Drug Detail:Kadcyla (Ado-trastuzumab emtansine [ ay-doe-tras-tooz-ue-mab-em-tan-seen ])
Generic Name: TRASTUZUMAB EMTANSINE 20mg in 1mL
Dosage Form: injection, powder, lyophilized, for solution
Drug Class: HER2 inhibitors
Patient Selection
Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens [see Indications and Usage (1), Clinical Studies (14)]. Assessment of HER2 protein overexpression and/or HER2 gene amplification should be performed using FDA-approved tests specific for breast cancers by laboratories with demonstrated proficiency. Information on the FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at: http://www.fda.gov/CompanionDiagnostics.
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.
Recommended Doses and Schedules
Do not substitute trastuzumab for or with KADCYLA.
The recommended dose of KADCYLA is 3.6 mg/kg given as an intravenous infusion every 3 weeks (21-day cycle). Do not administer KADCYLA at doses greater than 3.6 mg/kg.
Closely monitor the infusion site for possible subcutaneous infiltration during drug administration [see Warnings and Precautions (5.9)].
First infusion: Administer infusion over 90 minutes. Observe patients during the infusion and for at least 90 minutes following the initial dose for fever, chills, or other infusion-related reactions [see Warnings and Precautions (5.5)].
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.
Dose Modifications
Do not re-escalate the KADCYLA 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 KADCYLA if the patient develops an infusion-related reaction. Permanently discontinue KADCYLA for life-threatening infusion-related reactions [see Warnings and Precautions (5.5)].
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 KADCYLA as per guidelines provided in Tables 1 and 2.
| Dose Reduction Schedule | Dose Level |
|---|---|
| Starting dose | 3.6 mg/kg |
| First dose reduction | 3 mg/kg |
| Second dose reduction | 2.4 mg/kg |
| Requirement for further dose reduction | Discontinue treatment |
| ALT = alanine transaminase; AST = aspartate transaminase, CHF = congestive heart failure, DILI = Drug Induced Liver Injury; LVEF = left ventricular ejection fraction, LVSD = left ventricular systolic dysfunction, TBILI = Total Bilirubin, ULN = upper limit of normal | ||
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| Dose Modifications for Patients with MBC | ||
| Adverse reaction | Severity | Treatment modification |
| Increased Transaminase (AST/ALT) | Grade 2 (> 2.5 to ≤ 5× the ULN) |
Treat at the same dose level. |
| Grade 3 (> 5 to ≤ 20× the ULN) |
Do not administer KADCYLA until AST/ALT recovers to Grade ≤ 2, and then reduce one dose level | |
| Grade 4 (> 20× the ULN) |
Discontinue KADCYLA | |
| Hyperbilirubinemia | Grade 2 (> 1.5 to ≤ 3× the ULN) |
Do not administer KADCYLA until total bilirubin recovers to Grade ≤ 1, and then treat at the same dose level. |
| Grade 3 (> 3 to ≤ 10× the ULN) |
Do not administer KADCYLA until total bilirubin recovers to Grade ≤ 1 and then reduce one dose level. | |
| Grade 4 (> 10× the ULN) |
Discontinue KADCYLA | |
| Drug Induced Liver Injury (DILI) | Serum transaminases > 3 × ULN and concomitant total bilirubin > 2 × ULN | Permanently discontinue KADCYLA in the absence of another likely cause for the elevation of liver enzymes and bilirubin, e.g. liver metastasis or concomitant medication |
| Nodular Regenerative Hyperplasia (NRH) | All Grades | Permanently discontinue KADCYLA |
| Thrombocytopenia | Grade 3 (25,000 to < 50,000/mm3) |
Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm3), and then treat at the same dose level |
| Grade 4 (< 25,000/mm3) |
Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm3), and then reduce one dose level | |
| Left Ventricular Dysfunction | Symptomatic CHF | Discontinue KADCYLA |
| LVEF < 40% | Do not administer KADCYLA Repeat LVEF assessment within 3 weeks. If LVEF < 40% is confirmed, discontinue KADCYLA |
|
| LVEF 40% to ≤ 45% and decrease is ≥ 10% points from baseline | Do not administer KADCYLA Repeat LVEF assessment within 3 weeks. If the LVEF has not recovered to within 10% points from baseline, discontinue KADCYLA |
|
| LVEF 40% to ≤ 45% and decrease is < 10% points from baseline | Continue treatment with KADCYLA. Repeat LVEF assessment within 3 weeks. |
|
| LVEF > 45% | Continue treatment with KADCYLA. | |
| Pulmonary Toxicity | Interstitial lung disease (ILD) or pneumonitis | Permanently discontinue KADCYLA |
| Peripheral Neuropathy | Grade 3-4 | Do not administer KADCYLA until resolution Grade ≤ 2 |
| Dose Modification Guidelines for EBC | ||
| Adverse reaction | Severity | Treatment modification |
| Increased Alanine Transaminase (ALT) | Grade 2-3 (> 3.0 to ≤ 20 × ULN on day of scheduled treatment) |
Do not administer KADCYLA until ALT recovers to Grade ≤ 1, and then reduce one dose level |
| Grade 4 (> 20 × ULN at any time) |
Discontinue KADCYLA | |
| Increased Aspartate Transaminase (AST) | Grade 2 (> 3.0 to ≤ 5 × ULN on day of scheduled treatment) |
Do not administer KADCYLA until AST recovers to Grade ≤ 1, and then treat at the same dose level |
| Grade 3 (> 5 to ≤ 20 × ULN on day of scheduled treatment) |
Do not administer KADCYLA until AST recovers to Grade ≤ 1, and then reduce one dose level | |
| Grade 4 (> 20 × ULN at any time) |
Discontinue KADCYLA | |
| Hyperbilirubinemia | TBILI > 1.0 to ≤ 2.0 × the ULN on day of scheduled treatment |
Do not administer KADCYLA until total bilirubin recovers to ≤ 1.0 × ULN, and then reduce one dose level |
| TBILI > 2 × ULN at any time |
Discontinue KADCYLA | |
| Nodular Regenerative Hyperplasia (NRH) | All Grades | Permanently discontinue KADCYLA |
| Thrombocytopenia | Grade 2-3 on day of scheduled treatment (25,000 to < 75,000/mm3) |
Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm3), and then treat at the same dose level. If a patient requires 2 delays due to thrombocytopenia, consider reducing dose by one level. |
| Grade 4 at any time < 25,000/mm3 |
Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm3), and then reduce one dose level. | |
| Left Ventricular Dysfunction | LVEF < 45% | Do not administer KADCYLA Repeat LVEF assessment within 3 weeks. If LVEF < 45% is confirmed, discontinue KADCYLA. |
| LVEF 45% to < 50% and decrease is ≥ 10% points from baseline* | Do not administer KADCYLA Repeat LVEF assessment within 3 weeks. If the LVEF remains < 50% and has not recovered to < 10% points from baseline, discontinue KADCYLA. |
|
| LVEF 45% to < 50% and decrease is < 10% points from baseline* | Continue treatment with KADCYLA. Repeat LVEF assessment within 3 weeks. |
|
| LVEF ≥ 50% | Continue treatment with KADCYLA. | |
| Heart Failure | Symptomatic CHF, Grade 3-4 LVSD or Grade 3-4 heart failure, or Grade 2 heart failure accompanied by LVEF < 45% |
Discontinue KADCYLA |
| Peripheral Neuropathy | Grade 3-4 | Do not administer KADCYLA until resolution Grade ≤ 2 |
| Pulmonary Toxicity | Interstitial lung disease (ILD) or pneumonitis | Permanently discontinue KADCYLA |
| Radiotherapy-Related Pneumonitis | Grade 2 | Discontinue KADCYLA if not resolving with standard treatment |
| Grade 3-4 | Discontinue KADCYLA | |
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 KADCYLA (ado-trastuzumab emtansine) and not trastuzumab.
Administration:
- Administer KADCYLA 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 KADCYLA, 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 KADCYLA vial, or 8 mL of Sterile Water for Injection into the 160 mg KADCYLA 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°F to 46°F); discard unused KADCYLA 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 KADCYLA [see Dosage and Administration (2.1)].
- Calculate the volume of the 20 mg/mL reconstituted KADCYLA 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 KADCYLA 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°F to 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.
