): Withhold until ALT, AST recover to ≤ grade 2, then resume with one dose level reduction.
Grade 4 ALT, AST elevations (>20 times ULN): Discontinue treatment.
Grade 2 hyperbilirubinemia (>1.5 to ≤3 times ULN): Withhold until bilirubin recovers to ≤ grade 1, then resume at the same dose level.
Grade 3 hyperbilirubinemia (>3 to ≤10 times ULN): Withhold until bilirubin recovers to ≤ grade 1, then resume with one dose level reduction.
Grade 4 hyperbilirubinemia (>10 times ULN): Discontinue treatment.
Drug-induced liver injury: ALT, AST >3 times ULN with concomitant total bilirubin >2 times ULN: Permanently discontinue treatment (in the absence of another likely cause for the elevations [eg, metastases or concomitant medication]).
Nodular regenerative hyperplasia (all grades): Early or metastatic breast cancer: Permanently discontinue treatment.
American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2: Utilize patient's actual body weight for calculation of BSA- or weight-based dosing; manage regimen-related toxicities in the same manner as for patients with a BMI <30 kg/m2 (Ref). Note: Per the manufacturer’s labeling, do not re-escalate ado-trastuzumab emtansine dose following a dose reduction.
|
Dose reduction |
Dose level |
|---|---|
|
Starting dose |
3.6 mg/kg |
|
First dose reduction |
3 mg/kg |
|
Second dose reduction |
2.4 mg/kg |
|
Requirement for further dose reduction |
Discontinue treatment |
|
Note: After a dose reduction is implemented, do not re-escalate dose. | |
|
Adverse reaction |
Severity |
Treatment modification |
|---|---|---|
|
a Asymptomatic heart disease: Consider initiating heart failure medications (eg, angiotensin-converting enzyme inhibitors or an angiotensin receptor blocker, and/or beta-blockers) in patients with asymptomatic (stage B) heart disease (ASCO [Armenian 2017], ESC (Lyon 2022]). For mild cardiac dysfunction, continue treatment with close cardiovascular monitoring; for moderate dysfunction, consider continuing treatment with close cardiovascular monitoring - initiation of heart failure medications is recommended; for severe dysfunction, interrupt treatment and utilize a multidisciplinary approach when deciding if/when to restart - initiation of heart failure medications is recommended (ESC [Lyon 2022]). Symptomatic heart disease: Initiate heart failure medications; for mild cardiac dysfunction, consider a multidisciplinary approach for decisions regarding treatment interruption versus continuation; for moderate or severe cardiac dysfunction, interrupt treatment and consider a multidisciplinary approach for decisions regarding treatment reinitiation (ESC [Lyon 2022]). | ||
|
Thrombocytopenia |
Early breast cancer: Grades 2 to 3 thrombocytopenia on scheduled day of treatment (platelets 25,000/mm3 to <75,000/mm3) |
Withhold treatment until platelet count recovers to ≤ grade 1 (platelets ≥75,000/mm3), then resume treatment at the same dose level. If 2 dosage delays are required, consider reducing by 1 dose level. |
|
Metastatic breast cancer: Grade 3 thrombocytopenia (platelets 25,000/mm3 to <50,000/mm3) |
Withhold treatment until platelet count recovers to ≤ grade 1 (platelets ≥75,000/mm3), then resume treatment at the same dose level. | |
|
Grade 4 (platelets <25,000/mm3) at any time |
Withhold treatment until platelet count recovers to ≤ grade 1 (platelets ≥75,000/mm3), then resume treatment with 1 dose level reduction. | |
|
Cardiotoxicitya: Early breast cancer |
Left ventricular ejection fraction (LVEF) ≥50% |
Continue treatment. |
|
LVEF 45% to <50% and decrease is <10% points from baseline |
Continue treatment and repeat LVEF assessment within 3 weeks. | |
|
LVEF 45% to <50% and decrease is ≥10% points from baseline |
Withhold treatment and repeat LVEF assessment within 3 weeks; if repeat LVEF remains <50% and has not recovered to <10% points from baseline, discontinue treatment. | |
|
LVEF <45% |
Withhold treatment and repeat LVEF assessment within 3 weeks; if repeat LVEF <45% is confirmed, discontinue treatment. | |
|
Symptomatic heart failure, grade 3 to 4 left ventricular systolic dysfunction, grade 3 to 4 heart failure, or grade 2 heart failure with LVEF <45% |
Discontinue treatment. | |
|
Cardiotoxicitya: Metastatic breast cancer |
LVEF >45% |
Continue treatment. |
|
LVEF 40% to ≤45% and decrease is <10% points from baseline |
Continue treatment and repeat LVEF assessment within 3 weeks. | |
|
LVEF 40% to ≤45% and decrease is ≥10% points from baseline |
Withhold treatment and repeat LVEF assessment within 3 weeks; if repeat LVEF has not recovered to within 10% points from baseline, discontinue treatment. | |
|
LVEF <40% |
Withhold treatment and repeat LVEF assessment within 3 weeks; if repeat LVEF <40% is confirmed, discontinue treatment. | |
|
Symptomatic heart failure |
Discontinue treatment. | |
|
Infusion-related reaction/hypersensitivity |
Any |
If reaction occurs, decrease infusion rate. Medications for the treatment of reactions should be available for immediate use. |
|
Severe |
Interrupt infusion; permanently discontinue for life-threatening reactions. | |
|
Peripheral neuropathy |
Grade 3 or 4 |
Temporarily discontinue until resolves to ≤ grade 2. |
|
Pulmonary toxicity |
Interstitial lung disease or pneumonitis |
Permanently discontinue. |
|
Radiation therapy-related pneumonitis (adjuvant setting) |
Grade 2 |
Discontinue ado-trastuzumab emtansine if not resolving with standard treatment. |
|
Grade 3 or 4 |
Discontinue treatment. | |
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%:
Dermatologic: Skin rash (1% to 12%)
Gastrointestinal: Abdominal pain (11% to 19%), constipation (17% to 27%), diarrhea (12% to 24%; grades 3/4: ≤2%), nausea (40% to 42%; grades 3/4: <1%), stomatitis (14% to 15%; grades 3/4: <1%), vomiting (15% to 19%; grades 3/4: <1%), xerostomia (14% to 17%)
Hematologic & oncologic: Anemia (10% to 14%; grades 3/4: 1% to 4%), hemorrhage (29% to 32%; grades 3/4: ≤2%), thrombocytopenia (29% to 31%; grades 3/4: 6% to 15%; including patients of Asian descent: grades 3/4: 19% to 45%)
Hepatic: Increased serum alanine aminotransferase (55% to 82%), increased serum aspartate aminotransferase (79% to 98%), increased serum bilirubin (7% to 17%)
Nervous system: Asthenia (≤18%), fatigue (36% to 50%), headache (28%), insomnia (12% to 14%), peripheral neuropathy (21% to 28%; grades 3/4: 2%)
Neuromuscular & skeletal: Arthralgia (19% to 26%), musculoskeletal pain (30% to 36%), myalgia (14% to 15%)
Respiratory: Cough (14% to 18%), dyspnea (8% to 12%), epistaxis (22% to 23%)
Miscellaneous: Fever (10% to 19%)
1% to 10%:
Cardiovascular: Hypertension (5% to 6%), left ventricular dysfunction (2% to 3%), peripheral edema (4% to 7%)
Dermatologic: Pruritus (6% to 7%)
Endocrine & metabolic: Hypokalemia (7% to 10%)
Gastrointestinal: Dysgeusia (8%), dyspepsia (4% to 9%)
Genitourinary: Urinary tract infection (9% to 10%)
Hematologic & oncologic: Neutropenia (7% to 8%)
Hepatic: Increased serum alkaline phosphatase (5% to 8%)
Hypersensitivity: Hypersensitivity reaction (2% to 3%), infusion-related reaction (1% to 2%)
Immunologic: Antibody development (4% to 6%; neutralizing: 1% to 3%)
Nervous system: Chills (5% to 8%), dizziness (10%)
Ophthalmic: Blurred vision (4% to 5%), conjunctivitis (4%), dry eye syndrome (4% to 5%), increased lacrimation (3% to 6%)
Respiratory: Pneumonitis (1%), radiation pneumonitis (2%)
<1%:
Cardiovascular: Portal hypertension (including nodular regenerative hyperplasia)
Hypersensitivity: Nonimmune anaphylaxis
Frequency not defined:
Endocrine: Increased gamma-glutamyl transferase
Hepatic: Hepatic encephalopathy, hepatic failure, hepatotoxicity (including severe hepatoxicity)
Respiratory: Acute respiratory distress syndrome, interstitial pulmonary disease
Postmarketing:
Cardiovascular: Decreased left ventricular ejection fraction, heart failure
Hematologic & oncologic: Tumor lysis syndrome
US labeling: There are no contraindications listed in the manufacturer's labeling.
Canadian labeling: Hypersensitivity to trastuzumab emtansine or any component of the formulation.
Concerns related to adverse effects:
• Bone marrow suppression: Thrombocytopenia may occur (nadir achieved by day 8; generally resolves to ≤ grade 1 by the next scheduled dose), including ≥ grade 3 thrombocytopenia. Rare cases of severe and prolonged (>90 days) ≥ grade 3 thrombocytopenia have been reported; most patients received concurrent therapy with recombinant human thrombopoietin. The incidence of thrombocytopenia was higher in patients of Asian ancestry. Has not been studied in patients with platelets <100,000/mm3 prior to treatment initiation.
• Cardiotoxicity: May result in left ventricular ejection fraction (LVEF) reductions. Serious cases of heart failure have been observed. Ado-trastuzumab emtansine use has not been studied in patients with LVEF <50%, with a history of symptomatic CHF, serious arrhythmia, or recent history (within 6 months) of myocardial infarction, or unstable angina.
• Extravasation reactions: Irritant with vesicant-like properties; avoid extravasation. Local reactions (erythema, irritation, pain, swelling, or tenderness) secondary to extravasation have been noted. These were generally mild and typically occurred within 24 hours of infusion. There is a case report of skin necrosis (delayed) following extravasation (Shafaee 2017). Monitor infusion site during infusion for possible infiltration.
• Hemorrhage: Hemorrhagic events, including central nervous system, respiratory, and gastrointestinal hemorrhage, have been observed; some hemorrhages were fatal. Some events occurred in patients who were receiving anticoagulation or antiplatelet therapy, or in patients with thrombocytopenia, although bleeding also occurred in patients without additional risk factors. Use caution when administering with antiplatelet agents or anticoagulants.
• Hepatotoxicity: Serious hepatotoxicity, including liver failure and death, has been reported. Hepatotoxicity is typically manifested by asymptomatic and transient increases in transaminases, although fatal cases of severe drug-induced liver injury and associated hepatic encephalopathy have occurred; may be confounded by comorbidities or concomitant hepatotoxic medications. All fatal cases occurred in patients with metastatic breast cancer. Use with caution in patients with known active hepatic disease (eg, hepatitis B or C virus). Cases of nodular regenerative hyperplasia (NRH), a rare liver disorder characterized by widespread benign transformation of hepatic parenchyma into small regenerative nodules, have been observed (by biopsy). NRH may lead to noncirrhotic portal hypertension. Consider NRH in patients with clinical symptoms of portal hypertension and/or cirrhosis-like pattern seen on liver CT scan, although without associated transaminase elevations or other manifestations of cirrhosis. Diagnosis of NRH is confirmed only by histopathology.
• Hypersensitivity/infusion-related reactions: Infusion reactions (flushing, chills, fever, bronchospasm, dyspnea, wheezing, hypotension, and/or tachycardia) have been reported. After termination of infusion, these reactions generally resolved within several hours to a day. Medications for the treatment of reactions should be available for immediate use. Serious allergic/anaphylactic reaction was observed (rare). Use is not recommended in patients who had trastuzumab permanently discontinued due to infusion reaction or hypersensitivity (has not been evaluated).
• Peripheral neuropathy: Sensory peripheral neuropathy has been reported, usually grade 1, although grade 3 or higher peripheral neuropathy was also described. In the adjuvant setting, sensory and motor neuropathy were observed, with nearly one-third of cases not yet resolved at study analysis.
• Pulmonary toxicity: Interstitial lung disease, including pneumonitis has been reported; some cases resulted in acute respiratory distress syndrome and/or fatalities. Grade 3 pneumonitis has occurred. Signs and symptoms of pneumonitis include dyspnea, cough, fatigue, and pulmonary infiltrates. Radiation pneumonitis has been reported, including grade 3 toxicity. Patients with dyspnea at rest due to complications of advanced malignancy, comorbidities, or concurrent pulmonary radiation therapy may be at increased risk for pulmonary toxicity.
Special populations:
• Asian ancestry: The incidence of thrombocytopenia was higher in patients of Asian ancestry.
Dosage form specific issues:
• Do not interchange: Ado-trastuzumab emtansine and conventional trastuzumab are NOT interchangeable. Do not substitute. Ado-trastuzumab emtansine is also not interchangeable with fam-trastuzumab deruxtecan, trastuzumab/hyaluronidase, or pertuzumab/trastuzumab/hyaluronidase. Dosing and treatment schedules between ado-trastuzumab emtansine (Kadcyla) and fam-trastuzumab deruxtecan (Enhertu), conventional trastuzumab (Herceptin or trastuzumab biosimilars), trastuzumab/hyaluronidase (Herceptin Hylecta), or pertuzumab/trastuzumab/hyaluronidase (Phesgo) are different; confusion between the products may potentially cause harm to the patient. In Canada, the generic name for Kadcyla is trastuzumab emtansine (without the Ado- prefix) and may be confused with conventional trastuzumab. Verify product label prior to reconstitution and administration to prevent medication errors.
Other warnings/precautions:
• Human epidermal growth factor receptor 2 expression: Patients should be selected for therapy based on an approved companion diagnostic test for human epidermal growth factor receptor 2 (HER2) protein overexpression or HER2 gene amplification in tumor specimens. HER2 testing should be conducted using tests specific for breast cancers and by labs with demonstrated proficiency. Information on approved tests for HER2 testing is available at http://www.fda.gov/CompanionDiagnostics. Improper assay performance (including sub-optimally fixed tissue), failure to use specific reagents, deviation form assay instructions, and failure to include appropriate assay validation controls may lead to unreliable results.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous [preservative free]:
Kadcyla: 100 mg (1 ea); 160 mg (1 ea)
No
Solution (reconstituted) (Kadcyla Intravenous)
100 mg (per each): $4,670.10
160 mg (per each): $7,472.15
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous:
Kadcyla: 160 mg (1 ea)
Kadcyla: 20 mg/mL (5 mL, 8 mL) [contains mouse (murine) and/or hamster protein]
IV: Infuse over 90 minutes (first infusion) or over 30 minutes (subsequent infusions if prior infusions were well tolerated) through a 0.2- or 0.22-micron inline polyethersulfone filter. Do not administer IV push or bolus. Do not administer with other medications.
Monitor patient during infusion for signs of infusion-related reactions (eg, fever, chills); monitor for at least 90 minutes following initial infusion and (if tolerated) for at least 30 minutes following subsequent infusions.
Check label to ensure appropriate product is being administered (ado-trastuzumab emtansine [United States] or trastuzumab emtansine [Canada] and fam-trastuzumab deruxtecan, conventional trastuzumab, trastuzumab/hyaluronidase, or pertuzumab/trastuzumab/hyaluronidase are different products and are NOT interchangeable).
Irritant with vesicant-like properties; avoid extravasation. Ensure proper needle or catheter position prior to administration. Closely monitor infusion site during administration.
Extravasation management: If extravasation occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity.
Hazardous agent (NIOSH 2016 [group 1]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Breast cancer, early: Adjuvant treatment (single agent) of human epidermal growth factor receptor 2 (HER2)-positive early breast cancer in patients with residual invasive disease following neoadjuvant taxane and trastuzumab-based treatment.
Breast cancer, metastatic: Treatment (single agent) of HER2-positive, metastatic breast cancer in patients who previously received trastuzumab and a taxane, separately or in combination, and have either received prior therapy for metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy.
Limitations of use: Patients should be selected for therapy based on an approved companion diagnostic test for HER2 protein overexpression or HER2 gene amplification in tumor specimens.
Ado-trastuzumab emtansine may be confused with fam-trastuzumab deruxtecan, pertuzumab, pertuzumab/trastuzumab/hyaluronidase, trastuzumab, trastuzumab/hyaluronidase.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
In the United States, ado-trastuzumab emtansine (Kadcyla) may be confused with fam-trastuzumab deruxtecan, conventional trastuzumab (Herceptin), trastuzumab/hyaluronidase (Herceptin Hylecta), or pertuzumab/trastuzumab/hyaluronidase (Phesgo); products are not interchangeable.
In Canada, trastuzumab emtansine (Kadcyla) may be confused with conventional trastuzumab (Herceptin); products are not interchangeable.
Substrate of CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Anthracyclines: Ado-Trastuzumab Emtansine may enhance the cardiotoxic effect of Anthracyclines. Management: When possible, patients treated with ado-trastuzumab emtansine should avoid anthracycline-based therapy for up to 7 months after stopping ado-trastuzumab emtansine. Monitor closely for cardiac dysfunction in patients receiving this combination. Risk D: Consider therapy modification
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Chloramphenicol (Systemic): Myelosuppressive Agents may enhance the myelosuppressive effect of Chloramphenicol (Systemic). Risk X: Avoid combination
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase serum concentrations of the active metabolite(s) of Ado-Trastuzumab Emtansine. Specifically, strong CYP3A4 inhibitors may increase concentrations of the cytotoxic DM1 component. Management: Avoid concomitant use of ado-trastuzumab emtansine and strong CYP3A4 inhibitors when possible. Consider alternatives that do not inhibit CYP3A4 or consider administering after CYP3A4 inhibitor discontinuation. Monitor for toxicities if combined. Risk D: Consider therapy modification
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Rozanolixizumab: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
[US Boxed Warning]: Exposure to ado-trastuzumab emtansine during pregnancy can result in embryo-fetal harm. Advise patients of these risks and the need for effective contraception.
Evaluate pregnancy status prior to treatment in patients who could become pregnant; effective contraception should be used during therapy and for 7 months after the last dose of ado-trastuzumab emtansine. Patients with partners who could become pregnant should use effective contraception during therapy and for 4 months after the last dose.
[US Boxed Warning]: Exposure to ado-trastuzumab emtansine during pregnancy can result in embryo-fetal harm. Advise patients of these risks.
Oligohydramnios and oligohydramnios sequence (manifested as pulmonary hypoplasia, skeletal malformations, and neonatal death) were observed following trastuzumab exposure during pregnancy (trastuzumab is the antibody component of ado-trastuzumab emtansine). Monitor for oligohydramnios if trastuzumab exposure occurs during pregnancy or within 7 months prior to conception; conduct appropriate fetal testing if oligohydramnios occurs. Based on the mechanism of action, the DM1 component of the ado-trastuzumab emtansine formulation may also cause fetal harm if administered during pregnancy.
European Society for Medical Oncology guidelines for cancer during pregnancy recommend delaying treatment with HER-2 targeted agents until after delivery in pregnant patients with HER-2 positive disease (ESMO [Peccatori 2013]).
Data collection to monitor pregnancy and infant outcomes following exposure to ado-trastuzumab emtansine is ongoing. If ado-trastuzumab emtansine exposure occurs during pregnancy or within 7 months prior to conception, healthcare providers should report the exposure to the Genentech (888-835-2555).
It is not known if ado-trastuzumab emtansine is present in breast milk.
Endogenous immunoglobulins are found in breast milk. Based on the mechanism of action, the DM1 component of the ado-trastuzumab emtansine formulation may cause serious adverse reactions in a breastfed infant. The manufacturer does not recommend breastfeeding during treatment and for 7 months following the last dose of ado-trastuzumab emtansine.
HER2 expression status; platelet count (at baseline and prior to each dose), transaminases and bilirubin (at baseline and prior to each dose). Verify pregnancy status (prior to treatment initiation in patients who could become pregnant). Evaluate left ventricular function (prior to and at least every 3 months during treatment; more frequently for decreased left ventricular ejection fraction). Monitor infusion site during infusion for possible infiltration; monitor closely for infusion reactions during infusion (especially with the initial infusion) and for 90 minutes after initial infusion and for 30 minutes after subsequent infusions. Monitor for signs and symptoms of bleeding (monitor closely if at bleeding risk due to thrombocytopenia and/or with concomitant anticoagulant or antiplatelet agents), neurotoxicity, including peripheral neuropathy, and/or pulmonary toxicity.
Additional cardiovascular monitoring (guideline recommendations): Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (ASCO [Armenian 2017], ESC [Lyon 2022]). Obtain a baseline echocardiography (transthoracic preferred) and repeat every 3 months during treatment (may reduce to every 4 to 6 months if normal and asymptomatic), assess more frequently if clinically indicated and obtain echocardiography within 12 months after completion; in high- and very high-risk patients, assess troponin and natriuretic peptide at baseline and consider assessing every 2 to 3 cycles, and at 3 and 12 months after completion of therapy; in low- and moderate-risk patients, consider troponin and natriuretic peptide at baseline (post-anthracycline), every 3 months and 12 months after completion of therapy (ESC [Lyon 2022]).
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Ado-trastuzumab emtansine is a HER2-antibody drug conjugate which incorporates the HER2 targeted actions of trastuzumab with the microtubule inhibitor DM1 (a maytansine derivative). The conjugate, which is linked via a stable thioether linker, allows for selective delivery into HER2 overexpressing cells, resulting in cell cycle arrest and apoptosis.
Distribution: Vd: 3.13 L
Protein binding: DM1: 93%
Metabolism: DM1 undergoes hepatic metabolism via CYP3A4/5
Half-life elimination: ~4 days
Time to peak: Near the end of the infusion
Hepatic function impairment: Systemic exposure (AUC) was ~38% and ~67% lower in patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) impairment, respectively, compared to patients with normal hepatic function during cycles 1 and 2 of a 3.6 mg/kg ado-trastuzumab dose.
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