Trastuzumab is a recombinant DNA-derived humanized IgG1 kappa monoclonal antibody against the HER2 protein, indicated for the treatment of breast cancer and gastric cancer. Use should be limited to patients with documented overexpression of the HER2 protein. Due to differences in tumor histopathology, detection of HER2 protein overexpression should be accomplished using FDA-approved tests for the specific tumor type (breast or gastric/gastroesophageal adenocarcinoma). Gene amplification and HER2 protein overexpression are not as well correlated in gastric cancer as they are in breast cancer. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. Treatment with trastuzumab product can cause heart failure, with the highest incidence in patients receiving concomitant therapy with anthracyclines; monitor left ventricular function in all patients. Patients should also be monitored for infusion reactions, as severe and fatal occurrences have been reported in clinical trials and postmarketing experience.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Emetic Risk
-Minimal
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
NOTE: Patients should be selected based on the presence of HER2 protein overexpression or HER2 gene amplification in tumor specimens. Information on FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at http://www.fda.gov/CompanionDiagnostics. Tests should be specific for breast cancers due to differences in breast vs. gastric histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers.
Intravenous Administration
-Administer as an intravenous infusion; do not administer IV push or as a bolus.
-Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase.
-If a patient misses a dose by 1 week or less, administer the usual maintenance dose (weekly schedule, 2 mg/kg; every-3-week schedule, 6 mg/kg) as soon as possible; do not wait until the next planned cycle. Administer subsequent maintenance doses 7 days or 21 days later, according to the weekly or 3-weekly schedules, respectively.
-If a patient misses a dose by more than 1 week, administer a reloading dose (weekly schedule, 4 mg/kg; every-3-week schedule, 8 mg/kg) over approximately 90 minutes as soon as possible. Administer subsequent maintenance doses 7 days or 21 days later, according to the weekly or 3-weekly schedules, respectively.
-Observe patients for infusion-related reactions such as fever or chills, or more severe reactions including respiratory distress or severe hypersensitivity reactions. Interrupt the infusion for patients experiencing dyspnea (e.g., acute bronchospasm) or clinically significant hypotension. Decrease the rate of infusion for mild or moderate infusion reactions. Monitor patients until signs and symptoms completely resolve. Discontinue trastuzumab for severe or life-threatening infusion reactions and strongly consider permanent discontinuation of therapy.
-Do NOT mix or dilute with other drugs or dextrose solutions.
Reconstitution:
-420 mg multiple-dose vial: Inject 20 mL of Bacteriostatic Water for Injection (containing 0.9% to 1.1% benzyl alcohol) into the vial to result in a 21 mg/mL solution that delivers 20 mL. May also be reconstituted with 20 mL of Sterile Water for Injection USP (without a preservative) for patients with benzyl alcohol hypersensitivity, for single-use.
-150 mg single-dose vial: Inject 7.4 mL of Sterile Water for Injection into the vial, to result in a 21 mg/mL solution that delivers 7.15 mL.
-The stream of diluent should be directed into the lyophilized powder, which has a cake-like appearance. Swirl gently to aid dissolution; do not shake.
-Slight foaming of the product upon reconstitution is not unusual. Allow the vial to stand undisturbed for approximately 5 minutes. The solution should be free of visible particles, clear to slightly opalescent and colorless to pale yellow.
-Storage after reconstitution: Solutions reconstituted with Bacteriostatic Water for Injection are stable for 28 days under refrigeration (36 to 46 degrees F; 2 to 8 degrees C); do NOT freeze. If reconstituted with Sterile Water for Injection (no preservative), the vial should be used immediately for only 1 dose. If not used immediately, store reconstituted trastuzumab without preservative refrigerated for up to 24 hours (2 to 8 degrees Celsius or 36 to 46 degrees Fahrenheit); do NOT freeze. Discard any unused trastuzumab after 24 hours.
Dilution:
-Withdraw the appropriate amount of solution and add to 250 mL of 0.9% Sodium Chloride Injection in polyvinylchloride or polyethylene bags. Do not use 5% Dextrose Injection. Gently invert the bag to mix the solution.
Storage after dilution:
-Diluted solutions are stable for up to 24 hours under refrigeration (36 to 46 degrees F; 2 to 8 degrees C) in addition to any time allowed for the reconstituted vials; do NOT freeze.
Cardiotoxicity, including left ventricular dysfunction, arrhythmias, heart failure, cardiomyopathy, and cardiac death has been reported during treatment with trastuzumab product. There is a 4- to 6-fold increase in the incidence of symptomatic myocardial dysfunction in patients treated with trastuzumab products, either as monotherapy or in combination therapy, compared with those not receiving trastuzumab products; the highest risk occurs when the patient is also receiving an anthracycline. In the adjuvant breast cancer studies, the incidence of congestive heart failure (CHF) ranged from 0.4% to 4.6% (severe, NYHA III and IV, 0.8%) in trastuzumab-treated patients compared with 0.3% to 1.3% in the control arms; some cases were fatal. The incidence of CHF was higher in patients first treated with AC chemotherapy (2% to 3.2%). In a randomized clinical trial of adjuvant breast cancer treatment with 3-weekly trastuzumab (n = 1,678) for one year after completion of surgery and chemotherapy, compared with observation (n = 1,708), decreased ejection fraction (3.5% vs. 0.6%), CHF (2% vs. 0.3%), heart failure (0.5% vs. 0.2%), and ventricular dysfunction (0.2% vs. 0%) were reported. The rate of asymptomatic cardiac dysfunction was increased in patients receiving 2 years of treatment with 3-weekly trastuzumab compared to 1 year (8.1% vs. 4.6%). A new onset of an LVEF of 50% or less occurred in 8.5% to 23.1% of trastuzumab-treated patients in adjuvant breast cancer trials, with a 10% or more decrease from baseline in 5.9% to 18.5% of patients and a 16% or more decrease from baseline in 3% to 11.2% of patients. An absolute decrease in LVEF of 20% or more occurred in 3.4% to 13.2% of patients in these trials. In 2 clinical trials of adjuvant breast cancer therapy, approximately 24% of surviving patients had recovery to a normal LVEF (greater than or equal to 50%) and were asymptomatic on continued medical management at the time of last follow-up. The incidence of cardiac dysfunction was higher in metastatic breast cancer studies. In 2 clinical trials of patients with metastatic breast cancer, the incidence of sinus tachycardia and CHF was similar in patients treated with trastuzumab alone compared to AC alone or paclitaxel alone (5% vs. 5% vs. 4%); however, the incidence increased in patients treated with trastuzumab in combination with AC or paclitaxel (10% vs. 12%). Similarly, the incidence of CHF was similar among patients treated with trastuzumab alone compared to AC alone or paclitaxel alone (7% vs. 7% vs. 1%) but higher when trastuzumab was combined with AC or paclitaxel (28% vs. 11%). In one study, the incidence of grade 3 or 4 cardiac ischemia/myocardial infarction was higher in the trastuzumab-containing regimens (AC-TH, 0.3%; TCH, 0.2%) compared to non-trastuzumab regimens (AC-T, 0%). In another metastatic breast cancer study, 5% of patients treated with trastuzumab plus chemotherapy had an LVEF below 50% with a 10% or more decrease from baseline, compared to 1.1% of patients in the chemotherapy alone arm. There is some evidence of reversibility of left ventricular dysfunction, with 64% of patients treated with AC-TH and experiencing symptomatic CHF in one clinical trial being asymptomatic at the last follow-up, and 90.3% having full or partial LVEF recovery. The safety of continuing or resuming trastuzumab product in patients with treatment-induced left ventricular cardiac dysfunction has not been adequately studied. However, 22 of 25 patients who developed left ventricular dysfunction during adjuvant trastuzumab therapy (after anthracycline treatment) had stable LVEF measurements and no CHF recurrence after rechallenge once symptoms were stable and patients were on maximum tolerated doses of ACE inhibitors and beta blockers. In another study, 16 of 26 patients with metastatic breast cancer who developed trastuzumab-related cardiotoxicity and fully recovered did not experience additional cardiotoxicity upon rechallenge; 10 patients had a subsequent cardiac event, with varying degrees of resolution after trastuzumab discontinuation. Trastuzumab was continued in 17 of 34 metastatic breast cancer patients with asymptomatic cardiac dysfunction in an additional retrospective study; 13 of these patients had complete recovery without specific cardiac treatment, 2 had a complete recovery with treatment, and 2 were not assessed. In a randomized clinical trial of adjuvant breast cancer treatment with 3-weekly trastuzumab (n = 1,678) for one year after completion of surgery and chemotherapy, compared with observation (n = 1,708), the following additional cardiac events were reported: palpitations (3% vs. 0.7%), cardiac arrhythmias (3% vs. 1%), and cardiac disorder (0.3% vs. 0%).
Peripheral edema was reported in 5% of adjuvant breast cancer patients treated with 3-weekly trastuzumab (n = 1,678) for one year after completion of surgery and chemotherapy, compared with 2% of those in the observation arm (n = 1,708) of a randomized clinical trial. In patients with metastatic breast cancer treated with trastuzumab alone (n = 352) or in combination with chemotherapy (n = 234), the incidence of peripheral edema was 10% to 22%, which was similar to patients treated with paclitaxel monotherapy (n = 95; 20%) or AC chemotherapy (n = 135; n = 17%) without trastuzumab.
In a randomized clinical trial of patients receiving adjuvant treatment for breast cancer, grade 2 to 5 edema was reported in 4.7% of patients treated with trastuzumab plus paclitaxel after completion of AC chemotherapy (doxorubicin plus cyclophosphamide), compared with 2.7% of those receiving paclitaxel alone after AC; the majority of edema was grade 2 in severity. In 2 clinical trials of patients with metastatic breast cancer, the incidence of edema was similar in patients treated with trastuzumab alone or in combination with AC or paclitaxel, as well as in patients treated with AC alone or paclitaxel alone (8% to 11%).
In a randomized clinical trial of adjuvant treatment for breast cancer, hypertension was reported in 4% of patients treated with 3-weekly trastuzumab (n = 1,678) for one year after completion of surgery and chemotherapy, compared with 2% of those in the observation arm (n = 1,708). Patients with uncontrolled hypertension at baseline (diastolic greater than 100 mmHg or systolic greater than 180 to 200 mmHg) were generally excluded from clinical trials.
In 2 randomized clinical trials of patients receiving adjuvant treatment for breast cancer, the incidence of thrombosis was higher in patients treated with trastuzumab plus chemotherapy (2.5% to 3.7%) compared with chemotherapy alone (1.5% to 2.2%). Thrombosis also occurred more often in patients with metastatic breast cancer treated with trastuzumab plus chemotherapy compared to chemotherapy alone (2.1% vs. 0%).
Renal impairment occurred in 18% (grade 3 or 4 [renal failure (unspecified)], 2.7%) of patients with metastatic gastric cancer treated with trastuzumab plus FC chemotherapy compared with 14.5% (grade 3 or 4, 1.7%) of patients treated with FC alone. Rare cases of nephrotic syndrome with pathologic evidence of glomerulopathy (e.g., membranous glomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis) have also been reported in postmarketing experience, resulting in complications including volume overload and congestive heart failure. The time to onset of renal impairment ranged from 4 months to approximately 18 months from initiation of trastuzumab therapy.
Arthralgia has been reported in 6% to 8% of patients treated with adjuvant trastuzumab monotherapy in clinical trials. The incidence increases when administered in combination with paclitaxel compared to paclitaxel alone, in both adjuvant (12.2% vs. 9.1%) and metastatic breast cancer (37% vs. 21%); the incidence of arthralgia was not increased when trastuzumab was administered with AC in metastatic breast cancer (8% vs. 9%). Additional generalized and musculoskeletal adverse reactions reported in adjuvant breast cancer clinical trials included fatigue (29.5%), pain (unspecified) (5.5%), back pain (5%), asthenia (4.5%), myalgia (4%), bone pain (3%), and muscle spasms (3%). The incidence is higher in patients with metastatic breast cancer, whether trastuzumab was given alone or in combination with chemotherapy. When administered as monotherapy in metastatic breast cancer, pain (unspecified) occurred in 42% of patients, while asthenia (42%), back pain (22%), and bone pain (7%) were also reported. The addition of trastuzumab to chemotherapy also increased the incidence compared to chemotherapy alone: asthenia (54% to 62% vs. 55% to 57%), pain (unspecified) (57% to 61% vs. 42% to 62%), back pain (27% to 34% vs. 15% to 30%), and bone pain (7% to 24% vs. 7% to 18%). Fatigue was also reported in 35% (grade 3 or 4, 4%) of patients with metastatic gastric cancer treated with trastuzumab plus FC chemotherapy compared with 28% (grade 3 or 4, 2%) receiving FC alone.
Hematologic toxicities are infrequent following administration of trastuzumab alone; however, the incidence is higher when administered in combination with myelosuppressive chemotherapy and varies with the type of chemotherapy administered. In randomized controlled clinical trials, the overall incidence of anemia (30% vs. 21%), of selected grade 2 to 5 anemia (12.3% vs. 6.7%), and of anemia requiring transfusions (0.1% vs. 0 patients) were increased in patients receiving trastuzumab plus chemotherapy compared with those receiving chemotherapy alone. Anemia occurred in 4% (grade 3, less than 1%) of metastatic breast cancer patients treated with trastuzumab monotherapy in one clinical trial, compared with 9% of patients treated with paclitaxel and 14% of those who received trastuzumab plus paclitaxel; likewise, the incidence of anemia was 26% in metastatic breast cancer patients treated with AC compared with 36% of those receiving AC and trastuzumab. In patients with metastatic gastric cancer, anemia was reported in 21% (grade 3 or 4, 10.3%) of patients in the chemotherapy arm (FC) compared with 28% (grade 3 or 4, 12.2%) of patients treated with chemotherapy plus trastuzumab. Thrombocytopenia also occurred in 11% (grade 3 or 4, 3%) compared with 16% (grade 3 or 4, 5%) of patients in this trial, respectively. Immune-mediated thrombocytopenia has also been reported in postmarketing experience with trastuzumab.
Hematologic toxicities are infrequent following administration of trastuzumab alone; however, the incidence is higher when administered in combination with myelosuppressive chemotherapy and varies with the type of chemotherapy administered. In randomized controlled clinical trials in the adjuvant setting, the incidence of selected grade 4 to 5 neutropenia (1.7% vs. 0.8%) and of selected grade 2 to 5 neutropenia (6.4% vs. 4.3%) were increased in patients receiving trastuzumab and chemotherapy compared with those receiving chemotherapy alone. The incidence of leukopenia (3% vs. 24% to 52% vs. 17% to 34%) was also increased in patients with metastatic breast cancer treated with trastuzumab alone compared to trastuzumab plus chemotherapy (paclitaxel or AC) compared to chemotherapy alone; grade 3 or 4 neutropenia (32% vs. 22%) and febrile neutropenia (23% vs. 17%) were also increased in patients randomized to trastuzumab in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. In a clinical trial of patients with metastatic gastric cancer, neutropenia occurred in 78% (grade 3 or 4, 34% to 36.8%) of patients treated with trastuzumab and chemotherapy (FC) compared to 73% (grade 3 or 4, 28.9%) of patients treated with chemotherapy alone; febrile neutropenia occurred in 5.1% compared to 2.8%.
An increased incidence of infection has been reported with trastuzumab when administered as monotherapy or in combination with chemotherapy. In a randomized clinical trial of adjuvant treatment for breast cancer, 4% of patients treated with 3-weekly trastuzumab (n = 1,678) for one year after completion of surgery and chemotherapy reported influenza, compared with 0.5% of those in the observation arm (n = 1,708); an influenza-like illness was additionally reported in 2% versus 0.2% of patients, respectively. Naso-pharyngitis (8% vs. 0%), upper respiratory infections (3% vs. 1%), urinary tract infections (3% vs. 0%), rhinitis (2% vs. 0.4%), and sinusitis (2% vs. 0.3%) also occurred more often in the trastuzumab arm. The overall incidences of infection (46% vs. 30%), of selected grade 2 to 5 infection/febrile neutropenia (24.3% vs. 13.4%) and of selected grade 3 to 5 infection/febrile neutropenia (2.9% vs. 1.4%) were higher in patients receiving trastuzumab and chemotherapy compared with those receiving chemotherapy alone in adjuvant studies. The most common site of infections in the adjuvant setting involved the upper respiratory tract, skin, and urinary tract. Like other adverse reactions, the incidence of infection was increased in patients with metastatic breast cancer and was reported in 20% of patients receiving trastuzumab monotherapy, 37% to 47% of patients receiving trastuzumab plus chemotherapy (grade 3 or 4, less than or equal to 25%), and 27% to 31% of patients receiving chemotherapy alone (grade 3 or 4, less than or equal to 23%). Specifically, a flu-like syndrome occurred in 6%, 9% to 13%, and 3% to 4% of patients, respectively, while rhinitis (trastuzumab, 14%; trastuzumab plus chemotherapy, 22%; chemotherapy alone, 5% to 16%), pharyngitis (trastuzumab, 12%; trastuzumab plus chemotherapy, 22% to 30%; chemotherapy alone, 14% to 18%), sinusitis (trastuzumab, 9%; trastuzumab plus chemotherapy, 13% to 21%; chemotherapy alone, 6% to 7%), and urinary tract infection (trastuzumab, 5%; trastuzumab plus chemotherapy, 13% to 18%; chemotherapy alone, 7% to 14%) were also reported. Mild (grade 1 or 2) upper respiratory infections occurred in 19% of patients with metastatic gastric cancer treated with trastuzumab plus FC chemotherapy compared with 10% of those receiving chemotherapy alone, while mild naso-pharyngitis occurred in 13% versus 6% of patients, respectively.
Initial studies indicate a low-level antibody formation against trastuzumab. Of 903 patients evaluated, human anti-human antibody (HAHA) was only detected in one patient who did not experience any allergic manifestations. In a randomized clinical trial of adjuvant treatment for breast cancer, 4 out of 1,678 trastuzumab recipients (0.3%) experienced autoimmune thyroiditis compared to no patients in the observation group.
Dermatologic adverse reactions have been reported with a higher incidence in patients treated with trastuzumab compared to control arms. In adjuvant breast cancer clinical trials, rash (unspecified) (4% to 10.9%), nail disorders (2%), nail changes (11.5%), and pruritus (2%) were reported. In patients with metastatic breast cancer, the incidence of rash was increased compared to adjuvant therapy and was also increased when trastuzumab was added to chemotherapy compared to trastuzumab monotherapy. Rash occurred in 18% of patients with metastatic breast cancer treated with trastuzumab monotherapy, compared to 38% of patients treated with trastuzumab plus paclitaxel (paclitaxel alone, 18%) and 27% of patients treated with trastuzumab plus AC (AC alone, 17%). Additionally, herpes simplex was reported in 2% to 12% of metastatic breast cancer patients treated with trastuzumab monotherapy or in combination with chemotherapy, while acne vulgaris occurred in 2% to 11% of patients.
In a randomized clinical trial of adjuvant treatment for breast cancer, epistaxis was reported in 2% of patients treated with 3-weekly trastuzumab (n = 1,678) for one year after completion of surgery and chemotherapy, compared with 0.06% of those in the observation arm (n = 1,708).
Adverse reactions of the nervous system have been reported in patients treated with trastuzumab in clinical trials. In a randomized clinical trial of adjuvant treatment for breast cancer, dizziness was reported in 4% of patients treated with 3-weekly trastuzumab (n = 1,678) for one year after completion of surgery and chemotherapy, compared with 2% of those in the observation arm (n = 1,708); headache (10% vs. 3%) and paresthesias (2% vs. 0.6%) were also reported in these patients. Hot flashes (17.1% vs. 15%), headache (6.2% vs. 3.8%), and insomnia were also reported more frequently among adjuvant breast cancer patients receiving trastuzumab plus chemotherapy compared with chemotherapy alone; the majority of events were grade 2 in severity. As with other adverse reactions, headache (26%), insomnia (14%), dizziness (13%), and paresthesias (9%) occurred more often in patients with metastatic breast cancer receiving trastuzumab monotherapy. The addition of trastuzumab to chemotherapy in metastatic breast cancer often increased the incidence compared to chemotherapy alone, including insomnia (paclitaxel plus trastuzumab, 25% vs. paclitaxel alone, 13%; AC plus paclitaxel, 29% vs. AC alone, 15%), dizziness (paclitaxel plus trastuzumab, 22% vs. paclitaxel alone, 24%; AC plus paclitaxel, 24% vs. AC alone, 18%), and paresthesias (paclitaxel plus trastuzumab, 48% vs. paclitaxel alone, 39%; AC plus paclitaxel, 17% vs. AC alone, 11%). Depression (monotherapy, 6%; paclitaxel plus trastuzumab, 12% vs. paclitaxel alone, 13%; AC plus paclitaxel, 20% vs. AC alone, 12%), peripheral neuritis (monotherapy, 2%; paclitaxel plus trastuzumab, 23% vs. paclitaxel alone, 16%; AC plus paclitaxel, 2% vs. AC alone, 2%), and peripheral neuropathy (monotherapy, 1%; paclitaxel plus trastuzumab, 13% vs. paclitaxel alone, 5%; AC plus paclitaxel, 4% vs. AC alone, 4%) were also reported in these patients.
Hypokalemia was reported in 28% (grade 3 or 4, 10%) of patients with metastatic gastric cancer treated with trastuzumab plus FC chemotherapy compared with 24% (grade 3 or 4, 6%) of patients who received FC alone.
Gastrointestinal (GI) adverse reactions have been reported with an increased incidence in patients treated with trastuzumab (either as monotherapy or with chemotherapy) compared to controls. In randomized clinical trials of adjuvant treatment for breast cancer, diarrhea was reported in 2.2% to 7% of patients treated with trastuzumab compared with less than or equal to 1% of those in control groups. In a randomized clinical trial of adjuvant treatment for breast cancer, nausea (6% vs. 1%), vomiting (3.5% vs. 0.6%), constipation (2% vs. 1%), dyspepsia (2% vs. 0.5%), upper abdominal pain (2% vs. 1%), and pharyngolaryngeal pain (2% vs. 0.5%) were additionally reported in patients treated with 3-weekly trastuzumab (n = 1,678) for one year after completion of surgery and chemotherapy compared with observation (n = 1,708). As with other adverse reactions, the incidence of GI events increases in patients with metastatic disease, whether trastuzumab is used as monotherapy or in combination with chemotherapy. In patients with metastatic breast cancer, nausea (33%), diarrhea (25%), vomiting (23%), abdominal pain (22%), nausea and vomiting (8%), and anorexia (14%) have been reported with trastuzumab monotherapy. In metastatic breast or gastric cancer, in combination with chemotherapy versus chemotherapy alone, the following GI events were reported: nausea (paclitaxel, 51% vs. 9%; AC, 76% vs. 77%), diarrhea (paclitaxel, 45% vs. 29%; AC, 45% vs. 26%; FC, 37% [grade 3 or 4, 9%] vs. 28% [grade 3 or 4, 4%]), vomiting (paclitaxel, 37% vs. 28%; AC, 53% vs. 49%), abdominal pain (paclitaxel, 34% vs. 22%; AC, 23% vs. 18%), nausea and vomiting (paclitaxel, 14% vs. 11%; AC, 18% vs. 9%), and anorexia (paclitaxel, 24% vs. 16%; AC, 31% vs. 26%). Stomatitis (all grade, 24% vs. 15%; grade 3 or 4, 1% vs. 2%), dysphagia (all grade, 6% vs. 3%; grade 3 or 4, 2% vs. less than or equal to 1%), mucosal inflammation (all grade, 13% vs. 6%; grade 3 or 4, 2% vs. 1%), and weight loss (all grade, 23% vs. 14%; grade 3 or 4, 2% vs. 2%) were also reported in patients with metastatic gastric cancer treated with trastuzumab plus FC compared with FC alone.
In a randomized clinical trial of patients with metastatic gastric cancer, mild (grade 1 or 2) dysgeusia was reported in 10% of patients treated with trastuzumab plus FC chemotherapy compared with 5% receiving chemotherapy alone.
An allergic reaction to trastuzumab was reported in 0.6% to 8% of patients in adjuvant breast cancer trials, with trastuzumab administered either as monotherapy or in combination with chemotherapy. During the initial infusion of trastuzumab, approximately 40% of patients across clinical trials experienced infusion-related reactions; the most commonly reported symptoms were chills (all grade, 5% to 41%; grade 3 or 4, less than or equal to 1%) and fever (all grade, 6% to 56%; grade 3 or 4, less than or equal to 1%) of trastuzumab-treated patients in clinical trials. The reactions were treated with acetaminophen, diphenhydramine, and meperidine with or without slowing the trastuzumab infusion; permanent discontinuation of trastuzumab for infusion reactions was reported in less than 1% of patients. Infusion-related reactions occurred in 21% (severe, 1.4%) of patients during subsequent infusions of trastuzumab monotherapy, and in 35% (severe, 9%) of patients treated with trastuzumab in combination with chemotherapy. Symptoms included nausea, vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, elevated blood pressure, rash, and asthenia. In the postmarketing setting, severe and fatal infusion reactions have been reported, including bronchospasm, anaphylaxis (anaphylactoid reactions, anaphylactic shock), angioedema, hypoxia, and severe hypotension. The onset and clinical course varied, including progressive worsening, initial improvement followed by clinical deterioration, or delayed events with rapid deterioration. For fatal events, death occurred within hours to days following a serious infusion reaction. Infusions of trastuzumab product should be interrupted for dyspnea or clinically significant hypotension; discontinue therapy for anaphylaxis, angioedema, or acute respiratory distress syndrome. Strongly consider discontinuation of therapy in patients with other severe reactions, as no data exist regarding the most appropriate method of identification of patients who may safely be retreated with trastuzumab. Most patients who experienced a severe infusion reaction were premedicated with antihistamines and/or corticosteroids before resumption of trastuzumab infusion. Some patients tolerated trastuzumab, but some patients had recurrent severe infusion reactions despite premedications.
Trastuzumab product can result in serious and fatal pulmonary toxicity, including dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusion, non-cardiogenic pulmonary edema, pulmonary insufficiency, hypoxia, acute respiratory distress syndrome (ARDS), and pulmonary fibrosis; these events can occur as sequelae of infusion reactions. Grade 2 or higher pulmonary toxicity occurred in 3.4% to 14.3% of patients treated with trastuzumab plus chemotherapy in adjuvant breast cancer trials (n = 2,000). Pneumonitis/pulmonary infiltrates occurred in 0.7% of patients receiving trastuzumab plus chemotherapy compared with 0.3% of those receiving chemotherapy alone; fatal respiratory failure occurred in 3 patients receiving trastuzumab compared to 1 patient receiving chemotherapy alone. In randomized clinical trials of adjuvant treatment for breast cancer, dyspnea was the most common pulmonary toxicity, reported in 2.4% to 11.8% of patients treated with 3-weekly trastuzumab either as monotherapy or in combination with chemotherapy (n = 3,678), compared with 0.2% to 4.6% of those in comparator arms (n = 3,363); dyspnea was mostly grade 2 in severity. In one adjuvant breast cancer trial, additional respiratory adverse reactions included cough (5% vs. 2%), pulmonary hypertension (0.2% vs. 0%), and interstitial pneumonitis (0.2% vs. 0%) in patients treated with 3-weekly trastuzumab (n = 1,678) for one year after completion of surgery and chemotherapy compared with observation (n = 1,708). The incidence of pulmonary toxicity was increased in patients with metastatic breast cancer treated with trastuzumab either as monotherapy or in combination with chemotherapy (paclitaxel or AC) compared with chemotherapy alone, including cough (26% vs. 41% to 43% vs. 22% to 29%) and dyspnea (22% vs. 27% to 42% vs. 25% to 26%).
Oligohydramnios resulting in teratogenesis (e.g., pulmonary hypoplasia and skeletal abnormalities) and neonatal death has been reported in postmarketing surveillance of trastuzumab. Oligohydramnios has occurred in pregnant women who received trastuzumab alone or in combination with chemotherapy. In some women, the amniotic fluid index increased after trastuzumab cessation. In one case, treatment was resumed with trastuzumab after the amniotic fluid index improved, resulting in a recurrence of oligohydramnios.
Cases of tumor lysis syndrome (TLS) have been reported in patients treated with trastuzumab. Patients with significant tumor burden (e.g., bulky metastases) may be at higher risk. Patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure (unspecified); consider additional monitoring and/or treatment as clinically indicated.
Administration of trastuzumab products can result in infusion-related reactions characterized by fever and chills, nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia. In postmarketing experience, serious and fatal infusion reactions have also been reported, including bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension. Infusion reactions were usually reported during or immediately following the initial infusion, but the onset and clinical course may vary, including progressive worsening, initial improvement followed by clinical deterioration, or delayed post-infusion events with rapid deterioration. For fatal events, death occurred within hours to days following a serious infusion reaction. Decrease the infusion rate for mild to moderate infusion reactions. Hold the infusion of trastuzumab product in all patients experiencing dyspnea or clinically significant hypotension, or if medical intervention (e.g., epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen) is required. Monitor patients until complete resolution of signs and symptoms. Discontinue trastuzumab product for anaphylaxis, angioedema, or acute respiratory distress syndrome; strongly consider discontinuation of therapy in patients with other severe reactions, as no data exist regarding the most appropriate method of identification of patients who may safely be retreated with trastuzumab. Most patients who experienced a severe infusion reaction were premedicated with antihistamines and/or corticosteroids before resumption of trastuzumab infusion. Some patients tolerated trastuzumab, but some patients had recurrent severe infusion reactions despite premedications.
Use trastuzumab products with caution in patients with preexisting chronic lung disease (CLD) such as chronic obstructive pulmonary disease (COPD), asthma, or pulmonary fibrosis. Trastuzumab products can cause serious and fatal pulmonary toxicity, including dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis, which may be more severe in patients with symptomatic intrinsic lung disease or with more extensive tumor involvement of the lungs that results in dyspnea at rest. These reactions can also occur as sequelae of infusion reactions. Discontinue trastuzumab product for interstitial pneumonitis.
Use trastuzumab products with caution in patients with a history of cardiac disease, heart failure, cardiomyopathy, ventricular dysfunction, hypertension, or cardiac arrhythmias, as trastuzumab products can cause these issues as well as cardiac death; an asymptomatic decline in the left ventricular ejection fraction (LVEF) is also possible. The risk of cardiac dysfunction was increased in geriatric patients compared to younger patients in clinical trials. Obtain a baseline measurement of LVEF by echocardiogram or MUGA immediately prior to initiation of trastuzumab products, every 3 months during treatment, upon completion of therapy, and every 6 months for at least 2 years after treatment for adjuvant therapy. An interruption or discontinuation of therapy may be necessary for a decline in LVEF; the safety of continuing or resuming trastuzumab product in patients with treatment-induced left ventricular cardiac dysfunction has not been adequately studied. However, 22 of 25 patients who developed left ventricular dysfunction during adjuvant trastuzumab therapy (after anthracycline treatment) had stable LVEF measurements and no CHF recurrence after rechallenge once symptoms were stable and patients were on maximum tolerated doses of ACE inhibitors and beta-blockers. In another study, 16 of 26 patients with metastatic breast cancer who developed trastuzumab-related cardiotoxicity and fully recovered did not experience additional cardiotoxicity upon rechallenge; 10 patients had a subsequent cardiac event, with varying degrees of resolution after trastuzumab discontinuation. Trastuzumab was continued in 17 of 34 metastatic breast cancer patients with asymptomatic cardiac dysfunction in an additional retrospective study; 13 of these patients had complete recovery without specific cardiac treatment, 2 had complete recovery with treatment, and 2 were not assessed. Monitoring of the LVEF should occur more frequently, at 4-week intervals, if treatment is held for significant left ventricular cardiac dysfunction. Elevated troponin I immediately before or after trastuzumab administration may also be a predictor of cardiotoxicity. Patients who receive anthracycline therapy after stopping a trastuzumab product may be at increased risk of cardiac dysfunction; among patients receiving trastuzumab products as a single agent or in combination therapy, the highest absolute incidence of symptomatic cardiac dysfunction occurs when trastuzumab product is administered with an anthracycline.
Multidose vials of trastuzumab product are supplied in a carton with a vial of bacteriostatic water for injection as diluent, containing 1.1% benzyl alcohol as a preservative. For patients with known benzyl alcohol hypersensitivity, do not use the supplied diluent but reconstitute trastuzumab product with sterile water for injection.
Initial studies indicate a low level of immunogenicity of trastuzumab. Of 903 patients evaluated, human anti-human antibody (HAHA) was only detected in one patient who did not experience any allergic manifestations. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Results may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. Comparison of the incidence of antibodies to trastuzumab with the incidence of antibodies to other products may be misleading.
Trastuzumab product may exacerbate chemotherapy-induced neutropenia; monitor patients closely. The incidence of grade 3 or 4 neutropenia and febrile neutropenia was higher in patients treated with trastuzumab in combination with myelosuppressive chemotherapy compared to chemotherapy alone in randomized clinical trials; however, the rate of septic death was similar among these two groups.
Cases of tumor lysis syndrome (TLS) have been reported in patients treated with trastuzumab. Patients with significant tumor burden (e.g., bulky metastases) may be at higher risk. Patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure (unspecified); consider additional monitoring and/or treatment as clinically indicated.
Intravenous trastuzumab has different dosage and administration recommendations than trastuzumab; hyaluronidase, fam-trastuzumab deruxtecan, or ado-trastuzumab emtansine. Ensure correct formulation selection and dose before preparation and administration.
Serious fetal harm can occur if trastuzumab product is administered during pregnancy or within 7 months prior to conception. Counsel women to avoid pregnancy during trastuzumab therapy and for 7 months after the last dose. If a woman becomes pregnant while receiving or within 7 months of receiving trastuzumab, inform her of the fetal risks, monitor for oligohydramnios, and immediately report to the pregnancy pharmacovigilance program at Genentech (1-888-835-2555). If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and is consistent with community standards of care. Oligohydramnios and oligohydramnios sequence (manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death) have occurred in pregnant women who received trastuzumab alone or in combination with chemotherapy. In some women, the amniotic fluid index increased after trastuzumab cessation. In one case, treatment was resumed with trastuzumab after the amniotic fluid index improved, resulting in a recurrence of oligohydramnios.
Counsel patients about the reproductive risk and contraception requirements during and after treatment with trastuzumab product. Trastuzumab can be teratogenic if taken by the mother during pregnancy or within 7 months prior to conception. Females should avoid pregnancy and use effective contraception during and for at least 7 months after treatment with trastuzumab product. Females of reproductive potential should undergo pregnancy testing prior to treatment initiation. Women who become pregnant while receiving trastuzumab or within 7 months of the last dose should be apprised of the potential hazard to the fetus; healthcare providers and patients should immediately report trastuzumab exposure to Genentech (1-888-835-2555).
It is not known whether trastuzumab products are excreted into human milk. Published data suggest human IgG is present in human milk but does not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in a nursing infant, advise women to discontinue breast-feeding during treatment with trastuzumab product and for 7 months after the last dose.
For the treatment of patients with HER2-positive breast cancer:
NOTE: Patients should be selected based on the presence of HER2 protein overexpression or HER2 gene amplification in tumor specimens. Information on FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at http://www.fda.gov/CompanionDiagnostics. Tests should be specific for breast cancers due to differences in breast vs. gastric histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers.
-for the neoadjuvant treatment of HER2-positive breast cancer sequential to and in combination with doxorubicin, paclitaxel, and CMF chemotherapy*:
Intravenous dosage:
Adults: 8 mg/kg IV over 90 minutes on day 1 (of cycle 1 only), followed 3 weeks later by 6 mg/kg IV over 30 minutes repeated every 3 weeks for 10 cycles, in combination with the following chemotherapy regimens. Doxorubicin (60 mg/m2 IV), followed by paclitaxel (150 mg/m2 IV over 3 hours) every 3 weeks for 3 cycles beginning on day 1 of trastuzumab therapy; then give paclitaxel (175 mg/m2 IV) alone every 3 weeks for an additional 4 cycles. After completion of doxorubicin/paclitaxel, administer cyclophosphamide (600 mg/m2 IV), methotrexate (40 mg/m2 IV), and fluorouracil (600 mg/m2 IV) on days 1 and 8, every 4 weeks for 3 cycles (CMF); trastuzumab may be administered every 4 weeks during CMF chemotherapy. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. Patients with ER-/PR-positive breast cancer should receive an antiestrogen agent per guidelines. Surgery followed by radiation therapy should be scheduled after the completion of chemotherapy. In the clinical trial, additional cycles of trastuzumab were administered after surgery, beginning before or during radiotherapy, until the completion of one year total of trastuzumab therapy. In a phase 3 clinical trial, event-free survival was significantly improved at 3 years with the addition of trastuzumab to neoadjuvant doxorubicin/paclitaxel followed by CMF (71% vs. 56%) in patients with locally advanced HER2-positive breast cancer. In addition, the addition of trastuzumab significantly improved pathologic complete response rates compared to patients who did not receive trastuzumab (38% vs. 19%). Adverse events were similar between the treatment groups.
-for the neoadjuvant treatment of HER2-positive breast cancer in combination with paclitaxel, after completion of 4 cycles of fluorouracil and cyclophosphamide (FEC-75)*:
Intravenous dosage:
Adults: 4 mg/kg IV over 90 minutes on week 1, then 2 mg/kg IV over 30 minutes once weekly, in combination with paclitaxel 80 mg/m2 IV once weekly, every 21 days for 4 cycles (12 weeks). Administer after completion of 4 cycles of cyclophosphamide (500 mg/m2 IV), epirubicin (75 mg/m2 IV), and fluorouracil (500 mg/m2 IV) on day 1, every 21 days for 4 cycles (FEC-75). Epirubicin dose adjustments for subsequent cycles are recommended by the manufacturer based on nadir ANC and platelet counts. Surgery should be performed after completion of paclitaxel plus trastuzumab therapy, followed by trastuzumab 6 mg/kg IV every 3 weeks for a total of 52 weeks from the first preoperative dose. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. In a randomized, phase 3 clinical trial, neoadjuvant treatment with FEC-75 followed by paclitaxel plus trastuzumab (sequential therapy) resulted in similar rates of pathologic complete response (pCR), disease-free survival (DFS), and overall survival (OS) compared with paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab (concurrent therapy). Sequential therapy was better tolerated and had a lower incidence of cardiac adverse reactions.
-for adjuvant treatment of HER2-positive, node-positive or node-negative (ER/PR negative or with one high-risk feature) breast cancer as monotherapy, following multimodality anthracycline-based chemotherapy:
Intravenous dosage:
Adults: 8 mg/kg IV over 90 minutes on day 1 (of the first cycle only), followed 3 weeks later by 6 mg/kg IV over 30 to 90 minutes, repeated every 21 days for a total of 52 weeks. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. Trastuzumab therapy should begin within 3 weeks after completion of multi-modality, anthracycline-based chemotherapy. Extending treatment beyond 1 year is not recommended as it increased the risk of asymptomatic cardiac dysfunction (2 years, 8.1%; 1 year, 4.6%) and grade 3 or higher adverse reactions (2 years, 20.4%; 1 year, 16.3%) without improving efficacy. In a randomized clinical trial of patients with HER2-positive breast cancer, one year of adjuvant trastuzumab after the completion chemotherapy and radiation (if applicable) resulted in significantly improved disease-free survival compared with observation; overall survival was not significantly improved.
-for adjuvant treatment of HER2-positive, node-positive or node-negative (ER/PR negative or with one high-risk feature) breast cancer in combination with docetaxel, after completion of doxorubicin and cyclophosphamide chemotherapy (AC-TH):
Intravenous dosage:
Adults: 4 mg/kg IV over 90 minutes on day 1 (of first cycle only), then 2 mg/kg IV over 30 minutes once weekly for a total of 12 weeks, in combination with docetaxel (100 mg/m2 IV every 21 days) beginning on day 1 for a total of 4 cycles (12 weeks). On week 13, begin trastuzumab 6 mg/kg IV over 30 to 90 minutes every 3 weeks as monotherapy for a total of 52 weeks of trastuzumab therapy. Begin docetaxel plus trastuzumab after the completion of 4 cycles of AC chemotherapy (doxorubicin 60 mg/m2 IV and cyclophosphamide 600 mg/m2 IV every 21 days); trastuzumab should NOT be administered concurrently with doxorubicin and cyclophosphamide. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. Extending treatment beyond 1 year is not recommended as it increased the risk of asymptomatic cardiac dysfunction (2 years, 8.1%; 1 year, 4.6%) and grade 3 or higher adverse reactions (2 years, 20.4%; 1 year, 16.3%) without improving efficacy. In a randomized clinical trial of patients with HER2-positive breast cancer, adjuvant treatment with docetaxel plus trastuzumab after completion of AC chemotherapy significantly improved disease-free survival compared with docetaxel alone.
-for adjuvant treatment of HER2-positive, node-positive or node-negative (ER/PR negative or with one high-risk feature) breast cancer in combination with paclitaxel, following completion of doxorubicin and cyclophosphamide chemotherapy (AC-TH):
Intravenous dosage:
Adults: 4 mg/kg IV over 90 minutes on day 1 (of first cycle only), then 2 mg/kg IV over 30 minutes once weekly for a total of 12 weeks, in combination with paclitaxel (either 80 mg/m2 IV weekly or 175 mg/m2 IV every 3 weeks) beginning on day 1 for a total of 12 weeks. On week 13, begin trastuzumab 6 mg/kg IV over 30 to 90 minutes every 3 weeks as monotherapy for a total of 52 weeks of trastuzumab therapy. Begin paclitaxel plus trastuzumab after the completion of 4 cycles of AC chemotherapy (doxorubicin 60 mg/m2 IV and cyclophosphamide 600 mg/m2 IV every 21 days); trastuzumab should NOT be administered concurrently with doxorubicin and cyclophosphamide. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. Extending treatment beyond 1 year is not recommended as it increased the risk of asymptomatic cardiac dysfunction (2 years, 8.1%; 1 year, 4.6%) and grade 3 or higher adverse reactions (2 years, 20.4%; 1 year, 16.3%) without improving efficacy. In an efficacy analysis of two randomized clinical trials of patients with HER2-positive breast cancer (n = 3,752), the adjuvant combination of paclitaxel plus trastuzumab after the completion of AC chemotherapy significantly improved both disease-free survival and overall survival compared with paclitaxel alone.
-for adjuvant treatment of HER2-positive, node-positive or node negative (ER/PR negative or with one high-risk feature) breast cancer, in combination with carboplatin and docetaxel (TCH):
Intravenous dosage:
Adults: 4 mg/kg IV over 90 minutes on day 1 (of first cycle only), then 2 mg/kg IV over 30 minutes once weekly for a total of 18 weeks, in combination with docetaxel (75 mg/m2 IV) followed by carboplatin (AUC 6 IV over 30 to 60 minutes) every 3 weeks beginning on day 1 for a total of 6 cycles (18 weeks). On week 19, begin trastuzumab 6 mg/kg IV over 30 to 90 minutes every 3 weeks as monotherapy for a total of 52 weeks of trastuzumab therapy. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. Extending treatment beyond 1 year is not recommended as it increased the risk of asymptomatic cardiac dysfunction (2 years, 8.1%; 1 year, 4.6%) and grade 3 or higher adverse reactions (2 years, 20.4%; 1 year, 16.3%) without improving efficacy. In a randomized clinical trial, adjuvant treatment with trastuzumab in combination with docetaxel and carboplatin significantly improved disease-free survival compared with doxorubicin plus cyclophosphamide (AC) followed by docetaxel.
-for the treatment of HER2-positive, hormone receptor-positive metastatic breast cancer, in combination with anastrozole*:
Intravenous dosage:
Adults: 4 mg/kg IV over 90 minutes on day 1 (of the first cycle only), then 2 mg/kg IV over 30 minutes once weekly, in combination with anastrozole (1 mg PO once daily) until disease progression or unacceptable toxicity. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. Progression-free survival was significantly improved with the addition of trastuzumab to anastrozole therapy compared with anastrozole alone in a phase 3 clinical trial (4.8 months vs. 2.4 months); overall survival was not significantly different between the treatment groups. Of note, 70% of patients in the anastrozole alone arm received a trastuzumab-containing regimen after developing progressive disease on anastrozole. Cardiac events occurred more frequently in the trastuzumab arm (14 events vs. 2 events); however, the incidence of grade 3 of 4 events was similar between the groups (2 events each).
-for the treatment of HER2-positive metastatic breast cancer, in combination with docetaxel*:
Intravenous dosage:
Adults: 4 mg/kg IV over 90 minutes on day 1 (of first cycle only), then 2 mg/kg IV over 30 minutes once weekly until disease progression or unacceptable toxicity, in combination with docetaxel (100 mg/m2 IV on day 1) every 21 days for 6 to 8 cycles. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. In a phase 2 trial of 186 patients with previously untreated HER2-positive metastatic breast cancer, docetaxel/trastuzumab significantly improved overall response rate (ORR) compared to docetaxel alone (61% vs 34%); time-to-progression (TTP) (11.7 vs. 6.1 months) and overall survival (OS) (31.2 vs. 22.7 months) were also significantly improved in the docetaxel/trastuzumab arm. This benefit has been confirmed in other clinical trials, including a phase 3 trial of 263 patients where it was shown to produce a similar TTP and OS to docetaxel/carboplatin/trastuzumab, a regimen with known activity against breast cancer in the adjuvant setting. In a phase 2 trial of 30 women with HER2-overexpressed metastatic breast cancer, docetaxel 35 mg/m2 IV on days 1, 8, and 15 was studied in combination with trastuzumab 2 mg/kg IV (4 mg/kg IV on day 0 of first cycle only) on days 1, 8, and 15, repeated every 28 days until disease progression or unacceptable toxicity; the ORR was 63%.
-for the first-line treatment of HER2-positive metastatic breast cancer, in combination with paclitaxel:
Intravenous dosage:
Adults: 4 mg/kg IV over 90 minutes on day 1 (of the first cycle only), then 2 mg/kg IV over 30 minutes once weekly until disease progression, in combination with paclitaxel (175 mg/m2 IV over 3 hours on day 1) every 21 days for at least 6 cycles. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. In a multicenter, randomized, open-label clinical trial of patients with previously untreated metastatic breast cancer, treatment with trastuzumab plus paclitaxel significantly improved the median time to progression (6.7 vs. 2.5 months), overall response rate (38% vs. 15%), and duration of response (8.3 vs. 4.3 months) compared with paclitaxel alone; overall survival was not significantly improved.
-for the treatment of HER2-positive metastatic breast cancer, in combination with vinorelbine*:
Intravenous dosage, EVERY-3-WEEK VINORELBINE:
Adults: 8 mg/kg IV over 90 minutes on day 1 (of the first cycle only), followed 3 weeks later by 6 mg/kg IV over 30 minutes on day 1 every 3 weeks, in combination with vinorelbine (30 mg/m2 or 35 mg/m2 IV bolus on days 1 and 8) every 3 weeks, until disease progression or unacceptable toxicity. Administer vinorelbine after trastuzumab. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. In a phase 3 trial, patients with previously untreated locally advanced or metastatic breast cancer randomized to receive trastuzumab plus vinorelbine (n = 141) had a nonsignificant improvement in median time to progression (15.3 vs. 12.4 months) and overall survival (38.8 vs. 35.7 months) compared with trastuzumab plus docetaxel (n = 143). Grade 3 or 4 febrile neutropenia, leukopenia, infection, fever, neuropathy, and edema were significantly worse in the docetaxel arm.
Intravenous dosage, WEEKLY VINORELBINE:
Adults: 4 mg/kg IV over 90 minutes on day 1 (of the first cycle only), then 2 mg/kg IV over 30 minutes once weekly, in combination with vinorelbine (25 mg/m2 IV once weekly) beginning on day 1, until disease progression or unacceptable toxicity. Administer vinorelbine after trastuzumab. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. Trastuzumab plus vinorelbine had a response rate of 51% to 58% in two small clinical trials.
-for the front-line treatment of HER2-overexpressing metastatic breast cancer, in combination with carboplatin and paclitaxel*:
Intravenous dosage, EVERY-3-WEEK CARBOPLATIN/PACLITAXEL:
Adults: 4 mg/kg IV over 90 minutes on day 1 (of first cycle only), then 2 mg/kg IV over 30 minutes once weekly, in combination with paclitaxel (175 mg/m2 IV) followed by carboplatin (AUC 6 IV) administered on day 2 every 3 weeks, for at least 6 cycles. After chemotherapy is complete, continue trastuzumab 2 mg/kg IV over 30 minutes once weekly until disease progression or unacceptable toxicity. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. The primary endpoint of overall response rate was significantly increased with the addition of carboplatin to trastuzumab/paclitaxel compared with paclitaxel alone in a phase 3 clinical trial (52% vs. 36%). Progression-free survival was also superior in the carboplatin arm (10.7 vs. 7.1 months). Grade 4 neutropenia (36% vs. 12%) and grade 3 thrombocytopenia (9% vs. 1%) occurred more frequently in the carboplatin arm.
Intravenous dosage, WEEKLY CARBOPLATIN/PACLITAXEL:
Adults: 4 mg/kg IV over 90 minutes on day 1 (of first cycle only), then 2 mg/kg IV over 30 minutes once weekly, in combination with paclitaxel (80 mg/m2 IV over 1 hour) followed by carboplatin (AUC 2 IV over 15 minutes) on days 1, 8, and 15, repeated every 28 days for a maximum of 6 cycles. On days 1, 8, and 15 in the clinical trial, trastuzumab was administered immediately after paclitaxel and carboplatin infusions. After chemotherapy is complete, continue trastuzumab (2 mg/kg IV over 30 minutes once weekly, or 6 mg/kg IV every 3 weeks) until disease progression or unacceptable toxicity. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. In a parallel, multicenter phase 2 trial, weekly administration of paclitaxel/carboplatin/trastuzumab had an overall response rate of 81% compared to 65% with every-3-week therapy; median time to progression and median overall survival were also improved.
-for first-line treatment of HER2-positive metastatic breast cancer in combination with pertuzumab and docetaxel*:
NOTE: Pertuzumab is FDA approved in combination with trastuzumab and docetaxel for the first-line treatment of HER2-positive metastatic breast cancer.
Intravenous dosage:
Adults: 8 mg/kg IV over 90 minutes on day 1 (of first cycle only), followed 3 weeks later by trastuzumab 6 mg/kg IV over 30 to 90 minutes, repeated every 3 weeks until disease progression or unacceptable toxicity, in combination with pertuzumab (840 mg IV over 60 minutes initially, followed 3 weeks later by pertuzumab 420 mg IV over 30 to 60 minutes, repeated every 3 weeks until disease progression or unacceptable toxicity) and docetaxel (75 mg/m2 IV every 3 weeks for at least 6 cycles; dose may be escalated to 100 mg/m2 if the initial dose is well-tolerated). Pertuzumab and trastuzumab can be given in any order; however, both agents should precede docetaxel. If trastuzumab is given after pertuzumab, delay the infusion 30 to 60 minutes to observe for pertuzumab-related infusion reactions. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. Progression-free survival time was significantly improved in patients with HER2-positive metastatic breast cancer (CLEOPATRA study) treated with pertuzumab plus trastuzumab and docetaxel arm compared with those who received placebo plus trastuzumab and docetaxel (18.5 vs. 12.4 months) in a multicenter, double-blind, placebo-controlled trial. In a second interim analysis, median overall survival (OS) was also significantly improved in the pertuzumab-containing arm (not reached vs. 37.6 months).
-for the treatment of HER2-positive metastatic breast cancer in patients who have failed one or more chemotherapy regimens for metastatic disease as monotherapy:
Intravenous dosage:
Adults: 4 mg/kg IV over 90 minutes on day 1 (first week only), then 2 mg/kg IV over 30 minutes once weekly until disease progression. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. Monotherapy with trastuzumab resulted in an overall response rate of 14% (complete response, 2%; partial response, 12%) in a multicenter, open-label, single-arm clinical trial in patients with relapse after 1 or more prior chemotherapy regimens for metastatic disease. Complete responses only occurred in patients with disease limited to the skin and lymph nodes. The response rate for patients with tumors that tested as CTA 3+ was 18%, while the response rate was 6% for tumors that tested as CTA 2+.
-for the treatment of HER2-positive, trastuzumab-refractory metastatic breast cancer, in combination with lapatinib*:
Intravenous dosage:
Adults: 4 mg/kg IV over 90 minutes on week 1 (of the first cycle only), then 2 mg/kg IV over 30 minutes once weekly, in combination with lapatinib (1,000 mg PO once daily) beginning on day 1. Continue until disease progression or unacceptable toxicity. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. Progression-free survival was significantly improved in patients with HER2-positive, trastuzumab-refractory metastatic breast cancer treated with lapatinib plus trastuzumab compared with lapatinib alone in a phase 3 clinical trial (12 weeks vs. 8.1 weeks); the overall response rate was not significantly different between the two arms. Diarrhea occurred significantly more often in the combination therapy arm (60% vs. 48%); the incidence of symptomatic (2% vs. 0.7%) and asymptomatic (3.4% vs. 1.4%) cardiac events were also higher in the combination therapy arm.
-for the treatment of HER2-positive, trastuzumab-resistant, advanced breast cancer in patients previously treated with a taxane, in combination with vinorelbine and everolimus*:
Intravenous dosage:
Adults: 4 mg/kg IV over 90 minutes on day 1 (of the first cycle only), then 2 mg/kg IV over 30 minutes once weekly, in combination with vinorelbine (25 mg/m2 IV once weekly) and everolimus (5 mg PO once daily) until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided with everolimus or everolimus dosage adjustments may be necessary; review drug interactions. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. Everolimus plus vinorelbine and trastuzumab significantly improved progression-free survival compared with placebo plus vinorelbine and trastuzumab in patients with HER2-positive, trastuzumab-resistant advanced breast cancer in patients who had received prior taxane therapy; objective response rate and overall survival were not significantly improved.
-for the treatment of advanced unresectable or metastatic HER2-positive breast cancer in patients who have received at least one prior anti-HER2-based regimen in the metastatic setting, in combination with tucatinib and capecitabine*:
Intravenous dosage:
Adults: 8 mg/kg IV over 90 minutes on day 1 (of cycle 1 only), followed 3 weeks later by 6 mg/kg IV over 30 minutes repeated every 21 days. This is given in combination with tucatinib and capecitabine until disease progression or unacceptable toxicity; tucatinib and capecitabine can be taken at the same time. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The addition of tucatinib to trastuzumab and capecitabine significantly improved median progression-free survival (PFS) (7.8 months vs. 5.6 months) and overall survival (21.9 months vs. 17.4 months) compared with placebo plus trastuzumab and capecitabine in patients with HER2-positive, unresectable locally advanced or metastatic breast cancer after prior HER2 treatment in a randomized, double-blind clinical trial (HER2CLIMB); all patients had received prior trastuzumab and ado-trastuzumab emtansine and all but 2 patients had prior pertuzumab. The confirmed objective response rate was also significantly improved with the addition of tucatinib (40.6% vs. 22.8%; complete response, 3% vs. 2%) for a median duration of 8.3 months versus 6.3 months, respectively. Patients with brain metastases were eligible for inclusion in the HER2CLIMB study as long as they were neurologically stable and did not require immediate radiation or surgery; patients with leptomeningeal disease were excluded. The median PFS in patients with brain metastases was similar to the overall population (7.6 months vs. 5.4 months).
For the treatment of gastric cancer:
-for the treatment of patients with previously untreated HER2-positive metastatic gastric cancer or gastroesophageal junction adenocarcinoma, in combination with cisplatin and fluorouracil:
NOTE: Patients should be selected based on the presence of HER2 protein overexpression or HER2 gene amplification in tumor specimens. Information on FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at www.fda.gov/CompanionDiagnostics. Tests should be specific for gastric cancers due to differences in breast vs. gastric histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers.
Intravenous dosage:
Adults: 8 mg/kg IV over on day 1 (of first cycle only), followed 3 weeks later by 6 mg/kg IV over every 21 days until disease progression or unacceptable toxicity, in combination with cisplatin (80 mg/m2 IV on day 1) plus either fluorouracil (800 mg/m2 per day by continuous IV infusion on days 1 to 5), every 21 days for 6 cycles. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. The primary endpoint of median overall survival was significantly improved in previously untreated patients with metastatic gastric cancer who received trastuzumab plus cisplatin and fluorouracil or capecitabine (n = 298) compared with chemotherapy alone (n = 296) (13.1 months vs. 11.7 months) in open-label clinical trial.
-for the treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma in patients who have not received prior treatment for metastatic disease, in combination with cisplatin and capecitabine:
NOTE: Patients should be selected based on the presence of HER2 protein overexpression or HER2 gene amplification in tumor specimens. Information on FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at www.fda.gov/CompanionDiagnostics. Tests should be specific for gastric cancers due to differences in breast vs. gastric histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers.
Intravenous dosage:
Adults: 8 mg/kg IV on day 1 of cycle 1 (then 6 mg/kg IV on day 1 of subsequent cycles), in combination with capecitabine (1,000 mg/m2 PO twice daily on days 1 to 14) and cisplatin (80 mg/m2 IV on day 1), every 3 weeks until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. In a phase 3 trial, patients with inoperable, locally advanced, recurrent, or metastatic adenocarcinoma of the stomach or gastroesophageal junction were randomized to receive 6 cycles of cisplatin and fluorouracil or capecitabine, with or without trastuzumab which was continued until disease progression or unacceptable toxicity. Overall survival (13.5 months vs. 11 months), the primary endpoint, and objective response rate (47% vs. 35%) were significantly increased with the addition of trastuzumab. An updated survival analysis conducted 1 year after the final analysis showed a continued overall survival benefit in the trastuzumab arm (13.1 months vs. 11.7 months). A subgroup analysis revealed an even greater increase in overall survival (18 months vs. 13.2 months) for the trastuzumab arm in patients with high expression of the HER2 protein. Cardiac dysfunction (LVEF decrease of 10% or more from baseline to an absolute value less than 50%) occurred in 5% of patients who received trastuzumab vs. 1.1% of patients who did not receive trastuzumab.
-for the first-line treatment of HER2-positive, PD-L1 positive (combined positive score [CPS] 1 or higher), locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, in combination with pembrolizumab, cisplatin, and fluorouracil*:
NOTE: Pembrolizumab is FDA-approved for this indication in combination with trastuzumab, cisplatin, and fluorouracil.
NOTE: Select patients for treatment based on the presence of positive PD-L1 expression. Information on FDA-approved tests for the detection of PD-L1 expression in gastric cancer is available at: www.fda.gov/CompanionDiagnostics.
Intravenous dosage:
Adults: 8 mg/kg IV on day 1 of cycle 1, followed 3 weeks later by 6 mg/kg IV every 3 weeks in subsequent cycles. Administer in combination with pembrolizumab (200 mg IV every 3 weeks OR 400 mg IV every 6 weeks until disease progression, unacceptable toxicity, or for up to 24 months in patients without disease progression), followed by cisplatin (80 mg/m2 IV every 3 weeks for up to 6 cycles) and fluorouracil (800 mg/m2 per day by continuous IV infusion on days 1 to 5 every 3 weeks). In the clinical trial, treatment with fluorouracil could continue after completion of 6 cycles of cisplatin, per protocol. Administer pembrolizumab prior to trastuzumab and chemotherapy when given on the same day. Treatment with pembrolizumab plus trastuzumab and investigator's choice of chemotherapy (cisplatin plus fluorouracil, or capecitabine plus oxaliplatin) significantly improved objective response rate (ORR) (74% vs. 52%; complete response, 11% vs. 3.1%) compared with placebo plus trastuzumab and chemotherapy in the overall population of patients with previously untreated HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma at an interim analysis of a multicenter, randomized phase 3 trial (KEYNOTE-811). In a prespecified subgroup analysis, the ORR in patients with PD-L1 positive disease was 76% in the pembrolizumab arm versus 51% in the control arm; in patients who were PD-L1 negative, the ORR was 63% versus 58%, respectively. In a subsequent interim analysis, the hazard ratios for progression-free survival and overall survival were nonsignificant in patients with PD-L1 negative disease.
-for the first-line treatment of HER2-positive locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, in combination with pembrolizumab, oxaliplatin, and capecitabine (XELOX; CapeOx)*:
NOTE: Pembrolizumab is FDA-approved for this indication in combination with trastuzumab, oxaliplatin, and capecitabine.
Intravenous dosage:
Adults: 8 mg/kg IV on day 1 of cycle 1, followed 3 weeks later by 6 mg/kg IV every 3 weeks in subsequent cycles. Administer in combination with pembrolizumab (200 mg IV every 3 weeks OR 400 mg IV every 6 weeks until disease progression, unacceptable toxicity, or for up to 24 months in patients without disease progression), followed by oxaliplatin (130 mg/m2 IV every 3 weeks for up to 6 to 8 cycles) and capecitabine (1,000 mg/m2 PO twice daily on days 1 to 14 every 3 weeks). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Administer pembrolizumab prior to trastuzumab and chemotherapy when given on the same day. Treatment with pembrolizumab plus trastuzumab and investigator's choice of chemotherapy (cisplatin plus fluorouracil, or capecitabine plus oxaliplatin) significantly improved objective response rate (74% vs. 52%; complete response, 11% vs. 3.1%) compared with placebo plus trastuzumab and chemotherapy in patients with previously untreated HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma at an interim analysis of a multicenter, randomized phase 3 trial (KEYNOTE-811). The median duration of response was 10.6 months in the pembrolizumab arm compared with 9.5 months in the placebo arm; 65% versus 53% of patients, respectively, had a duration of response of at least 6 months.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicity
Cardiac
-First, second, or third occurrence, greater than or equal to 16% absolute decrease in left ventricular ejection fraction (LVEF) from baseline, or LVEF below institutional limit of normal with greater than or equal to 10% absolute decrease in LVEF from baseline: Hold trastuzumab product for 4 to 8 weeks and monitor ejection fraction with a MUGA scan or echocardiogram every 4 weeks. If LVEF returns to normal limits with an absolute decrease from baseline of less than or equal to 15% within 4 to 8 weeks, resume trastuzumab therapy. If a decrease in LVEF persists beyond 8 weeks, permanently discontinue trastuzumab product therapy.
-Fourth occurrence, greater than or equal to 16% absolute decrease in left ventricular ejection fraction (LVEF) from baseline, or LVEF below institutional limit of normal with greater than or equal to 10% absolute decrease in LVEF from baseline: Permanently discontinue trastuzumab product therapy.
Infusion Reactions
-Mild to moderate reactions: Decrease the rate of infusion of trastuzumab product. Interrupt the infusion if dyspnea or clinically significant hypotension occurs, or if medical therapy is administered (e.g., epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen). Monitor until patients completely resolve.
-Severe or life-threatening reactions (e.g., anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome): Discontinue treatment with trastuzumab product.
Maximum Dosage Limits:
-Adults
Every-3-week dosing: 8 mg/kg IV initially, then 6 mg/kg IV every 3 weeks.
Weekly dosing: 4 mg/kg IV initially, then 2 mg/kg IV every 2 weeks.
-Geriatric
Every-3-week dosing: 8 mg/kg IV initially, then 6 mg/kg IV every 3 weeks.
Weekly dosing: 4 mg/kg IV initially, then 2 mg/kg IV every 2 weeks.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Anthracyclines: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cyclophosphamide: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with trastuzumab is necessary as there is an increased risk of cardiotoxicity.
Daunorubicin Liposomal; Cytarabine Liposomal: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
Daunorubicin: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Doxorubicin Liposomal: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
Doxorubicin: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
Epirubicin: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
Idarubicin: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Trastuzumab is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of HER2. Trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) preferentially acts on cancer cells that overexpress HER2 compared with cancer cells that do not overexpress HER2. The c-erbB2 gene is an oncogene that encodes for the HER2 transmembrane receptor protein (185 Kd) and is structurally related to the epidermal growth factor receptor. The overexpression of HER2 in tumor cells is closely associated with increased angiogenesis and expression of vascular epidermal growth factor (VEGF); when the VEGF pathway is inhibited, tumor growth is suppressed. In cells treated with trastuzumab, the HER2 receptor is downregulated, cyclin-dependent kinase inhibitor p27 accumulates, and cell cycle arrest occurs. Trastuzumab also inhibits the constitutive HER2 cleavage/shedding mediated by metalloproteases, which may correlate with the clinical activity of trastuzumab.
Trastuzumab products are administered intravenously. In a pooled pharmacokinetic analysis of patients with breast cancer and metastatic gastric cancer (n = 1,582), total clearance increased with decreasing concentrations due to parallel linear and nonlinear elimination pathways. The total clearance range at steady state was 0.173 to 0.283 L/day in patients with breast cancer who received a trastuzumab loading dose of 8 mg/kg IV followed by 6 mg/kg IV every 3 weeks; the total clearance range was 0.201 to 0.244 L/day after a loading dose of 4 mg/kg IV followed by 2 mg/kg IV weekly (n = 1,195). In patients with metastatic gastric cancer (n = 274), the total clearance range at steady state was 0.189 to 0.337 L/day.
-Route-Specific Pharmacokinetics
Intravenous Route
Based on population parameters, patients treated with trastuzumab will experience approximately a 97% washout by 7 months after completion of therapy. The time to steady state is 9 weeks in patients with metastatic gastric cancer and 12 weeks in breast cancer patients.
The average trastuzumab exposure after the first cycle in breast cancer patients was higher with 3-weekly dosing (8 mg/kg load followed by 6 mg/kg every 3 weeks) compared to weekly administration (4 mg/kg load followed by 2 mg/kg weekly), but the average steady-state exposure was essentially the same. The average trastuzumab exposure after the first cycle and at steady state, as well as the time to steady-state, was higher in breast cancer patients compared to metastatic gastric cancer patients at the same dose; the reason for this difference is unknown. The median Cmin after the first dose for trastuzumab with 3-weekly dosing was 29.4 mcg/mL in breast cancer patients and 23.1 mcg/mL in patients with gastric cancer; the median Cmax was 178 mcg/mL and 132 mcg/mL, while the median AUC was 1,373 mcg x day/mL and 1,109 mcg x day/mL, respectively. For weekly administration, the median Cmin after the first dose was 37.7 mcg/mL, median Cmax 88.3 mcg/mL, and median AUC 1,066 mcg x day/mL. At steady-state, the median Cmin for breast cancer and gastric cancer patients receiving 3-weekly dosing is 47.4 mcg/mL and 32.9 mcg/mL, respectively; the median Cmax at steady-state is 179 mcg/mL for breast cancer patients and 131 mcg/mL for gastric cancer patients, and the median AUC was 1,794 mcg x day/mL and 1,338 mcg x day/mL, respectively. With breast cancer patients receiving weekly administration of trastuzumab, the median Cmin was 66.1 mcg/mL, median Cmax 109 mcg/mL, and median AUC 1,765 mcg x day/mL. The time to steady-state for breast cancer patients, whether receiving 3-weekly or weekly dosing, was 12 weeks; the time to steady-state for patients with metastatic gastric cancer was 9 weeks.
-Special Populations
Hepatic Impairment
The pharmacokinetics of trastuzumab products have not been studied in patients with hepatic impairment.
Renal Impairment
Based on a population analysis, mild (CrCl 60 to 90 mL/minute; n = 636) or moderate (CrCl 30 to 60 mL/minute; n = 133) renal impairment does not significantly affect the pharmacokinetics of trastuzumab. The pharmacokinetics of trastuzumab products in patients with severe renal impairment or end-stage renal disease (with or without hemodialysis) is unknown.
Geriatric
Based on a population analysis, age does not significantly affect the pharmacokinetics of trastuzumab.
Ethnic Differences
Based on a population analysis, ethnicity (Asian, n = 264; non-Asian, n = 1,324) does not significantly affect the pharmacokinetics of trastuzumab.