Kadcyla

• HER2-Positive Metastatic Breast Cancer:
• For patients previously treated with trastuzumab and a taxane, either separately or in combination.
• For patients with disease progression following prior therapy.
• Adjuvant Treatment of HER2-Positive Early Breast Cancer:
• In patients with residual invasive disease after neoadjuvant taxane and trastuzumab-based therapy.
• Off-label Uses:
• Investigational in other HER2-positive solid tumors under clinical trials.

• Route: Intravenous infusion.
• Adult Dose: 3.6 mg/kg IV every 3 weeks.
• Infusion Time: Initial infusion over 90 minutes; if tolerated, subsequent infusions over 30 minutes.
• Dose Adjustments:
• Hepatic impairment: Use caution in moderate impairment; avoid in severe impairment.
• Renal impairment: No specific adjustment; monitor closely in severe impairment.
• Hematologic toxicity: Dose delay or reduction recommended for thrombocytopenia or elevated liver enzymes.
• Pediatrics: Safety and efficacy not established.
• Elderly: No dose adjustment; monitor closely for toxicity.

Trastuzumab emtansine is an antibody-drug conjugate combining trastuzumab, a monoclonal antibody targeting the HER2 receptor, with emtansine (DM1), a potent microtubule inhibitor. Trastuzumab directs the conjugate to HER2-overexpressing cancer cells, enabling internalization. Inside the cell, emtansine is released, disrupting microtubule assembly, leading to cell cycle arrest and apoptosis. The trastuzumab component also inhibits HER2 signaling and mediates immune responses, providing a dual mechanism to combat HER2-positive tumors.

• Absorption: IV administration, 100% bioavailability.
• Distribution: Volume of distribution approx. 3.8 L; limited extravascular distribution.
• Metabolism: Proteolytic degradation of trastuzumab; emtansine metabolized by lysosomal degradation and hepatic CYP3A4/5 pathways.
• Half-life: Approximately 4 days (trastuzumab moiety); emtansine ~3.5 days.
• Elimination: Emtansine primarily eliminated via biliary excretion; trastuzumab catabolized into peptides and amino acids.

• Pregnancy: Category D (FDA) — evidence of fetal risk based on animal data and mechanism. Use only if benefits justify risks.
• Lactation: Unknown if excreted in human milk; breastfeeding not recommended during treatment and for at least 7 months after last dose.

• Antineoplastic agent
• Antibody-drug conjugate (HER2-targeted microtubule inhibitor)

• Hypersensitivity to trastuzumab, emtansine, or excipients.
• Severe hepatic impairment.
• Known severe thrombocytopenia or bleeding disorders contraindicating therapy.

• Hepatotoxicity: Monitor liver enzymes; severe hepatic injury reported.
• Cardiotoxicity: Monitor left ventricular function; risk of heart failure.
• Thrombocytopenia: Risk of severe low platelet counts; monitor CBC regularly.
• Infusion reactions: May occur; monitor during and post-infusion.
• Pulmonary toxicity: Rare cases of interstitial lung disease reported.
• Embryo-fetal toxicity: Avoid in pregnancy.

• Common: Fatigue, nausea, musculoskeletal pain, thrombocytopenia, increased liver enzymes, headache.
• Serious: Hepatotoxicity, cardiotoxicity (heart failure), severe thrombocytopenia with bleeding, infusion-related reactions, pulmonary toxicity.

• CYP3A4/5 Modulators: Strong inhibitors (e.g., ketoconazole) or inducers (e.g., rifampin) may alter emtansine metabolism, affecting toxicity.
• Other hepatotoxic drugs: Increased risk of liver injury.
• No significant interaction with CYP450 substrates as trastuzumab is not metabolized by these enzymes.

• Approved by FDA for adjuvant treatment in early breast cancer with residual disease after neoadjuvant therapy.
• Updated guidelines emphasize cardiac monitoring and management of hematologic toxicities.
• Ongoing studies evaluating combination with immune checkpoint inhibitors and other targeted agents.

• Store refrigerated at 2°C to 8°C (36°F to 46°F).
• Protect from light.
• Do not freeze or shake.
• Use reconstituted/diluted solutions promptly as per manufacturer instructions.