Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639, Grenzach-Wyhlen, Germany
Kadcyla, as a single agent, is indicated for the adjuvant treatment of adult patients with HER2-positive early breast cancer who have residual invasive disease, in the breast and/or lymph nodes, after neoadjuvant taxane-based and HER2-targeted therapy.
Kadcyla, as a single agent, is indicated for the treatment of adult patients with HER2-positive, unresectable locally advanced or metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either:
Kadcyla should only be prescribed by a physician and administered as an intravenous infusion under the supervision of a healthcare professional who is experienced in the treatment of cancer patients (i.e. prepared to manage allergic/anaphylactic infusion reactions and in an environment where full resuscitation facilities are immediately available (see section 4.4)).
Patients treated with trastuzumab emtansine should have HER2 positive tumour status, defined as a score of 3 + by immunohistochemistry (IHC) or a ratio of ≥ 2.0 by in situ hybridization (ISH) or by fluorescence in situ hybridization (FISH) assessed by a CE-marked In Vitro Diagnostic (IVD) medical device. If a CE-marked IVD is not available, the HER2-status should be assessed by an alternate validated test.
In order to prevent medicinal product errors it is important to check the vial labels to ensure that the medicinal product being prepared and administered is Kadcyla (trastuzumab emtansine) and not Herceptin (trastuzumab).
The recommended dose of trastuzumab emtansine is 3.6 mg/kg bodyweight administered as an intravenous infusion every 3 weeks (21-day cycle).
The initial dose should be administered as a 90 minute intravenous infusion. Patients should be observed during the infusion and for at least 90 minutes following the initial infusion for fever, chills, or other infusion-related reactions. The infusion site should be closely monitored for possible subcutaneous infiltration during administration (see section 4.8).
If the prior infusion was well tolerated, subsequent doses of trastuzumab emtansine may be administered as 30 minute infusions. Patients should be observed during the infusion and for at least 30 minutes after infusion.
The infusion rate of trastuzumab emtansine should be slowed or interrupted if the patient develops infusion-related symptoms (see sections 4.4 and 4.8). Trastuzumab emtansine should be discontinued in case of life-threatening infusion reactions.
Patients should receive treatment for a total of 14 cycles unless there is disease recurrence or unmanageable toxicity.
Patients should receive treatment until disease progression or unmanageable toxicity.
Management of symptomatic adverse reactions may require temporary interruption, dose reduction, or treatment discontinuation of trastuzumab emtansine as per guidelines provided in text and Tables 1 and 2.
Trastuzumab emtansine dose should not be re-escalated after a dose reduction is made.
Table 1. Dose reduction schedule:
| Dose reduction schedule (Starting dose is 3.6 mg/kg) | Dose to be administered |
|---|---|
| First dose reduction | 3 mg/kg |
| Second dose reduction | 2.4 mg/kg |
| Requirement for further dose reduction | Discontinue treatment |
Table 2. Dose Modification Guidelines:
| Dose Modifications for Patients with EBC | ||
|---|---|---|
| Adverse reaction | Severity | Treatment modification |
| Thrombocytopenia | Grade 2-3 on day of scheduled treatment (25,000 to <75,000/mm3) | Do not administer trastuzumab emtansine 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 trastuzumab emtansine until platelet count recovers to ≤ Grade 1 (≥75,000/mm3), and then reduce one dose level. | |
| Increased Alanine Transaminase (ALT) | Grade 2-3 (>3.0 to ≤20 x ULN on day of scheduled treatment) | Do not administer trastuzumab emtansine until ALT recovers to Grade ≤1, and then reduce one dose level |
| Grade 4 (>20 x ULN at any time) | Discontinue trastuzumab emtansine | |
| Increased Aspartate Transaminase (AST) | Grade 2 (>3.0 to ≤ 5 x ULN on day of scheduled treatment) | Do not administer trastuzumab emtansine until AST recovers to Grade ≤1, and then treat at the same dose level |
| Grade 3 (>5 to ≤20 x ULN on day of scheduled treatment) | Do not administer trastuzumab emtansine until AST recovers to Grade ≤1, and then reduce one dose level | |
| Grade 4 (>20 x ULN at any time) | Discontinue trastuzumab emtansine | |
| Hyperbilirubinemia | TBILI >1.0 to ≤2.0 x the ULN on day of scheduled treatment | Do not administer trastuzumab emtansine until total bilirubin recovers to ≤1.0 × ULN, and then reduce one dose level |
| TBILI >2 x ULN at any time | Discontinue trastuzumab emtansine | |
| Drug Induced Liver Injury (DILI) | Serum transaminases >3 x ULN and concomitant total bilirubin >2 x ULN | Permanently discontinue trastuzumab emtansine 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 trastuzumab emtansine |
| Peripheral Neuropathy | Grade 3-4 | Do not administer trastuzumab emtansine until resolution Grade 2 |
| Left Ventricular Dysfunction | LVEF <45% | Do not administer trastuzumab emtansine. Repeat LVEF assessment within 3 weeks. If LVEF <45% is confirmed, discontinue trastuzumab emtansine |
| LVEF 45% to <50% and decrease is ≥10% points from baseline* | Do not administer trastuzumab emtansine. Repeat LVEF assessment within 3 weeks. If the LVEF remains <50% and has not recovered to <10% points from baseline, discontinue trastuzumab emtansine. | |
| LVEF 45% to <50% and decrease is <10% points from baseline* | Continue treatment with trastuzumab emtansine. Repeat LVEF assessment within 3 weeks. | |
| LVEF ≥50% | Continue treatment with trastuzumab emtansine | |
| Heart Failure | Symptomatic CHF, Grade 3-4 LVSD or Grade 3-4 heart failure, or Grade 2 heart failure accompanied by LVEF <45% | Discontinue trastuzumab emtansine |
| Pulmonary Toxicity | Interstitial lung disease (ILD) or pneumonitis | Permanently discontinue trastuzumab emtansine |
| Radiotherapy-Related Pneumonitis | Grade 2 | Discontinue trastuzumab emtansine if not resolving with standard treatment |
| Grade 3-4 | Discontinue trastuzumab emtansine | |
| Dose Modifications for Patients with MBC | ||
| Adverse reaction | Severity | Treatment modification |
| Thrombocytopenia | Grade 3 (25,000 to <50,000/mm3) | Do not administer trastuzumab emtansine 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 trastuzumab emtansine until platelet count recovers to ≤ Grade 1 (≥75,000/mm3), and then reduce one dose level | |
| Increased Transaminase (AST/ALT) | Grade 2 (>2.5 to ≤5 x the ULN) | Treat at the same dose level |
| Grade 3 (>5 to ≤20 x the ULN) | Do not administer trastuzumab emtansine until AST/ALT recovers to Grade ≤2, and then reduce one dose level | |
| Grade 4 (>20 x the ULN) | Discontinue trastuzumab emtansine | |
| Hyperbilirubinemia | Grade 2 (>1.5 to ≤3 x the ULN) | Do not administer trastuzumab emtansine until total bilirubin recovers to Grade ≤1, and then treat at the same dose level |
| Grade 3 (>3 to ≤10 x the ULN) | Do not administer trastuzumab emtansine until total bilirubin recovers to Grade ≤1 and then reduce one dose level | |
| Grade 4 (>10 x the ULN) | Discontinue trastuzumab emtansine | |
| Drug Induced Liver Injury (DILI) | Serum transaminases >3 x ULN and concomitant total bilirubin >2 x ULN | Permanently discontinue trastuzumab emtansine in the absence of another likely cause for the elevation of liver enzymes and bilirubin, e.g. liver metastasis or concomitant medication |
| Left Ventricular Dysfunction | Symptomatic CHF | Discontinue trastuzumab emtansine |
| LVEF <40% | Do not administer trastuzumab emtansine. Repeat LVEF assessment within 3 weeks. If LVEF <40% is confirmed, discontinue trastuzumab emtansine | |
| LVEF 40% to ≤45% and decrease is ≥10% points from baseline | Do not administer trastuzumab emtansine. Repeat LVEF assessment within 3 weeks. If the LVEF has not recovered to within 10% points from baseline, discontinue trastuzumab emtansine | |
| LVEF 40% to ≤45% and decrease is <10% points from baseline | Continue treatment with trastuzumab emtansine. Repeat LVEF assessment within 3 weeks | |
| LVEF >45% | Continue treatment with trastuzumab emtansine | |
ALT = alanine transaminase; AST = aspartate transaminase, CHF = congestive heart failure, LVEF = left ventricular ejection fraction, LVSD = left ventricular systolic dysfunction, TBILI = Total Bilirubin, ULN = upper limit of normal
* Prior to starting trastuzumab emtansine treatment.
If a planned dose is missed, it should be administered as soon as possible; without waiting until the next planned cycle. The schedule of administration should be adjusted to maintain a 3-week interval between doses. The next dose should be administered in accordance with the dosing recommendations above.
Trastuzumab emtansine should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2. At retreatment a dose reduction may be considered according to the dose reduction schedule (see Table 1).
No dose adjustment is required in patients aged ≥65 years. There are insufficient data to establish the safety and efficacy in patients ≥75 years due to limited data in this subgroup. Population pharmacokinetic analysis indicates that age does not have a clinically meaningful effect on the pharmacokinetics of trastuzumab emtansine (see sections 5.1 and 5.2).
No adjustment to the starting dose is needed in patients with mild or moderate renal impairment (see section 5.2). The potential need for dose adjustment in patients with severe renal impairment cannot be determined due to insufficient data and therefore patients with severe renal impairment should be monitored carefully.
No adjustment to the starting dose is required for patients with mild or moderate hepatic impairment. Trastuzumab emtansine has not been studied in patients with severe hepatic impairment. Treatment of patients with hepatic impairment should be undertaken with caution due to known hepatotoxicity observed with trastuzumab emtansine (see section 4.4 and 5.2).
The safety and efficacy in children and adolescents below 18 years of age have not been established as there is no relevant use in the paediatric population for the indication of breast cancer.
Kadcyla is for intravenous use. Trastuzumab emtansine must be reconstituted and diluted by a healthcare professional and administered as an intravenous infusion. It must not be administered as an intravenous push or bolus.
For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.
There is no known antidote for trastuzumab emtansine overdose. In case of overdose, the patient should be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted. Cases of overdose have been reported with trastuzumab emtansine treatment, most associated with thrombocytopenia, and there was one death. In the fatal case, the patient incorrectly received trastuzumab emtansine 6 mg/kg and died approximately 3 weeks following the overdose; a causal relationship to trastuzumab emtansine was not established.
Unopened vial: 3 years.
Reconstituted solution: Chemical and physical in-use stability of the reconstituted solution has been demonstrated for up to 24 hours at 2°C to 8°C. From a microbiological point of view, the product should be used immediately. If not used immediately, the reconstituted vials can be stored for up to 24 hours at 2°C to 8°C, provided it was reconstituted under controlled and validated aseptic conditions, and must be discarded thereafter.
Diluted solution: The reconstituted Kadcyla solution diluted in infusion bags containing sodium chloride 9 mg/mL (0.9%) solution for infusion, or sodium chloride 4.5 mg/mL (0.45%) solution for infusion, is stable for up to 24 hours at 2°C to 8°C, provided it was prepared under controlled and validated aseptic conditions. Particulates may be observed on storage if diluted in 0.9% sodium chloride (see section 6.6).
Store in a refrigerator (2°C–8°C).
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.
Kadcyla 100 mg powder for concentrate for solution for infusion: Kadcyla is provided in 15 mL (100 mg) Type 1 glass vial closed with a grey-butyl rubber stopper coated with fluoro-resin laminate, and sealed with an aluminium seal with a white plastic flip-off cap.
Pack of 1 vial.
Kadcyla 160 mg powder for concentrate for solution for infusion: Kadcyla is provided in 20 mL (160 mg) Type 1 glass vial closed with a grey-butyl rubber stopper coated with fluoro resin laminate, and sealed with an aluminium seal with a purple plastic flip-off cap.
Pack of 1 vial.
Appropriate aseptic technique should be used. Appropriate procedures for the preparation of chemotherapeutic medicinal products should be used.
The reconstituted Kadcyla solution should be diluted in polyvinyl chloride (PVC) or latex-free PVC-free polyolefin infusion bags.
The use of 0.20 or 0.22 micron in-line polyethersulfone (PES) filter is required for the infusion when the concentrate for infusion is diluted with sodium chloride 9 mg/mL (0.9%) solution for infusion.
In order to prevent medicinal product errors it is important to check the vial labels to ensure that the medicinal product being prepared is Kadcyla (trastuzumab emtansine) and not Herceptin (trastuzumab).
Reconstituted solution should be inspected visually for particulate matter and discolouration prior to administration. The reconstituted solution should be free of visible particulates, clear to slightly opalescent. The colour of the reconstituted solution should be colourless to pale brown. Do not use if the reconstituted solution contains visible particulates, or is cloudy or discoloured.
Determine the volume of the reconstituted solution required based on a dose of 3.6 mg trastuzumab emtansine/kg body weight (see section 4.2):
Volume (mL) = Total dose to be administered (body weight (kg) x dose (mg/kg)) / 20 (mg/mL, concentration of reconstituted solution)
The appropriate amount of solution should be withdrawn from the vial and added to an infusion bag containing 250 mL of sodium chloride 4.5 mg/mL (0.45%) solution for infusion or sodium chloride 9 mg/mL (0.9%) solution for infusion. Glucose (5%) solution should not be used (see section 6.2). Sodium chloride 4.5 mg/mL (0.45%) solution for infusion may be used without a polyethersulfone (PES) 0.20 or 0.22-μm in-line filter. If sodium chloride 9 mg/mL (0.9%) solution for infusion is used for infusion, a 0.20 or 0.22 micron in-line polyethersulfone (PES) filter is required. Once the infusion is prepared it should be administered immediately. Do not freeze or shake the infusion during storage.
The reconstituted product contains no preservative and is intended for single use only. Discard any unused portion.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
