Dosage & Administration
For intravenous (IV) infusion only. Do not administer as an intravenous push or bolus.
Do not substitute TRAZIMERA (trastuzumab-qyyp) for or with ado-trastuzumab emtansine. ( 2.2)
Perform HER2 testing using FDA-approved tests by laboratories with demonstrated proficiency.
Adjuvant Treatment of HER2-Overexpressing Breast Cancer
Administer at either:
Metastatic HER2-Overexpressing Breast Cancer
Metastatic HER2-Overexpressing Gastric Cancer
Trazimera Prescribing Information
Cardiomyopathy
Administration of trastuzumab products can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving trastuzumab with anthracycline-containing chemotherapy regimens.
Evaluate left ventricular function in all patients prior to and during treatment with TRAZIMERA. Discontinue TRAZIMERA treatment in patients receiving adjuvant therapy and withhold TRAZIMERA in patients with metastatic disease for clinically significant decrease in left ventricular function [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].
Infusion Reactions; Pulmonary Toxicity
Administration of trastuzumab products can result in serious and fatal infusion reactions and pulmonary toxicity. Symptoms usually occur during or within 24 hours of administration. Interrupt TRAZIMERA infusion for dyspnea or clinically significant hypotension. Monitor patients until symptoms completely resolve. Discontinue TRAZIMERA for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome [see Warnings and Precautions (5.2, 5.4)].
Embryo-Fetal Toxicity
Exposure to trastuzumab products during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.3)].
Adjuvant Breast Cancer
TRAZIMERA is indicated for adjuvant treatment of HER2-overexpressing node positive or node negative (ER/PR negative or with one high risk feature [see Clinical Studies (14.1)]) breast cancer
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- as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
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- as part of a treatment regimen with docetaxel and carboplatin
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- as a single agent following multi-modality anthracycline based therapy.
Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product [see Dosage and Administration (2.1)].
Metastatic Breast Cancer
TRAZIMERA is indicated:
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- In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer
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- As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease.
Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product [see Dosage and Administration (2.1)].
Metastatic Gastric Cancer
TRAZIMERA is indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease.
Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product [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) and Clinical Studies (14)]. Assessment of HER2 protein overexpression and HER2 gene amplification should be performed using FDA-approved tests specific for breast or gastric 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.
Assessment of HER2 protein overexpression and HER2 gene amplification in metastatic gastric cancer should be performed using FDA-approved tests specifically for gastric cancers due to differences in gastric vs. breast histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers.
Improper assay performance, including use of suboptimally 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
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- Do not administer as an intravenous push or bolus. Do not mix TRAZIMERA with other drugs.
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- Do not substitute TRAZIMERA (trastuzumab-qyyp) for or with ado-trastuzumab emtansine.
Adjuvant Treatment, Breast Cancer
Administer according to one of the following doses and schedules for a total of 52 weeks of TRAZIMERA therapy:
During and following paclitaxel, docetaxel, or docetaxel and carboplatin:
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- Initial dose of 4 mg/kg as an intravenous infusion over 90 minutes then at 2 mg/kg as an intravenous infusion over 30 minutes weekly during chemotherapy for the first 12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel and carboplatin).
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- One week following the last weekly dose of TRAZIMERA, administer TRAZIMERA at 6 mg/kg as an intravenous infusion over 30 to 90 minutes every three weeks.
As a single agent within three weeks following completion of multi-modality, anthracycline-based chemotherapy regimens:
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- Initial dose at 8 mg/kg as an intravenous infusion over 90 minutes.
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- Subsequent doses at 6 mg/kg as an intravenous infusion over 30 to 90 minutes every three weeks [see Dosage and Administration (2.3)].
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- Extending adjuvant treatment beyond one year is not recommended [see Adverse Reactions (6.1)].
Metastatic Treatment, Breast Cancer
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- Administer TRAZIMERA, alone or in combination with paclitaxel, at an initial dose of 4 mg/kg as a 90-minute intravenous infusion followed by subsequent once weekly doses of 2 mg/kg as 30-minute intravenous infusions until disease progression.
Metastatic Gastric Cancer
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- Administer TRAZIMERA at an initial dose of 8 mg/kg as a 90-minute intravenous infusion followed by subsequent doses of 6 mg/kg as an intravenous infusion over 30 to 90 minutes every three weeks until disease progression [see Dosage and Administration (2.3)].
Important Dosing Considerations
If the patient has missed a dose of TRAZIMERA by one week or less, then the usual maintenance dose (weekly schedule: 2 mg/kg; three-weekly schedule: 6 mg/kg) should be administered as soon as possible. Do not wait until the next planned cycle. Subsequent TRAZIMERA maintenance doses should be administered 7 days or 21 days later according to the weekly or three-weekly schedules, respectively.
If the patient has missed a dose of TRAZIMERA by more than one week, a re-loading dose of TRAZIMERA should be administered over approximately 90 minutes (weekly schedule: 4 mg/kg; three-weekly schedule: 8 mg/kg) as soon as possible. Subsequent TRAZIMERA maintenance doses (weekly schedule: 2 mg/kg; three-weekly schedule 6 mg/kg) should be administered 7 days or 21 days later according to the weekly or three-weekly schedules, respectively.
Infusion Reactions
[See Boxed Warning, Warnings and Precautions (5.2)]
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- Decrease the rate of infusion for mild or moderate infusion reactions
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- Interrupt the infusion in patients with dyspnea or clinically significant hypotension
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- Discontinue TRAZIMERA for severe or life-threatening infusion reactions.
Cardiomyopathy
[See Boxed Warning, Warnings and Precautions (5.1)]
Assess left ventricular ejection fraction (LVEF) prior to initiation of TRAZIMERA and at regular intervals during treatment. Withhold TRAZIMERA dosing for at least 4 weeks for either of the following:
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- ≥ 16% absolute decrease in LVEF from pre-treatment values
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- LVEF below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values.
TRAZIMERA may be resumed if, within 4 to 8 weeks, the LVEF returns to normal limits and the absolute decrease from baseline is ≤ 15%.
Permanently discontinue TRAZIMERA for a persistent (> 8 weeks) LVEF decline or for suspension of TRAZIMERA dosing on more than 3 occasions for cardiomyopathy.
Preparation for Administration
To prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is TRAZIMERA (trastuzumab-qyyp) and not ado-trastuzumab emtansine.
420 mg Multiple-Dose Vial
Reconstitution
Reconstitute each 420 mg vial of TRAZIMERA with 20 mL of Bacteriostatic Water for Injection (BWFI) containing 1.1% benzyl alcohol as a preservative to yield a multiple-dose solution containing 21 mg/mL trastuzumab-qyyp that delivers 20 mL (420 mg trastuzumab-qyyp). In patients with known hypersensitivity to benzyl alcohol, reconstitute with 20 mL of Sterile Water for Injection (SWFI) without preservative to yield a single use solution.
Use appropriate aseptic technique when performing the following reconstitution steps:
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- Using a sterile syringe, slowly inject the 20 mL of diluent into the vial containing the lyophilized powder of TRAZIMERA, which has a cake-like appearance. The reconstituted vial yields a solution for multiple-dose use, containing 21 mg/mL trastuzumab-qyyp.
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- Swirl the vial gently to aid reconstitution. DO NOT SHAKE.
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- Slight foaming of the product may be present upon reconstitution. Allow the vial to stand undisturbed for approximately 5 minutes.
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- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect visually for particulates and discoloration. The solution should be free of visible particulates, clear to slightly opalescent and colorless to pale yellow-brown.
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- Store reconstituted TRAZIMERA in the refrigerator at 2°C to 8°C (36°F to 46°F); discard unused TRAZIMERA after 28 days. If TRAZIMERA is reconstituted with SWFI without preservative, use immediately and discard any unused portion. Do not freeze.
Dilution
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- Determine the dose (mg) of TRAZIMERA [see Dosage and Administration (2.2)].
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- Calculate the volume of the 21 mg/mL reconstituted TRAZIMERA solution needed.
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- Withdraw this amount from the vial and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP. DO NOT USE DEXTROSE (5%) SOLUTION.
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- Gently invert the bag to mix the solution.
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- The solution of TRAZIMERA for infusion diluted in polyvinylchloride, polyethylene, polypropylene, or ethylene vinyl acetate bags or glass intravenous bottles containing 0.9% Sodium Chloride Injection, USP, should be stored at 2°C to 8°C (36°F to 46°F) for no more than 24 hours prior to use. Do not freeze.
150 mg Single-Dose Vial
Reconstitution
Reconstitute each 150 mg vial of TRAZIMERA with 7.4 mL of Sterile Water for Injection (SWFI) (not supplied) to yield a single-dose solution containing 21 mg/mL trastuzumab-qyyp that delivers 7.15 mL (150 mg trastuzumab-qyyp).
Use appropriate aseptic technique when performing the following reconstitution steps:
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- Using a sterile syringe, slowly inject 7.4 mL of SWFI (not supplied) into the vial containing the lyophilized powder of TRAZIMERA, which has a cake-like appearance. The reconstituted vial yields a solution for single-dose use, containing 21 mg/mL trastuzumab-qyyp.
- •
- Swirl the vial gently to aid reconstitution. DO NOT SHAKE.
- •
- Slight foaming of the product may be present upon reconstitution. Allow the vial to stand undisturbed for approximately 5 minutes.
- •
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect visually for particulates and discoloration. The solution should be free of visible particulates, clear to slightly opalescent and colorless to pale yellow-brown.
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- Use the TRAZIMERA solution immediately following reconstitution with SWFI, as it contains no preservative and is intended for single-dose only. If not used immediately, store the reconstituted TRAZIMERA solution for up to 24 hours at 2°C to 8°C (36°F to 46°F); discard unused TRAZIMERA after 24 hours. Do not freeze.
Dilution
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- Determine the dose (mg) of TRAZIMERA [see Dosage and Administration (2.2)].
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- Calculate the volume of the 21 mg/mL reconstituted TRAZIMERA solution needed.
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- Withdraw this amount from the vial and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP. DO NOT USE DEXTROSE (5%) SOLUTION.
- •
- Gently invert the bag to mix the solution.
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- The solution of TRAZIMERA for infusion diluted in polyvinylchloride, polyethylene, polypropylene, or ethylene vinyl acetate bags or glass intravenous bottles containing 0.9% Sodium Chloride Injection, USP, should be stored at 2°C to 8°C (36°F to 46°F) for no more than 24 hours prior to use. Discard after 24 hours. This storage time is additional to the time allowed for the reconstituted vials. Do not freeze.
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- For injection: 150 mg of TRAZIMERA as a white lyophilized powder in a single-dose vial.
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- For injection: 420 mg of TRAZIMERA as a white lyophilized powder in a multiple-dose vial.
Pregnancy
Risk Summary
Trastuzumab products can cause fetal harm when administered to a pregnant woman. In post-marketing reports, use of trastuzumab during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence, manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death (see Data). Apprise the patient of the potential risks to a fetus. There are clinical considerations if a trastuzumab product is used in a pregnant woman or if a patient becomes pregnant within 7 months following the last dose of a trastuzumab product (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% to 4% and 15% to 20%, respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Monitor women who received TRAZIMERA 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
In post-marketing reports, use of trastuzumab during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence, manifesting in the fetus as pulmonary hypoplasia, skeletal abnormalities and neonatal death. 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
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 (up to 25 times the recommended weekly human dose of 2 mg/kg), 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 trastuzumab products in human milk, the effects on the breastfed infant, or the effects on milk production. Published data suggest human IgG is present in human milk but does not enter the neonatal and infant circulation in substantial amounts. Trastuzumab was present in the milk of lactating cynomolgus monkeys but not associated with neonatal toxicity (see Data). Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for TRAZIMERA treatment and any potential adverse effects on the breastfed child from TRAZIMERA or from the underlying maternal condition. This consideration should also take into account the trastuzumab product wash out period of 7 months [see Clinical Pharmacology (12.3)].
Data
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 (25 times the recommended weekly human dose of 2 mg/kg of trastuzumab products). 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 TRAZIMERA.
Contraception
Females
Trastuzumab products can cause embryo-fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment with TRAZIMERA and for 7 months following the last dose of TRAZIMERA [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].
Pediatric Use
The safety and effectiveness of trastuzumab products in pediatric patients have not been established.
Geriatric Use
Trastuzumab has been administered to 386 patients who were 65 years of age or over (253 in the adjuvant treatment and 133 in metastatic breast cancer treatment settings). The risk of cardiac dysfunction was increased in geriatric patients as compared to younger patients in both those receiving treatment for metastatic disease in Studies 5 and 6, or adjuvant therapy in Studies 1 and 2. Limitations in data collection and differences in study design of the 4 studies of trastuzumab in adjuvant treatment of breast cancer preclude a determination of whether the toxicity profile of trastuzumab in older patients is different from younger patients. The reported clinical experience is not adequate to determine whether the efficacy improvements (ORR, TTP, OS, DFS) of trastuzumab treatment in older patients is different from that observed in patients <65 years of age for metastatic disease and adjuvant treatment.
In Study 7 (metastatic gastric cancer), of the 294 patients treated with trastuzumab, 108 (37%) were 65 years of age or older, while 13 (4.4%) were 75 and over. No overall differences in safety or effectiveness were observed.
None.