Ogivri

Antineoplastic Monoclonal Antibodies Targeting HER2/neu

Emetic Risk
Minimal

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.[28061] [62658] [63839] [63887]

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.[28061] [62658] [63839] [63887]
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.[62658] [63839]
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.[28061] [62658] [63839] [63887]
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.[28061] [62658] [63839] [63887]

neutropenia / Delayed / 1.7-34.0
heart failure / Delayed / 0.4-28.0
infection / Delayed / 0-25.0
hypokalemia / Delayed / 10.0-10.0
infusion-related reactions / Rapid / 1.4-9.0
thrombocytopenia / Delayed / 0-5.0
fatigue / Early / 0-4.0
thrombosis / Delayed / 2.1-3.7
renal failure (unspecified) / Delayed / 0-2.7
chills / Rapid / 0-1.0
fever / Early / 0-1.0
myocardial infarction / Delayed / 0-0.3
pulmonary hypertension / Delayed / 0-0.2
anemia / Delayed / 0-0.1
cardiomyopathy / Delayed / Incidence not known
glomerulonephritis / Delayed / Incidence not known
nephrotic syndrome / Delayed / Incidence not known
anaphylactic shock / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
acute respiratory distress syndrome (ARDS) / Early / Incidence not known
angioedema / Rapid / Incidence not known
pulmonary fibrosis / Delayed / Incidence not known
pulmonary toxicity / Early / Incidence not known
pleural effusion / Delayed / Incidence not known
pulmonary edema / Early / Incidence not known
teratogenesis / Delayed / Incidence not known
tumor lysis syndrome (TLS) / Delayed / Incidence not known

leukopenia / Delayed / 3.0-52.0
dyspnea / Early / 2.4-42.0
bone pain / Delayed / 3.0-24.0
peripheral edema / Delayed / 5.0-22.0
depression / Delayed / 6.0-20.0
hot flashes / Early / 0-17.1
sinus tachycardia / Rapid / 5.0-12.0
edema / Delayed / 4.7-11.0
hypertension / Early / 0-4.0
palpitations / Early / 0-3.0
neuritis / Delayed / 0-2.0
constipation / Delayed / 0-2.0
peripheral neuropathy / Delayed / 0-1.0
pneumonitis / Delayed / 0.2-0.7
antibody formation / Delayed / 0.1-0.1
dysphagia / Delayed / Incidence not known
stomatitis / Delayed / Incidence not known
hypoxia / Early / Incidence not known
hypotension / Rapid / Incidence not known
hyperuricemia / Delayed / Incidence not known
hyperphosphatemia / Delayed / Incidence not known

asthenia / Delayed / 4.5-62.0
headache / Early / 6.2-44.0
cough / Delayed / 5.0-43.0
rash / Early / 4.0-38.0
arthralgia / Delayed / 6.0-37.0
back pain / Delayed / 5.0-34.0
nausea / Early / 6.0-33.0
pharyngitis / Delayed / 8.0-30.0
insomnia / Early / 4.3-29.0
diarrhea / Early / 2.2-25.0
vomiting / Early / 3.5-23.0
rhinitis / Early / 2.0-22.0
abdominal pain / Early / 2.0-22.0
sinusitis / Delayed / 2.0-21.0
anorexia / Delayed / 0-14.0
influenza / Delayed / 2.0-13.0
dizziness / Early / 4.0-13.0
acne vulgaris / Delayed / 2.0-11.0
dysgeusia / Early / 0-10.0
paresthesias / Delayed / 2.0-9.0
myalgia / Early / 0-4.0
pruritus / Rapid / 0-2.0
epistaxis / Delayed / 0-2.0
dyspepsia / Early / 0-2.0
weight loss / Delayed / Incidence not known

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.[28061] [62658] [63839] [63887] [64521] [64524]

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.[33927] 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.[33928] 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.[33928] Monitoring of the LVEF should occur more frequently, at 4-week intervals, if treatment is held for significant left ventricular cardiac dysfunction.[28061] [62658] [63839] [63887] [64521] [64524] Elevated troponin I immediately before or after trastuzumab administration may also be a predictor of cardiotoxicity.[41906] 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.[28061] [62658] [63839] [63887] [64521] [64524]

Serious fetal harm can occur if trastuzumab product is administered during pregnancy or within 7 months prior to conception.[28061] [62658] [63839] [63887] 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).[28061] 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.[28061] [62658] [63839] [63887]

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).[28061]

Herceptin, Herzuma, KANJINTI, Ogivri, Ontruzant, Trazimera

Rx

Recombinant DNA-derived humanized IgG1 kappa monoclonal antibody against the HER2 protein
Used for breast and gastric cancers that overexpress HER2
Monitor left ventricular ejection fraction in all patients before, during, and after treatment; also watch for infusion-related reactions

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

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: (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 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.
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.
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.

Herceptin/Herzuma/KANJINTI/Ogivri/Ontruzant/Trastuzumab/Trazimera Intravenous Inj Pwd F/Sol: 150mg, 420mg
Trazimera Intravenous Inj Pwd: 150mg

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.

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.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

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.[28061] [62658] [63839] [63887] 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.[25663] 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.[25176]

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.[28061] [62658] [63887]

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.[28061] [62658] [63839] [63887] [64524] [64521]
 
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.[28061] [62658] [63839] [63887] [64524] [64521]

Serious fetal harm can occur if trastuzumab product is administered during pregnancy or within 7 months prior to conception.[28061] [62658] [63839] [63887] 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).[28061] 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.[28061] [62658] [63839] [63887]

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.[28061] [62658] [63839] [63887]