Dosage & Administration
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Kadcyla Prescribing Information
- Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin.
- Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function.
- Embryo-Fetal Toxicity: Exposure to KADCYLA during pregnancy can result in embryo-fetal harm. Advise patients of these risks and the need for effective contraception.
Metastatic Breast Cancer (MBC)
KADCYLA®, as a single agent, is indicated for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, 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.
Select patients for therapy based on an FDA-approved companion diagnostic for KADCYLA [see Dosage and Administration (2.1)].
Early Breast Cancer (EBC)
KADCYLA, as a single agent, is 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.
Select patients for therapy based on an FDA-approved companion diagnostic for KADCYLA [see Dosage and Administration (2.1)].
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.
Metastatic Breast Cancer (MBC)
Patients with MBC should receive treatment until disease progression or unmanageable toxicity.
Early Breast Cancer (EBC)
Patients with EBC should receive treatment for a total of 14 cycles unless there is disease recurrence or unmanageable toxicity.
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 | ||
| ||
| 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.
Lyophilized powder in single-dose vials: 100 mg per vial or 160 mg per vial of ado-trastuzumab emtansine.
Pregnancy
Pregnancy Pharmacovigilance Program
There is a pregnancy pharmacovigilance program for KADCYLA. If KADCYLA is administered during pregnancy, or if a patient becomes pregnant while receiving KADCYLA or within 7 months following the last dose of KADCYLA, health care providers and patients should immediately report KADCYLA exposure to Genentech at 1-888-835-2555.
Risk Summary
KADCYLA can cause fetal harm when administered to a pregnant woman. There are no available data on the use of KADCYLA in pregnant women. Cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death were observed in the postmarketing setting in patients treated with trastuzumab, the antibody component of KADCYLA [see Data]. Based on its mechanism of action, the DM1 component of KADCYLA can also cause embryo-fetal harm when administered to a pregnant woman [see Data]. Apprise the patient of the potential risks to a fetus. There are clinical considerations if KADCYLA is used in a pregnant woman, or if a patient becomes pregnant within 7 months following the last dose of KADCYLA [see Clinical Considerations].
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Monitor women who received KADCYLA during pregnancy or within 7 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care.
Data
Human Data
There are no available data on the use of KADCYLA in pregnant women. In the post-marketing setting, cases of oligohydramnios, and of oligohydramnios sequence, manifesting in the fetus as pulmonary hypoplasia, skeletal abnormalities and neonatal death were observed after treatment with trastuzumab during pregnancy. These case reports described oligohydramnios in pregnant women who received trastuzumab either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after trastuzumab was stopped. In one case, trastuzumab therapy resumed after amniotic index improved, and oligohydramnios recurred.
Animal Data
There were no reproductive and developmental toxicology studies conducted with ado-trastuzumab emtansine. DM1, the cytotoxic component of KADCYLA, disrupts microtubule function. DM1 is toxic to rapidly dividing cells in animals and is genotoxic, suggesting it has the potential to cause embryotoxicity and teratogenicity. In studies where trastuzumab was administered to pregnant cynomolgus monkeys during the period of organogenesis at doses up to 25 mg/kg given twice weekly (about 7 times the clinical dose), trastuzumab crossed the placental barrier during the early (Gestation Days 20 to 50) and late (Gestation Days 120 to 150) phases of gestation. The resulting concentrations of trastuzumab in fetal serum and amniotic fluid were approximately 33% and 25%, respectively, of those present in the maternal serum but were not associated with adverse developmental effects.
Lactation
Risk Summary
There is no information regarding the presence of ado-trastuzumab emtansine in human milk, the effects on the breastfed infant, or the effects on milk production. DM1, the cytotoxic component of KADCYLA, may cause serious adverse reactions in breastfed infants based on its mechanism of action [see Data]. Advise women not to breastfeed during treatment and for 7 months following the last dose of KADCYLA.
Data
There were no animal lactation studies conducted with ado-trastuzumab emtansine or the cytotoxic component of KADCYLA (DM1). In lactating cynomolgus monkeys, trastuzumab was present in breast milk at about 0.3% of maternal serum concentrations after pre- (beginning Gestation Day 120) and post-partum (through Post-partum Day 28) doses of 25 mg/kg administered twice weekly (about 7 times the clinical dose of KADCYLA). Infant monkeys with detectable serum levels of trastuzumab did not exhibit any adverse effects on growth or development from birth to 1 month of age.
Females and Males of Reproductive Potential
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to the initiation of KADCYLA.
Contraception
Females
KADCYLA can cause embryo-fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of KADCYLA [see Use in Specific Populations (8.1)].
Males
Because of the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment with KADCYLA and for 4 months following the last dose.
Infertility
Based on results from animal toxicity studies, KADCYLA may impair fertility in females and males of reproductive potential. It is not known if the effects are reversible [see Nonclinical Toxicology (13.1)].
Pediatric Use
Safety and effectiveness of KADCYLA have not been established in pediatric patients.
Geriatric Use
Of the 495 patients who were randomized to KADCYLA in EMILIA [see Clinical Studies (14.1)], 65 patients (13%) were ≥ 65 years of age and 11 patients (2%) were ≥ 75 years of age. In patients ≥ 65 years old (n=138 across both treatment arms) the hazard ratios for progression-free survival (PFS) and overall survival (OS) were 1.06 (95% CI: 0.68, 1.66) and 1.05 (95% CI: 0.58, 1.91), respectively. No overall differences in the safety of KADCYLA were observed in patients aged ≥ 65 compared to patients < 65 years of age. EMILIA did not include sufficient numbers of patients aged ≥ 75 years to draw conclusions on the safety or effectiveness of KADCYLA in this age group.
Of the 743 patients who were randomized to KADCYLA in KATHERINE [see Clinical Studies (14.2)], 58 patients (8%) were ≥ 65 years of age and 2 patients (0.3%) were ≥ 75 years of age. No overall differences in the safety or effectiveness of KADCYLA were observed in patients aged ≥ 65 compared to patients < 65 years of age. KATHERINE did not include sufficient numbers of patients aged ≥ 75 years to draw conclusions on the safety or effectiveness of KADCYLA in this age group.
Population pharmacokinetic analysis indicates that age does not have a clinically meaningful effect on the pharmacokinetics of ado-trastuzumab emtansine [see Clinical Pharmacology (12.3)].
Renal Impairment
No dedicated renal impairment trial for KADCYLA has been conducted. Based on the population pharmacokinetics, as well as analysis of Grade 3 or greater adverse reactions and dose modifications, dose adjustments of KADCYLA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 89 mL/min) or moderate (CLcr 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited data available [see Clinical Pharmacology (12.3)].
Hepatic Impairment
No adjustment to the starting dose is required for patients with mild or moderate hepatic impairment [see Clinical Pharmacology (12.3)]. KADCYLA was not studied in patients with severe hepatic impairment. Closely monitor patients with hepatic impairment due to known hepatotoxicity observed with KADCYLA [see Warnings and Precautions, Hepatotoxicity (5.1)].
None.