Kadcyla100 mg/vial

Established (FDA-Approved) Indications

• HER2-positive metastatic breast cancer: Kadcyla is indicated, as a single agent, for the treatment of patients with HER2-positive metastatic breast cancer who previously received trastuzumab and a taxane, either separately or in combination. Patients should have either received prior therapy for metastatic disease or developed disease recurrence during or within six months of completing adjuvant therapy.
• Adjuvant treatment of HER2-positive early breast cancer: Kadcyla is indicated as a single agent for the adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane- and trastuzumab-based treatment.

Patient Selection Requirement

HER2 tumor status must be confirmed using an FDA-approved test before starting Kadcyla, as Kadcyla is effective only in HER2-positive disease.

Not Indicated / Off-Label Use

Kadcyla is not indicated for HER2-negative breast cancer or for use in place of trastuzumab in HER2-positive early-stage disease where trastuzumab alone or with chemotherapy is standard of care. Kadcyla is not interchangeable with trastuzumab. Use of Kadcyla outside these approved settings (e.g. other HER2-positive tumor types) is considered off-label and should only be undertaken under specialist oncology guidance.

Each single-dose vial of Trastuzumab Emtansine contains Trastuzumab Emtansine as a lyophilized (freeze-dried) powder for reconstitution, supplied in strengths such as 100 mg and 160 mg per vial. Trastuzumab Emtansine is an antibody-drug conjugate composed of the humanized anti-HER2 monoclonal antibody trastuzumab covalently linked, via the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate), to the cytotoxic microtubule-inhibitor DM1 (a maytansinoid derivative).

Kadcyla (also known as ado-Kadcyla or T-DM1) is an antibody-drug conjugate (ADC) that combines the HER2-targeting properties of trastuzumab with the cytotoxic activity of a microtubule-inhibitory agent, DM1. In Kadcyla, trastuzumab binds specifically to the HER2 receptor overexpressed on certain breast cancer cells, allowing targeted intracellular delivery of the cytotoxic DM1 payload while limiting exposure of DM1 to healthy tissue.

Kadcyla is administered only as an intravenous infusion in a hospital or specialist oncology infusion setting under the supervision of a physician experienced in the treatment of cancer. Kadcyla carries boxed warnings for hepatotoxicity, cardiac toxicity, and embryo-fetal toxicity.

Kadcyla belongs to the class of antibody-drug conjugates (ADCs), specifically HER2-targeted antineoplastic agents. Kadcyla is classified as an anti-HER2 antibody-drug conjugate combining a monoclonal antibody (trastuzumab) with a cytotoxic microtubule inhibitor (DM1).

Mechanism

Trastuzumab Emtansine combines the mechanisms of trastuzumab and DM1. The trastuzumab component of Trastuzumab Emtansine binds to subdomain IV of the HER2 receptor extracellular domain, inhibiting HER2 receptor signaling, mediating antibody-dependent cellular cytotoxicity (ADCC), and inhibiting shedding of the HER2 extracellular domain. Upon binding to HER2, Trastuzumab Emtansine undergoes receptor-mediated internalization followed by lysosomal degradation, releasing DM1-containing cytotoxic catabolites inside the cell.

DM1, the cytotoxic component of Trastuzumab Emtansine, binds to tubulin and disrupts microtubule assembly/dynamics in the cell, arresting cells in the G2/M phase of the cell cycle and leading to apoptotic cell death. This targeted delivery mechanism is intended to concentrate the cytotoxic effect of Trastuzumab Emtansine within HER2-overexpressing tumor cells.

Pharmacokinetics

Following intravenous administration of Trastuzumab Emtansine, maximum serum concentration occurs at the end of infusion. Trastuzumab Emtansine is metabolized via proteolytic degradation (the antibody component) and by hepatic cytochrome P450 3A4/5-mediated oxidative metabolism (the DM1-related components). Elimination half-life of Trastuzumab Emtansine is approximately 4 days.

Kadcyla is for intravenous infusion only and must never be administered as an intravenous push or bolus injection, or mixed/diluted with dextrose (5%) solution, which causes protein aggregation of Kadcyla. Kadcyla should be administered through a dedicated intravenous line using an in-line filter. Administration of Kadcyla should occur in a setting equipped to manage infusion reactions and anaphylaxis, with a physician immediately available.

The first infusion of Kadcyla is given over 90 minutes; if tolerated, subsequent infusions of Kadcyla may be given over 30 minutes. Vital signs should be monitored before, during, and after each infusion of Kadcyla. Kadcyla must not be substituted for or with trastuzumab.

CYP3A4 Inhibitors

The DM1 component of Kadcyla is metabolized by CYP3A4/5. Concomitant use of Kadcyla with strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, ritonavir) may increase DM1 exposure and the risk of toxicity from Kadcyla. If concomitant use of a strong CYP3A4 inhibitor with Kadcyla cannot be avoided, close monitoring for adverse effects of Kadcyla is recommended, and use of an alternative, non-CYP3A4-inhibiting medication should be considered where possible.

Anticoagulants and Antiplatelet Agents

Kadcyla can cause thrombocytopenia. Concomitant use of Kadcyla with anticoagulants (e.g. warfarin, heparin) or antiplatelet agents may increase the risk of bleeding; platelet counts and clinical signs of bleeding should be monitored closely when these agents are used together with Kadcyla.

Other Anti-HER2 or Cytotoxic Agents

Kadcyla should not be co-administered with other anti-HER2 antibody-drug conjugates or with trastuzumab as a substitute regimen; combined use has not been established as safe and is not recommended outside of Kadcyla monotherapy in its approved indications.

Very Common / Common

• Fatigue, nausea, musculoskeletal pain, headache
• Constipation, diarrhea, abdominal pain
• Thrombocytopenia (low platelet count) and anemia
• Elevated liver enzymes (AST, ALT)
• Peripheral neuropathy (numbness/tingling in hands and feet)
• Epistaxis (nosebleeds)
• Infusion-related reactions (fever, chills, flushing)
• Dry mouth, decreased appetite

Serious Side Effects

• Hepatotoxicity, including nodular regenerative hyperplasia and, rarely, liver failure (see Precautions and Warnings)
• Cardiotoxicity with decreased left ventricular ejection fraction (see Precautions and Warnings)
• Interstitial lung disease/pneumonitis, including cases progressing to acute respiratory distress syndrome
• Severe thrombocytopenia with risk of bleeding
• Severe infusion reactions and hypersensitivity, including anaphylaxis

Patients experiencing severe or persistent side effects while receiving Kadcyla should contact their treating physician promptly.

Pregnancy

Kadcyla is contraindicated in pregnancy. Based on its mechanism of action and findings in animal reproduction studies, Kadcyla can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should be advised of the risk to the fetus and should use effective contraception during treatment with Kadcyla and for at least 7 months following the final dose of Kadcyla. If Kadcyla is used during pregnancy, or if a patient becomes pregnant while receiving Kadcyla or within 7 months after the last dose, the patient should be advised of the potential risk to the fetus and a physician should be consulted immediately.

Lactation

There is no information on the presence of Kadcyla in human milk or its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in a breastfed infant, women should be advised not to breastfeed during treatment with Kadcyla and for at least 7 months after the final dose of Kadcyla.

Boxed Warnings

Hepatotoxicity: Kadcyla can cause hepatotoxicity, including liver failure and death. Liver function tests (AST, ALT, bilirubin) should be monitored before each dose of Kadcyla; dose reduction, temporary interruption, or permanent discontinuation of Kadcyla is required depending on the severity of liver enzyme or bilirubin abnormalities.

Cardiac Toxicity: Kadcyla can cause left ventricular dysfunction. Left ventricular ejection fraction (LVEF) should be assessed at baseline and at regular intervals during treatment with Kadcyla; Kadcyla should be withheld for significant LVEF decline and discontinued if LVEF does not recover or if symptomatic congestive heart failure occurs.

Embryo-Fetal Toxicity: Kadcyla can cause fetal harm when administered during pregnancy (see Pregnancy and Lactation); pregnancy status should be verified before starting Kadcyla and effective contraception used during and after treatment.

Other Warnings and Precautions

• Infusion-related reactions: Kadcyla should be administered with close monitoring, particularly during and after the first infusion; Kadcyla should be discontinued for life-threatening infusion reactions.
• Pulmonary toxicity: Interstitial lung disease and pneumonitis, including fatal cases, have been reported with Kadcyla; Kadcyla should be permanently discontinued in patients diagnosed with interstitial lung disease or pneumonitis.
• Thrombocytopenia: Kadcyla frequently causes thrombocytopenia; platelet counts should be monitored before each dose of Kadcyla, with increased caution in patients on anticoagulant or antiplatelet therapy.
• Peripheral neuropathy: Kadcyla can cause peripheral neuropathy, usually mild and sensory; temporary interruption of Kadcyla should be considered for severe neuropathy.
• Not interchangeable with trastuzumab: Kadcyla is a distinct cytotoxic conjugate and must not be substituted for trastuzumab or other trastuzumab-containing products.
• HER2 testing: HER2-positive status must be confirmed with an FDA-approved/validated test before initiating Kadcyla, as Kadcyla is not effective in HER2-negative disease.

There is no known specific antidote for Kadcyla overdose. Doses of Kadcyla higher than recommended have been associated with worsening of known adverse effects, particularly thrombocytopenia and hepatotoxicity. If an overdose of Kadcyla is suspected or administered, the patient should be monitored closely for adverse reactions, and immediate medical attention should be sought. In case of suspected overdose of Kadcyla, contact a physician, hospital emergency department, or poison control center immediately; supportive care should be provided as clinically indicated.

Store the vial of Kadcyla refrigerated at 2°C to 8°C (36°F to 46°F) in its original carton to protect from light. Do not freeze. Keep out of reach of children. Reconstituted and diluted solutions of Kadcyla have limited stability and should be used within the timeframe specified by the hospital pharmacy/manufacturer instructions.

Renal Impairment

No dose adjustment of Kadcyla is required in patients with mild or moderate renal impairment. Kadcyla has not been adequately studied in patients with severe renal impairment; such patients should be monitored closely.

Hepatic Impairment

No dose adjustment of Kadcyla is needed for mild hepatic impairment; however, since Kadcyla carries a boxed warning for hepatotoxicity, liver function should be monitored closely. Kadcyla has not been established as safe in patients with moderate to severe hepatic impairment and should be used with caution, if at all, in such patients.

Elderly Patients

Available data suggest no overall difference in effectiveness of Kadcyla between elderly and younger patients, though some adverse reactions may be more frequent in patients 65 years and older; such patients should be monitored closely during treatment with Kadcyla.

Pediatric Population

Safety and efficacy of Kadcyla in pediatric patients have not been established (see Pediatric Uses).

In metastatic HER2-positive breast cancer, Kadcyla is continued once every 3 weeks until disease progression or unacceptable toxicity occurs. In the adjuvant treatment of early breast cancer, Kadcyla is administered for a total of 14 cycles (each cycle 3 weeks), unless disease recurrence or unacceptable toxicity occurs first. The duration and continuation of Kadcyla therapy should be determined by the treating oncologist based on response, toxicity, and overall clinical status.

Kadcyla is supplied as a lyophilized powder in single-dose vials and must be reconstituted by a healthcare professional using aseptic technique before administration. Each vial of Kadcyla should be reconstituted with Sterile Water for Injection to a final concentration of 20 mg/mL, gently swirled (not shaken) to avoid foaming/aggregation of the protein. The reconstituted Kadcyla solution should then be further diluted in an infusion bag containing 0.9% Sodium Chloride Injection; dextrose (5%) solutions must not be used, as they can cause protein aggregation of Kadcyla. The diluted infusion solution of Kadcyla should be used promptly or stored under refrigeration for the period specified by the manufacturer, and should be inspected visually for particulate matter and discoloration before administration.

Trastuzumab Emtansine belongs to the antibody-drug conjugate (ADC) class of antineoplastic agents, specifically the anti-HER2 monoclonal antibody-cytotoxic conjugate subclass. Trastuzumab Emtansine combines a HER2-directed monoclonal antibody with a maytansinoid microtubule inhibitor.

Trastuzumab Emtansine works through a dual mechanism directed by its two components. The trastuzumab antibody portion of Trastuzumab Emtansine binds specifically to the HER2 receptor on the surface of HER2-overexpressing tumor cells, blocking HER2-mediated signaling and triggering immune-mediated cell killing (ADCC). Binding of Trastuzumab Emtansine to HER2 leads to receptor-mediated internalization of the Trastuzumab Emtansine-HER2 complex into the tumor cell, followed by lysosomal degradation that releases the cytotoxic DM1 payload of Trastuzumab Emtansine inside the cell. DM1 then binds tubulin and disrupts microtubule networks, halting cell division and causing apoptosis of the HER2-positive cancer cell. This design allows Trastuzumab Emtansine to deliver its cytotoxic payload preferentially to HER2-expressing tumor cells while limiting systemic exposure to the cytotoxic component.

The safety and efficacy of Kadcyla in pediatric patients (below 18 years of age) have not been established. Kadcyla is not indicated for use in children, and clinical trials establishing appropriate dosing and safety of Kadcyla in this population have not been conducted. Kadcyla should not be administered to pediatric patients outside of a formal clinical trial setting.