KADCYLA
Clinical safety rating
cautionComprehensive clinical and safety monograph for KADCYLA (KADCYLA).
Comprehensive clinical and safety monograph for KADCYLA (KADCYLA).
Adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatmentTreatment of patients with HER2-positive metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combinationOff-label: Use in HER2-positive advanced gastric cancer (limited data)
Tiredness, Nausea, Musculoskeletal (bone, muscle or joint) pain, Bleeding, Low blood platelets, Headache, Liver disorder, Constipation, Nosebleeds
KADCYLA (ado-trastuzumab emtansine) is an antibody-drug conjugate composed of trastuzumab, a humanized anti-HER2 antibody, linked to the microtubule inhibitor DM1 (maytansinoid). It binds to HER2 receptors on tumor cells, internalized via receptor-mediated endocytosis, and releases DM1 intracellularly, causing cell cycle arrest and apoptosis.
| Metabolism | DM1 is primarily metabolized by CYP3A4 and to a lesser extent by CYP3A5. |
| Excretion | Primarily hepatic metabolism with biliary excretion; minimal renal elimination (<10% unchanged). |
| Half-life | Terminal half-life approximately 4 days (range 2.8-5.6 days), supporting every-3-week dosing. |
| Protein binding | 93% bound to plasma proteins (trastuzumab component). |
| Volume of Distribution | Approximately 2.58 L/m² (central Vd), indicating limited extravascular distribution. |
| Bioavailability | 100% (intravenous administration only). |
| Onset of Action | Not defined; clinical effect observed at first tumor assessment (typically 6-9 weeks after initiation). |
| Duration of Action | Continuous with repeated dosing; pharmacodynamic effect persists throughout treatment cycles. |
| Molecular Weight | 148506 |
| Action Class | HER2/neu (ErbB2) Inhibitor- Monoclonal antibody |
3.6 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity.
| Dosage form | VIAL |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Safety and efficacy not established in severe renal impairment (CrCl <30 mL/min). |
| Liver impairment | No dose adjustment for mild hepatic impairment (Child-Pugh A). Not recommended for moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment due to lack of data. |
| Pediatric use | Safety and efficacy in pediatric patients have not been established. |
| Geriatric use | No specific dose adjustment recommended for elderly patients. Clinical studies included patients aged ≥65 years, but no overall differences in safety or efficacy were observed. |
| 1st trimester | Ado-trastuzumab emtansine is an IgG1 conjugate that crosses the placenta. Based on its mechanism of action and evidence of trastuzumab-related oligohydramnios and fetal renal toxicity, it should be avoided in the first trimester unless potential benefit justifies potential risk to the fetus. |
| 2nd trimester | Exposure during the second trimester is associated with oligohydramnios, fetal renal impairment, and potential pulmonary hypoplasia. Use only if clearly needed and monitor amniotic fluid volume closely. |
| 3rd trimester | Use in the third trimester carries high risk of severe oligohydramnios, fetal renal failure, and neonatal death. Generally contraindicated; if necessary, monitor with serial ultrasound and consider alternative therapy. |
Clinical note
Comprehensive clinical and safety monograph for KADCYLA (KADCYLA).
| Placental transfer | Ado-trastuzumab emtansine is a large molecule (approximately 148,506 Da) that is an antibody-drug conjugate. Trastuzumab component crosses placenta actively via FcRn receptor; DM1 component likely crosses to a lesser extent but data in humans are limited. Animal studies show placental transfer and fetal toxicity. |
| Breastfeeding | It is not known whether ado-trastuzumab emtansine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from trastuzumab emtansine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. |
| Lactation Rating | L5 (Contraindicated due to potential serious adverse reactions and lack of safety data) |
| Teratogenic Risk | Kadcyla (ado-trastuzumab emtansine) is an antibody-drug conjugate. Trastuzumab component can cause oligohydramnios, fetal renal impairment, and pulmonary hypoplasia when administered during the second and third trimesters. The DM1 component (emtansine) is a microtubule inhibitor with potential embryofetal toxicity. Based on its mechanism and animal studies, there is risk for teratogenicity in the first trimester, including structural anomalies. Avoid use during pregnancy unless benefit outweighs risk; advise effective contraception. |
| Fetal Monitoring | Monitor for oligohydramnios via ultrasound if Kadcyla is used during pregnancy. Assess fetal renal function and amniotic fluid volume. Monitor maternal cardiac function (LVEF) due to trastuzumab component as risk of cardiomyopathy. Monitor for infusion reactions and hepatotoxicity. |
| Fertility Effects | Kadcyla may impair fertility in humans based on findings in animal studies with DM1 (microtubule inhibitor). In female rats, emtansine caused disrupted estrous cycles and reduced ovarian follicular development. Advise patients of potential impact on fertility. |
■ FDA Black Box Warning
WARNING: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY Hepatotoxicity: Severe hepatotoxicity has been observed, including liver failure and death. Monitor liver function tests prior to each dose and as clinically indicated. Cardiac Toxicity: Left ventricular ejection fraction (LVEF) should be assessed prior to initiation and at regular intervals during treatment. Discontinue for clinically significant decline. Embryo-Fetal Toxicity: Exposure during pregnancy can cause embryo-fetal harm. Advise patients of these risks and need for effective contraception.
| Serious Effects |
Hypersensitivity to ado-trastuzumab emtansine or any of its excipientsSevere hepatic impairment (Child-Pugh class C)
| Precautions | Hepatotoxicity: Monitor liver function tests; dose reduction or discontinuation may be required for elevated liver enzymes or bilirubin., Cardiac toxicity: Assess LVEF before and during treatment; discontinue if symptomatic heart failure or significant asymptomatic decline., Pulmonary toxicity: Interstitial lung disease (ILD) including pneumonitis has been reported; monitor for signs/symptoms and discontinue if confirmed., Extravasation: Administer as IV infusion; extravasation may cause tissue necrosis. Ensure proper IV access., Thrombocytopenia: Monitor platelet counts; dose modifications required for grade 3 or 4 thrombocytopenia., Neuropathy: Peripheral neuropathy may occur; monitor and manage accordingly., Embryo-fetal toxicity: Advise of risk and use effective contraception during and 7 months after treatment., Increased intracranial pressure: Cases of reversible posterior leukoencephalopathy syndrome (RPLS) reported; monitor and discontinue if occurs. |
| Food/Dietary | No specific food interactions are known for Kadcyla. However, avoid grapefruit and grapefruit juice as they may inhibit CYP3A4 and potentially increase exposure. Maintain a healthy diet to manage nausea and support overall health. |
| Clinical Pearls | Monitor left ventricular ejection fraction (LVEF) before and during treatment due to risk of cardiotoxicity. Infusion reactions are common; premedicate with antihistamines and corticosteroids. Do not substitute trastuzumab emtansine for trastuzumab or ado-trastuzumab emtansine. Avoid concomitant use with strong CYP3A4 inhibitors or inducers. Monitor for hepatotoxicity and pulmonary toxicity. Dose reduction required for thrombocytopenia or elevated transaminases. |
| Patient Advice | This drug is given as an IV infusion every 3 weeks. It may cause infusion reactions during or shortly after administration; tell your doctor immediately if you experience chills, fever, difficulty breathing, or chest pain. · Kadcyla can cause heart problems; you will have regular heart function tests (echocardiograms) before and during treatment. Report any new shortness of breath, cough, or swelling of ankles/legs. · This medication can cause liver damage; blood tests will be done to monitor liver function. Notify your doctor if you develop yellowing of skin/eyes, dark urine, or abdominal pain. · Kadcyla may lower platelet counts, increasing bleeding risk. Avoid activities that may cause injury or bruising. Report unusual bleeding or bruising. · This drug can cause severe birth defects; use effective contraception during treatment and for at least 7 months after the last dose. Do not breastfeed while taking Kadcyla. · You may experience fatigue, nausea, muscle/joint pain, or headache. Report persistent or severe symptoms to your healthcare provider. |
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