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International Nonproprietary Names (INN)Ado-trastuzumab emtansine
Prescription DrugYes
Class Antineoplastic Agents
US Brand NameKadcyla®
Other namesado-trastuzumab emtansine, trastuzumab-DM1, T-DM1
Available as a generic drugNo
Marketing AuthorizationGenentech/Roche
United States Adopted Name (USAN) Trastuzumab emtansine
FDA ApprovedYes
Initial U.S. ApprovalFebruary 22, 2013
IndicationHER2-positive, metastatic breast and HER2-positive early breast cancer
Supplied asNDC
One 100 mg vial, single-use vialNDC 50242-088-01
One 160 mg vial, single-use vialNDC 50242-087-01
Pregnancy CategoryN (Not classified yet)
Route of AdministrationIntravenous infusion
Biologic License Application (BLA)125427
Click on the link to download the complete Full Prescribing Information for additional Important Safety Information, including BOXED WARNINGS.

 

What is ado-trastuzumab emtansine
Ado-trastuzumab emtansine is a human epidermal growth factor receptor-2 (HER2-) targeted antibody-drug conjugate (ADC) which contains the humanized anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitory drug DM1 (a maytansine derivative) via the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate).

Emtansine refers to the MCC-DM1 complex. The antibody trastuzumab is a well-characterized recombinant monoclonal antibody product produced by mammalian (Chinese hamster ovary) cells, and the small molecule components (DM1 and MCC) are produced by chemical synthesis. Ado-trastuzumab emtansine contains an average drug to antibody ratio (DAR) of 3.5 DM1 molecules per antibody.

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Appearance
Ado-trastuzumab emtansine is a sterile, white to off-white preservative-free lyophilized powder in single-use vials. Each vial contains 100 mg or 160 mg ado-trastuzumab emtansine. Following reconstitution, each single-use vial contains ado-trastuzumab emtansine (20 mg/mL), polysorbate 20 [0.02% (w/v)], sodium succinate (10 mM), and sucrose [6% (w/v)] with a pH of 5.0 and density of 1.026 g/mL. The resulting solution containing 20 mg/mL ado-trastuzumab emtansine is administered by intravenous infusion following dilution.

Click on the link to download the complete Full Prescribing Information for additional Important Safety Information, including BOXED WARNINGS.

 

Logistics
Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of reconstitution. Do not freeze or shake.

Dosage forms and strength
Lyophilized powder in single-dose vials: 100 mg per vial or 160 mg per vial of ado-trastuzumab emtansine.

Special Handling
Follow procedures for proper handling and disposal of anticancer drugs.

 


Clinical Pharmacology

Mechanism of Action
The antibody used in ado-trastuzumab emtansine is the humanized anti-HER2 IgG1, trastuzumab which is conjugated to a small molecule cytotoxin, DM1, is a microtubule inhibitor.

Upon binding to sub-domain IV of the HER2 receptor, ado-trastuzumab emtansine undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in the intracellular release of DM1-containing cytotoxic catabolites. The binding of DM1 to tubulin disrupts microtubule networks in the cell, which results in cell cycle arrest and apoptotic cell death.

In addition, in vitro studies have shown that similar to trastuzumab, ado-trastuzumab emtansine inhibits HER2 receptor signaling, mediates antibody-dependent cell-mediated cytotoxicity, and inhibits shedding of the HER2 extracellular domain in human breast cancer cells that overexpress HER2.

Pharmacokinetics
The pharmacokinetics of ado-trastuzumab emtansine was evaluated in a phase I study and in a population pharmacokinetic analysis for the ado-trastuzumab emtansine conjugate (ADC) using pooled data from 5 trials in patients with breast cancer. A linear two-compartment model with first-order elimination from the central compartment adequately describes the ADC concentration-time profile. In addition to the ADC, the pharmacokinetics of total antibody (conjugated and unconjugated trastuzumab), DM1 were also determined.

Additional Information


 

Do not substitute trastuzumab for or with ado-trastuzumab emtansine.

 

Indication and usage
Ado-trastuzumab emtansine is a HER2-targeted antibody and microtubule inhibitor conjugate indicated, as a single agent, for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab (Herceptin®; Genentech/Roche) and a taxane (paclitaxel or docetaxel), separately or in combination. Eligible patients should have either:

  • Received prior therapy for metastatic disease, or
  • Developed disease recurrence during or within six months of completing adjuvant therapy.

Ado-trastuzumab emtansine, as a single agent, is also indicated 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
It is recommended to select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens. Assessment of HER2 protein overexpression and/or HER2 gene amplification should be performed using an FDA-approved companion diagnostic (tests) for breast cancer, specifically for the detection of HER2 protein overexpression and HER2 gene amplification by laboratories with demonstrated proficiency.*

Recommended Dosage, Administration, and Schedules
Ado-trastuzumab emtansine is for intravenous infusion only. Do not administer as an intravenous push or bolus. Do not use Dextrose (5%) solution.

The recommended dose of ado-trastuzumab emtansine is 3.6 mg/kg given as an intravenous infusion every 3 weeks (21-day cycle; Q3W) until disease progression or unacceptable toxicity. Do not administer ado-trastuzumab emtansine at doses greater than 3.6 mg/kg. Do not substitute ado-trastuzumab emtansine for or with trastuzumab.

  • First infusion
    • Administer infusion over 90 minutes. Physicians should observe patients during the infusion and for at least 90 minutes following the initial dose for fever, chills, or other infusion-related reactions
  • Subsequent infusions
    • Administer over 30 minutes if prior infusions were well tolerated. Observe patients during the infusion and for at least 30 minutes after infusion.
      • In the treatment of patients with Metastatic Breast Cancer (MBC), patients should receive treatment until disease progression or unmanageable toxicity.
      • In the treatment of patients with Early Breast Cancer (EBC), patients should receive treatment for a total of 14 cycles unless there is disease recurrence or unmanageable toxicity.

Dose Modifications
Do not re-escalate the ado-trastuzumab emtansine dose after a dose reduction is made.

  • If a planned dose is delayed or missed, administer as soon as possible; do not wait until the next planned cycle. Adjust the schedule of administration to maintain a 3-week interval between doses. Administer the infusion at the dose and rate the patient tolerated in the most recent infusion.
  • Slow or interrupt the infusion rate of ado-trastuzumab emtansine if the patient develops an infusion-related reaction. Permanently discontinue ado-trastuzumab emtansine for life-threatening infusion-related reactions.
  • Management of increased serum transaminases, hyperbilirubinemia, left ventricular dysfunction, thrombocytopenia, pulmonary toxicity or peripheral neuropathy may require temporary interruption, dose reduction, or treatment discontinuation of ado-trastuzumab emtansine as per guidelines provided in Table 1.0 and Table 2.0.
  • Hepatotoxicity. A reduction in the dose of KADCYLA is recommended in the case of hepatotoxicity exhibited as increases in serum transaminases and/or hyperbilirubinemia

 

Management of adverse events
Management of adverse events (infusion-related reactions, hepatotoxicity, left ventricular cardiac dysfunction, thrombocytopenia, pulmonary toxicity, or peripheral neuropathy) may require temporary interruption, dose reduction, or treatment discontinuation of ado-trastuzumab emtansine.

Closely monitor the infusion site for possible subcutaneous infiltration during drug administration [see Warnings and Precautions (5.10)]. First infusion: Administer infusion over 90 minutes. Patients should be observed during the infusion and for at least 90 minutes following the initial dose for fever, chills, or other infusion-related reactions. Subsequent infusions: Administer over 30 minutes if prior infusions were well tolerated. Patients should be observed during the infusion and for at least 30 minutes after infusion.

Click on the link to download the complete Full Prescribing Information for additional Important Safety Information, including BOXED WARNINGS.

 

Preparation for Administration

In order to prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is ado-trastuzumab emtansine and not trastuzumab.

Administration

  • Administer ado-trastuzumab emtansine as an intravenous infusion only with a 0.2 or 0.22-micron in-line polyethersulfone (PES) filter. Do not administer as an intravenous push or bolus.
  • Do not mix ado-trastuzumab emtansine, or administer as an infusion, with other medicinal products.

Reconstitution

  • Use aseptic technique for reconstitution and preparation of dosing solution. Appropriate procedures for the preparation of chemotherapeutic drugs should be used.
  • Using a sterile syringe, slowly inject 5 mL of Sterile Water for Injection into the 100 mg ado-trastuzumab emtansine vial, or 8 mL of Sterile Water for Injection into the 160 mg ado-trastuzumab emtansine vial to yield a solution containing 20 mg/mL. Swirl the vial gently until completely dissolved. Do not shake. Inspect the reconstituted solution for particulates and discoloration.
  • The reconstituted solution should be clear to slightly opalescent and free of visible particulates. The color of the reconstituted solution should be colorless to pale brown. Do not use if the reconstituted solution contains visible particulates or is cloudy or discolored.
  • The reconstituted lyophilized vials should be used immediately following reconstitution with Sterile Water for Injection. If not used immediately, the reconstituted KADCYLA vials can be stored for up to 24 hours in a refrigerator at 2ºC to 8ºC (36°Fto 46°F); discard unused ado-trastuzumab emtansine after 24 hours. Do not freeze. The reconstituted product contains no preservative and is intended for single-dose only.

Dilution

Determine the correct dose (mg) of ado-trastuzumab emtansine.

  • Calculate the volume of the 20 mg/mL reconstituted ado-trastuzumab emtansine solution needed.
  • Withdraw this amount from the vial and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection. Do not use Dextrose (5%) solution.
  • Gently invert the bag to mix the solution in order to avoid foaming.
  • The diluted ado-trastuzumab emtansine infusion solution should be used immediately. If not used immediately, the solution may be stored in a refrigerator at 2°C to 8°C (36°Fto 46°F) for up to 24 hours prior to use. This storage time is additional to the time allowed for the reconstituted vials. Do not freeze or shake

Dosage forms and strengths

Lyophilized powder insingle-use vials: 100 mgper vialor 160 mg per vial of ado-trastuzumab emtansine.

Comntraindications

None


 

Avoid the of potential medication errors resulting from confusion regarding the nonproprietary name of ado-trastuzumab emtansine
The use of the incorrect nonproprietary name for ado-trastuzumab emtansine (Kadcyla®) in some medication-related electronic systems poses a risk of a mix-up with trastuzumab (Herceptin®) and may result in medication errors. Dosing and treatment schedules for these drugs are quite different, and, as a result, confusion between these products can lead to dosing errors and potential harm to patients.

Although the U.S. Food and Drug Administration (FDA) recommends the use of the FDA-approved nonproprietary name for ado-trastuzumab emtansine, physicians should be aware that some organizations and (international) publications use the United States Adopted Name (USAN) ‘trastuzumab emtansine’, and omit the ‘ado’ prefix and hyphen. While the no medication errors related to confusion between ado-trastuzumab emtansine and trastuzumab have been reported to FDA since the approval of the therapeutic agent on February 22, 2013 (medication errors did occur during the clinical trials that evaluated the safety and efficacy of ado-trastuzumab emtansine prior to approval), the use of this truncated version of ado-trastuzumab emtansine’s nonproprietary name may cause confusion with trastuzumab.

Therefore, health care professionals should use both the FDA-approved proprietary (brand) name Kadcyla® and its nonproprietary name ado-trastuzumab emtansine when communicating medication orders, on preprinted order sets, and in computerized order entry systems. Such redundancy may help to reduce the potential for medication errors.

Note
* Improper assay performance, including use of sub-optimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.

Reference
[1] KADCYLA Prescribing Information. Genentech, Inc. April 2016
[2] Occupational Safety and Health Administration (OSHA). Hazardous Drugs. Online. Last accessed on August 27, 2020.

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