KADCYLA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for KADCYLA (KADCYLA).
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. |
| 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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for KADCYLA (KADCYLA).
| Breastfeeding | It is not known whether Kadcyla is excreted in human milk. Due to the potential for serious adverse reactions in nursing infants, including tumorigenicity and developmental toxicity, advise women not to breastfeed during treatment and for at least 7 months after the last dose. M/P ratio is unknown. |
| 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. |
■ 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 |
["Known hypersensitivity to ado-trastuzumab emtansine or any of its components","Pregnancy (can cause embryo-fetal harm)"]
| 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."] |
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| 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. |