What is Herceptin?

WARNING Myocardial toxicity, infusion reactions, and embryotoxic myotoxicity Trastuzumab causes subclinical and clinical heart failure, and its incidence and severity are highest in patients treated with trastuzumab combined with anthracycline antibiotics.
Left ventricular function needs to be evaluated before and during trastuzumab administration. Trastuzumab treatment was discontinued in patients with clinically significant left ventricular dysfunction and patients with metastatic breast cancer who received adjuvant therapy.
Infusion reactions; Lung toxicity Trastuzumab causes severe infusion reactions and lung toxicity. Fatal infusion reactions have been reported. In most cases, symptoms occur during or within 24 hours of trastuzumab infusion. In patients with dyspnea or clinically significant hypotension, trastuzumab infusion should be stopped immediately. Patients should be monitored until symptoms have completely disappeared. Patients with allergies, angioedema, interstitial pneumonia, or acute respiratory distress syndrome should stop infusion.
Embryo Toxicity Use of trastuzumab during pregnancy can cause oligohydramnios and cause lung hypoplasia, skeletal abnormalities, and neonatal death.

Herceptin (trastuzumab for injection), indication for metastatic breast cancer: This product is suitable for metastatic breast cancer with overexpression of HER2: as a single drug treatment for metastases that have received 1 or more chemotherapy regimens Breast cancer; in combination with paclitaxel or docetaxel, for patients with metastatic breast cancer who have not received chemotherapy. Adjuvant breast cancer treatment: This single drug is suitable for adjuvant treatment of HER2 overexpressing breast cancer after surgery, adjuvant chemotherapy with anthracyclines and radiotherapy (if applicable). Metastatic gastric cancer: This product combined with capecitabine or 5-fluorouracil and cisplatin is suitable for patients with metastatic gastric adenocarcinoma or gastroesophageal junction adenocarcinoma who have not previously received treatment for metastatic disease with HER2 overexpression. Trastuzumab can only be used in patients with metastatic gastric cancer whose HER2 is overexpressed. HER2 overexpression is defined as IHC3 + or IHC2 + / FISH + results obtained using validated detection methods.

Drug Name: Herceptin

Drug type: prescription
Use classification: Antitumor gene therapy drugs

Herceptin warning

Herceptin ingredients

Active ingredient: Trastuzumab.
Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody produced by mammalian cells (Chinese hamster ovary cells CHO) suspended in a sterile medium. The purification process includes specific virus killing The activation and removal steps are performed using affinity chromatography and ion exchange.
The diluted solution was 20 ml of sterile water for injection (hereinafter referred to as the diluted solution) containing 1.1% benzyl alcohol.
Excipients: L-histidine hydrochloride, L-histidine, , -biscarboxytrehalose, polysorbate 20.

Herceptin traits

Each bottle contains 440mg of trastuzumab concentrated powder, which is a white to light yellow lyophilized powder. It is formulated as a colorless or pale yellow clear or microemulsion solution for intravenous infusion. The concentration of trastuzumab after dissolution was 21 mg / ml.

Herceptin indications

Metastatic breast cancer:
This product is suitable for HER2 overexpressing metastatic breast cancer: as a single drug treatment of metastatic breast cancer that has received 1 or more chemotherapy regimens; combined with paclitaxel or docetaxel, for metastatic breast cancer without chemotherapy Breast cancer patients.
Adjuvant breast cancer treatment:
This product is a single drug suitable for adjuvant treatment of breast cancer with HER2 overexpression after surgery, anthracycline-containing adjuvant chemotherapy, and radiotherapy (if applicable).
Metastatic gastric cancer:
This product combined with capecitabine or 5-fluorouracil and cisplatin is suitable for patients with metastatic gastric adenocarcinoma or gastroesophageal junction adenocarcinoma who have not previously received treatment for metastatic disease with HER2 overexpression.
Trastuzumab can only be used in patients with metastatic gastric cancer whose HER2 is overexpressed. HER2 overexpression is defined as IHC3 + or IHC2 + / FISH + results obtained using validated detection methods.

Herceptin specifications

440 mg (20 ml) / bottle.

Herceptin dosage

Please fully dilute the reconstituted drug according to the requirements of Infusion Preparation and use it.
Do not push or intravenously.
Before treatment with this product, HER2 testing should be performed.
This product should be administered by intravenous infusion.
Initial loading dose of metastatic breast cancer: The initial loading of this product is recommended to be 4mg / kg. Intravenous infusion over 90 minutes. The patient should be observed for fever, chills, or other infusion-related symptoms (see Adverse Reactions). Stopping the infusion can control these symptoms and continue the infusion after the symptoms disappear.
Maintenance dose: The recommended weekly dosage of this product is 2mg / kg. If the initial load is tolerable, this dose can be infused intravenously for 30 minutes. Maintain treatment until disease progression.
Adjuvant therapy for breast cancer begins trastuzumab treatment after completion of all chemotherapy. Trastuzumab was administered as follows: an initial loading of 8 mg / kg followed by a maintenance amount of 6 mg / kg every 3 weeks and an intravenous drip for approximately 90 minutes. A total of 17 doses were used (52 weeks of treatment).
A dosing regimen for metastatic gastric cancer is recommended every three weeks, with an initial loading dose of 8 mg / kg and subsequent 6 mg / kg once every three weeks. The first infusion takes about 90 minutes. If the patient is well tolerated at the first infusion, the subsequent infusion can be changed to 30 minutes. Maintain treatment until the disease develops.
In clinical trials, patients with metastatic breast cancer or metastatic gastric cancer are treated with trastuzumab until the disease progresses, and patients with early breast cancer use trastuzumab as an adjuvant therapy for 1 year (52 weeks) or less. Disease recurrence (whichever comes first).
Dose-adjusted infusion reactions Infusion rates should be reduced for patients with mild to moderate infusion reactions Infusion should be discontinued for patients with dyspnea or clinically significant hypotension For patients with severe and life-threatening infusion reactions: strongly recommended Myocardial toxicity after trastuzumab infusion is permanently discontinued. Trastuzumab should be tested for left ventricular ejection fraction (LVEF) before starting treatment. LVEF should also be closely monitored during treatment. Trastuzumab should be stopped for at least 4 weeks when the following conditions occur, and LVEF should be tested every 4 weeks
LVEF is 16% lower than the absolute value before treatment.
LVEF is lower than the normal range of the testing center and LVEF is 10% lower than the absolute value before treatment.
Within 4-8 weeks, the LVEF will rise back to the normal range or the LVEF will be 15% lower than the absolute value before treatment. Trastuzumab can be resumed.
LVEF continues to decrease (> 8 weeks), or trastuzumab treatment is stopped 3 or more times due to cardiomyopathy, and trastuzumab should be stopped permanently.
Trastuzumab has not been used in dose-reduction clinical trials. Patients can continue to use this product in the process of bone marrow suppression caused by reversible chemotherapy. Whether to reduce or continue the use of chemotherapy drugs requires special guidance. Do not push or intravenously. See the preparation of infusion for instructions on the use and handling of the drug.
Missed use If the patient has not used trastuzumab for more than one week, they should be given a regular maintenance dose of trastuzumab as soon as possible (weekly dosing regimen; 2 mg / kg; once every three weeks) 6mg / kg), without waiting for the next treatment cycle. Thereafter, a maintenance dose of trastuzumab should be given in accordance with the original dosing schedule (weekly dosing schedule: 2 mg / kg; every three weeks dosing schedule: 6 mg / kg).
If the patient has missed trastuzumab for more than a week, the initial loading dose of trastuzumab should be re-administrated (weekly dosing regimen: 4mg / kg; every three weeks dosing regimen: 8mg / kg The infusion time is 90 minutes. Thereafter, a maintenance dose of trastuzumab should be given in accordance with the original dosing schedule (weekly dosing schedule: 2 mg / kg; every three weeks dosing schedule: 6 mg / kg).
The preparation of the infusion preparation solution should be performed using the correct aseptic technique. Each bottle of trastuzumab for injection should be diluted with the diluent distributed at the same time. The prepared solution can be used multiple times. The concentration of trastuzumab is 21mg / ml, and the pH is about 6.0. The prepared solution is a colorless to pale yellow transparent liquid. Visual inspection should be performed for particle generation and discoloration before injection of the solution. Discard the prepared solution for more than 28 days.
Water for injection (not supplied) can also be used for single-dose infusion preparation. Other liquids cannot be used in the preparation of solutions. Avoid using solvents other than the delivered diluent unless contraindicated. For patients allergic to benzyl alcohol, trastuzumab must be formulated with sterile water for injection.
Calculate the required solution volume based on the initial load of trastuzumab 4mg / kg or maintenance 2mg / kg:
The required solution volume = [u] body weight (Kg) × dose (4mg / Kg load or 2mg / Kg maintenance) [/ u]
21 (mg / ml, configured solution concentration)
Calculate the required solution volume based on the initial loading of trastuzumab at 8 mg / kg or every 6 weeks thereafter:
The required solution volume = [u] weight (Kg) x dose (8mg / Kg load or 6mg / Kg maintenance) [/ u]
21 (mg / ml, configured solution concentration)
The required amount of solution is aspirated from the vial and added to a 250ml 0.9% sodium chloride infusion bag. Do not use 5% glucose solution (see compatibility contraindications). Gently invert the infusion bag to prevent air bubbles. All parenteral medications should be inspected visually for particles or discoloration before use. It should be used as soon as the infusion solution is prepared. If diluted under sterile conditions, it can be stored in a refrigerator at 2-8 ° C for 24 hours.
Compatibility is contraindicated. Use of polyvinyl chloride, polyethylene or polypropylene bags has not been observed.
A 5% glucose solution cannot be used because it can aggregate proteins.
This product cannot be mixed or diluted with other medicines.
Disposal of unused / expired medicines should minimize the release of medicines into the environment. Do not discard the medicine in waste water or domestic garbage. If a local drug recovery system is available, this system should be used to recover unused or expired drugs.

Herceptin adverse reactions

The following adverse reactions are discussed in more detail elsewhere in the label:
Myocardial toxicity [see note]
Infusion reaction [see note]
Aggravated neutropenia caused by chemotherapy Pulmonary toxicity [see precautions]
The most common adverse reactions to trastuzumab are: fever, nausea, vomiting, infusion reactions, diarrhea, infection, worsening cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia. Adverse reactions that require interruption or discontinuation of trastuzumab therapy include: congestive heart failure, a significant decrease in left ventricular function, severe infusion reactions, and pulmonary toxicity.
Trastuzumab is used in the treatment of gastric cancer. The most common adverse reactions (10%), that is, the side effects of the trastuzumab group increased by more than 5% compared with the chemotherapy group are: neutropenia, Diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and taste disorders. In addition to disease progression, the most common adverse reactions that led to discontinuation of treatment were infections, diarrhea, and febrile neutropenia.
This section uses the following incidence classifications: very common (1 / 10), common (1 / 100 to [1/10), uncommon (1 / 1,000 to [1/100), rare (1 / 10,000) To [1 / 1,000], extremely rare ([1 / 10,000), unknown (cannot be estimated from available data). Within each incidence category, adverse reactions are listed in order of increasing incidence.
The following list of adverse reactions are reported in key clinical trials of trastuzumab alone or in combination with other chemotherapeutics. All terms are based on the highest incidence in key clinical trials. Because trastuzumab is often used in combination with other chemotherapy and radiotherapy, it is difficult to determine the causal relationship of adverse events to specific drugs / radiotherapy.

Cardiac function (LVEF) is continuously monitored in breast cancer adjuvant clinical trials. In HERA (BO16348), the median follow-up time was 12.6 months (12.4 months in the observation group and 12.6 months in the trastuzumab 1-year group); in NSAPB B31 and NCTCG N9831, the median AC-TH group The follow-up time was 23 months and 24 months, respectively. In NSAPB B31 and NCCTG N9831, 6% of patients did not start trastuzumab treatment after AC regimen due to cardiac insufficiency (VEF [50% or 15% reduction from baseline at the end of AC regimen) . In NSAPB B31 and NCCTG N9831, after trastuzumab treatment was started, the incidence of dose-restricted cardiac dysfunction in the trastuzumab + paclitaxel group was higher than in the paclitaxel monotherapy group. The incidence of dose-restricted cardiac dysfunction was significantly higher in patients receiving betizumab than in the placebo group (see Table 2, Figure 1, Figure 2).
Table 2 Proportion of patients with NSAPB B31, NCCTG N9831, and HERA (BO16348) center dysfunction (detection index LVEF)

In clinical trials of metastatic breast cancer, for the treatment of congestive heart failure, the New York Heart Association grading system (classified as NYHA I-IV, where IV indicates the most severe heart failure) is used to grade the severity of heart failure (See Table 5). In the metastatic breast cancer trial, patients with trastuzumab combined with anthracyclines had the highest incidence of cardiac insufficiency.
In the ToGA trial for metastatic gastric cancer, the median LVEF values of the fluorouracil / cisplatin (FP) group and the trastuzumab + fluorouracil / cisplatin (H + FP) group were 64% (range 48% -90) during the screening period. %) And 65% (range 50% ~ 86%). With the exception of one patient in the trastuzumab-containing group, whose LVEF decreased with heart failure, most of the LVEF reductions recorded in the ToGA trial were asymptomatic.

Infusion reactions In clinical trials, when trastuzumab was first infused, approximately 40% of patients experienced some infusion reactions, the most common being chills and fever. Can be treated with acetaminophen, diphenhydramine, and pethidine (with or without slowing the rate of trastuzumab infusion); less than 1% of patients permanently stop trastuzumab due to infusion reactions Treatment with betzumab. Other symptoms of infusion reactions include nausea, vomiting, pain (some at the tumor site), chills, headache, dizziness, dyspnea, hypotension, elevated blood pressure, rash, and fatigue. Patients treated with trastuzumab alone or in combination with chemotherapy had 21% or 35% infusion reactions during the second or subsequent infusions, and 1.4% or 9% in severe cases, respectively. After the introduction of trastuzumab, severe infusion reactions were reported, including hypersensitivity reactions, allergic reactions, and angioedema.
Hematological toxicity Breast cancer hematologic toxicity is uncommon in metastatic patients receiving trastuzumab monotherapy, and the incidence of leukopenia, thrombocytopenia, and anemia in WHO grade 3 is less than 1%. No WHO grade 4 toxicity was observed.
In a randomized controlled clinical trial of anemia, the overall incidence of anemia (30% vs 21% [HERA (BO16348)]), the overall incidence of NCI-CTC grades 2 to 5 (12.5% vs 6.6% [NSAPB B31]), And the overall incidence of anemia requiring transfusion (0.1% vs 0 [NCCTG N9831]), patients with trastuzumab combined with chemotherapy were higher than those treated with chemotherapy alone.
After trastuzumab monotherapy (H0649g), the incidence of NCI-CTC grade 3 anemia was [1%. The incidence of NCI-CTC grades 4 to 5 neutropenia in randomized controlled clinical trials for adjuvant treatment of neutropenia breast cancer (2% vs 0.7% [NCCTG N9831]) and grades 2 to 5 neutral The incidence of neutropenia (7.1% vs. 4.5% [NSAPB B31]) was higher in the trastuzumab plus chemotherapy group than in patients receiving chemotherapy alone. In a randomized controlled clinical trial of metastatic breast cancer, the incidence of NCI-CTC grade 3/4 neutropenia (32% vs 22%) and the incidence of febrile neutropenia (23% vs. 17%), patients with trastuzumab combined with chemotherapy were also higher than those treated with chemotherapy alone.
Metastatic gastric cancer is classified according to the SOC of the blood and lymphatic system diseases, and the most reported adverse events (3 grades, 1% in each group) are summarized in the table below.

Grade 3 in the fluorouracil / cisplatin group and the trastuzumab / fluorouracil / cisplatin group (NCI CTCAE version 3.0)
The proportion of patients with adverse events (according to the SOC classification method) was 38% and 40%, respectively. Overall, there were no significant differences in hematological toxicity between the treatment and control groups.
Liver and Kidney Toxicity Breast cancer trastuzumab monotherapy in patients with metastatic cancer has 12% of patients with WHO grade III or IV liver toxicity, which is associated with worsening liver disease in 60% of these patients.
Compared with paclitaxel monotherapy patients, patients treated with trastuzumab combined with paclitaxel experienced less frequent WHO III or IV liver toxicity (7% vs 15%). No incidence of WHO grade III or IV renal toxicity was observed. After listing, nephrotic syndrome with pathologically confirmed glomerular disease is rarely reported. Nephropathy occurs between 4 months and approximately 18 months after the start of trastuzumab treatment. The pathological manifestations of the kidney are: membranous glomerulonephritis, focal glomerulosclerosis, and fibroid glomerulonephritis. The complications of nephropathy include volume overload and congestive heart failure.
Metastatic gastric cancer In the ToGA trial, no significant differences in liver and kidney toxicity between the two treatment groups were observed. The incidence of NCI CTC AE (version 3.0) Grade 3 renal toxicity was not significantly higher in the FP + H group than in the FP group (the incidence rates in the two groups were 3% and 2%, respectively). NCI CTC AE (version 3.0) Grade 3 adverse events (adverse events recorded in SOC of hepatobiliary disease): The only adverse event reported was hyperbilirubinemia, which did not occur significantly more frequently in the FP + H group than in the FP + H group. Group (incidence rates were 1% and [1%) in both groups.
For patients infected with trastuzumab combined with chemotherapy, the overall incidence of infection (46% vs 30% [H0648g]) and the overall incidence of NCI-CTC grade 2-5 infection (22% vs 14% [NSAPB B31]) The overall incidence of grade 3-5 infections / fever neutropenia (3.3% vs 1.4% [NCCTG N9831]) was higher than that of patients treated with chemotherapy alone. The most common sites of infection in adjuvant therapy are the upper respiratory tract, skin, and urethra.
In randomized controlled clinical trials for the treatment of metastatic breast cancer, the incidence of febrile neutropenia in patients receiving the chemotherapy drug group of trastuzumab combined with myelosuppression was higher than (23% vs 17%) of chemotherapy alone. patient.
Adjuvant Therapy for Pulmonary Toxicity of Breast Cancer in Women with Adjuvant Therapy for Breast Cancer: Incidence of NCI-CTC Grade 2 to 5 Pulmonary Toxicity (14% vs 5% [NSAPB B31]) With the spontaneous reported incidence of grade 2 dyspnea (3.4% vs 1% [NCCTG N9831]), trastuzumab combined with chemotherapy was higher in patients treated with chemotherapy alone. The most common lung toxicity in patients with trastuzumab combined with chemotherapy and chemotherapy alone is dyspnea (NCI-CTC grades 2 to 5: 12% vs 4% [NSAPBB31]; NCI-CTC grades 2 to 5: 2.5% vs. 0.1% [NCCTG N9831]). The incidence of pneumonia / pulmonary infiltration was 0.7% in patients treated with trastuzumab and 0.3% in patients treated with chemotherapy alone. Of the patients treated with trastuzumab, 3 had fatal respiratory failure, and 1 of them had multiple organ failure syndrome. Among patients treated with chemotherapy alone, one case had fatal respiratory failure.
The incidence of lung toxicity has also increased in women with metastatic breast cancer who received trastuzumab. Pulmonary adverse events were reported after marketing as part of the infusion response. Pulmonary adverse events include: bronchospasm, hypoxemia, dyspnea, lung infiltration, pleural effusion, noncardiogenic pulmonary edema, and acute respiratory distress syndrome. For details, see the notes.
Thrombosis / embolism In three randomized controlled clinical trials, two trials found that the incidence of thrombosis in patients treated with trastuzumab combined with chemotherapy was higher than those treated with chemotherapy alone (3.0% vs 1.3% [NSAPB B31] and 2.1% vs 0% [H0648g]).
Female patients with adjuvant treatment of diarrhea and breast cancer, incidence of NCI-CTC grade 2 to 5 diarrhea (6.2% vs 4.8% [NSAPB B31]), incidence of NCI-CTC grade 3 to 5 diarrhea (1.6% vs 0% [ NCCTG N9831]), NCI-CTC grade 1 to 4 incidence of diarrhea (7% vs 1% [HERA (BO16348)]), trastuzumab combined with chemotherapy is higher than patients treated with chemotherapy alone. The incidence of diarrhea in patients with metastatic breast cancer who received trastuzumab monotherapy was 25%. Patients with metastatic breast cancer receiving trastuzumab plus chemotherapy have an increased incidence of diarrhea.
Metastatic gastric cancer In the ToGA trial, 109 patients (37%) and 80 patients (28%) in the trastuzumab-containing treatment group and the control group experienced diarrhea of all severity levels. According to the NCI-CTCAE version 3.0 severity criteria, 4% and 9% of patients in the FP group and FP + H group, respectively, had grade 3 diarrhea.
Immunogenicity It is possible for all therapeutic proteins to become immunogenic. Among 903 female patients with metastatic breast cancer who were treated with trastuzumab, one patient was detected with trastuzumab human anti-human antibody (HAHA) by enzyme chain immunosorbent assay (ELISA). The patient did not experience allergic symptoms. No HAHA evaluation samples were collected in adjuvant breast cancer trials. The incidence of antibody production is highly dependent on the sensitivity and specificity of the detection method. In addition, the positive rate of antibodies (including neutralizing antibodies) detected in the test will also be affected by other factors, including analysis methods, sample processing, sample collection time, concomitant medications, and other comorbidities. For these reasons, comparing the positive rates of trastuzumab antibodies with those of other products may be misleading.
Lab tests for abnormal febrile neutropenia are extremely common. Common adverse reactions include anemia, leukopenia, thrombocytopenia, and neutropenia. The incidence of hypothrombinemia is unknown.
Post-marketing experience Following approval of trastuzumab for marketing, the following adverse reactions were reported. Because these adverse reactions are reported in people of varying sizes, it is not possible to accurately estimate their incidence or determine a causal association with trastuzumab treatment.
Table 6 Adverse reactions reported in post-marketing treatment

Adverse events The following table shows the adverse events reported in patients who have previously been treated with trastuzumab. As there is no evidence of a causal relationship between trastuzumab and these events, these events are not expected events reported to management.
Table 7 Adverse events

Herceptin Taboo

It is contraindicated in patients who are known to be allergic to trastuzumab or to any other component of this product.
This product uses benzyl alcohol as a solvent, and it is prohibited for intramuscular injection in children.

Herceptin notes

Cardiotoxicity Trastuzumab can cause left ventricular dysfunction, arrhythmias, hypertension, symptomatic heart failure, cardiomyopathy, and cardiogenic death. It can also cause symptomatic left ventricular ejection fraction (LVEF).
Compared with patients who did not receive trastuzumab, patients who received trastuzumab alone or in combination had a symptomatic cardiac dysfunction that was 4-6 times higher. The absolute incidence of symptomatic cardiac insufficiency is highest when trastuzumab is used in combination with anthracyclines.
When the relative pre-treatment absolute reduction of LVEF is 16% or the LVEF is lower than the normal range of this parameter of the local medical institution and the absolute reduction is 10% relative to pre-treatment, trastuzumab treatment should be stopped. The safety of trastuzumab-induced left ventricular dysfunction in patients with trastuzumab-induced left ventricular dysfunction after continued use or discontinuation has not been studied.
If symptomatic heart failure occurs during trastuzumab therapy, the patient should be treated according to the standard treatment regimen for this disease. For patients with clinically significant heart failure, discontinuation of trastuzumab is strongly recommended unless the individual patient benefits outweigh the risks.
There are no prospective studies on the safety of continuing or resuming trastuzumab in patients who have developed cardiotoxicity. However, in pivotal trials, most patients with heart failure experienced symptoms after standard treatment. improve. These standard treatments include diuretics, cardiac glycosides, and / or angiotensin-converting enzyme inhibitors. Most patients with clinical symptoms of trastuzumab with cardiac symptoms did not experience any other clinical cardiac events while continuing to receive weekly trastuzumab treatment.
Cardiac function monitoring Before giving the first dose of trastuzumab, the patient's cardiac function should be fully assessed, including medical history, physical examination, and LVEF values measured by echocardiography or MUGA (radiocardiographic radiography) scans. In clinical trials, cardiac function monitoring is performed as follows:
Measure baseline LVEF before starting trastuzumab treatment.
LVEF measurements are taken every 3 months during trastuzumab treatment and at the end of treatment.
Perform LVEF measurements every 6 months for at least two years after trastuzumab treatment.
After trastuzumab is discontinued due to severe left ventricular insufficiency, LVEF measurements are taken every 4 weeks [see Dosage and Administration].
In NSAPB B31, 16% (136/844) of patients discontinued trastuzumab due to clinical evidence of cardiac insufficiency or severe LVEF (left ventricular ejection fraction) decline.
In HERA (BO16348), trastuzumab was discontinued due to cardiotoxicity in 2.6% (44/1678 patients). The following early breast cancer patients were excluded from the HERA trial, so there is no risk-benefit assessment data for these patients, so trastuzumab is not recommended for these patients:
A history of congestive heart failure.
High-risk uncontrolled arrhythmias.
Angina requiring medication.
Clinically significant valve disease.
An electrocardiogram shows a transmural myocardial infarction.
Poorly controlled high blood pressure.
Of the 32 patients with congestive heart failure (CHF) who underwent adjuvant chemotherapy (NSAPB B31, NCCTG N9831), one died of cardiomyopathy, and all other patients received cardiac medications at a later follow-up. Survival patients continued drug therapy, and approximately half of LVEF returned to normal at the last follow-up (defined as 50%). The safety of trastuzumab-induced left ventricular dysfunction in patients who continue or resume trastuzumab therapy has not been studied.
Table 8 Incidence of congestive heart failure in trastuzumab adjuvant therapy trials for breast cancer

Infusion reactions Infusion reactions include a range of symptoms, manifested as fever, chills, occasional nausea, vomiting, pain (in some cases at the tumor site), headaches, dizziness, dyspnea, hypotension, rash, and weakness (see Adverse reactions).
In post-market reports, severe and lethal infusion reactions have been reported. Severe reactions include bronchospasm, allergic reactions, angioedema, hypoxia, and severe hypotension, which usually occur during or immediately after the beginning of the infusion. However, seizures and clinical processes vary widely, including progressive deterioration, initial improvement and then deterioration, or delayed post-infusion events and rapid clinical deterioration. The deaths occurred hours or even days after a severe infusion reaction.
Patients with difficulty breathing at rest due to advanced malignant tumor complications or comorbidities may increase the risk of fatal infusion reactions. Therefore, care should be taken in treating these patients, taking into account the risk / benefit ratio of each patient.
In all patients with dyspnea or severe clinical hypotension, trastuzumab infusion should be discontinued and medication should be given at the same time. Medications include epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen. Patients should be evaluated and carefully monitored until symptoms and signs have completely resolved. All patients with severe infusion reactions should consider permanent discontinuation.
No information is currently available on the most appropriate method to identify patients who can safely receive trastuzumab after a severe infusion reaction. Patients who have experienced a severe infusion before receiving trastuzumab therapy are given prophylactic antihistamines and / or glucocorticoids. Some patients can tolerate re-trastuzumab therapy, while others Serious reactions have occurred despite the use of prophylactic medications. Benzyl alcohol used as a preservative for sterile water for injection in the 440 mg format has caused toxic reactions in newborns and children under 3 years of age. Patients known to be allergic to benzyl alcohol should be reconstituted with water for injection when given trastuzumab, and each bottle of trastuzumab should be administered only once. Discard the unused part.
Embryotoxicity Trastuzumab in pregnant women can cause harm to the fetus. Post-market reports indicate that trastuzumab use during pregnancy can cause oligohydramnios and cause lung dysplasia, skeletal abnormalities, and neonatal death. Patients should be advised that the use of trastuzumab during pregnancy may harm the fetus and provide contraceptive counselling services to patients of childbearing age (see Medications for pregnant and lactating women).
Pulmonary toxicity In the clinical application of trastuzumab after marketing, severe pulmonary toxicity events have been reported that occasionally lead to death. In addition, cases have been reported with interstitial lung disease (including pulmonary infiltration), acute respiratory distress syndrome, pneumonia, non-infectious pneumonia, pleural effusion, respiratory distress, acute pulmonary edema, and dysfunction. These adverse events can occur or be delayed as part of an infusion reaction (see Adverse Reactions). Patients with symptomatic lung disease or tumors that have difficulty breathing at rest in the lungs may experience more severe reactions. Risk factors for interstitial lung disease include previous or concurrent use of other anti-tumor therapies known to cause interstitial lung disease, such as taxanes, gemcitabine, vinorelbine, and radiotherapy. These events can be part of the infusion-related response, or delayed. Patients with dyspnea at rest due to advanced malignant tumor complications and comorbidities may be at high risk for pulmonary events. Therefore, these patients should not be treated with trastuzumab.
Chemotherapy-induced neutropenia aggravates NCI CTC grade 3 to 4 neutropenia in a randomized, controlled clinical trial of trastuzumab combined with chemotherapy in the treatment of metastatic breast cancer. The incidence of asthma and febrile neutropenia was higher than that of the chemotherapy alone group. The incidence of sepsis deaths has not increased significantly (see [Adverse Reactions]).
The HER2 test to detect HER2 protein overexpression is necessary to screen patients suitable for trastuzumab, because only patients with HER2 overexpression have been shown to benefit from treatment. Detection of HER2 overexpression and HER2 gene amplification should be performed by laboratories certified to be proficient in this particular technology. Incorrect operations, including the use of suboptimal fixation standards, failure to apply specific reagents, deviations from specific technical guidelines, and failure to include appropriate experimental controls can lead to unreliable results.
A number of approved commercial tests can help in the selection of patients receiving trastuzumab. These methods include HercepTestTM, and CONFIRM anti-HER-2 / neu (4B5) Primary Antibody (HER-2 / NEU antibody) (IHC detection); HER2 FISH pharmDxTM, INFORM HER2 DNA Probe, Rabbit anti -DNP Antibody and INFORM Chromosome 17 Probe and DDISH HER2 Probe (FISH detection). Users should consult the instructions in the package of these test kits to understand the verification results and operating methods of each test.
Limitations of accuracy (especially the IHC method), limitations of test results, and direct relationship between overexpression of trastuzumab target (FISH method) make it impossible to rely on only one method to rule out the potential benefits of trastuzumab take. A negative FISH result does not rule out the possibility of HER2 overexpression and potential benefit from trastuzumab treatment. The relationship between IHC and FISH detection and treatment results in the treatment of metastatic breast cancer (H0648g) is shown in Table 13. The relationship between IHC and FISH detection and treatment results in adjuvant breast cancer treatment (NCCTG N9831 and HERA) is shown in Table 10.
Approved detection methods should be used to assess HER2 overexpression and HER2 gene amplification in gastric cancer. This is particularly important for gastric cancer due to histopathological differences between the stomach and breast, including incomplete membrane staining and more HER2 genes in gastric cancer. Heterogeneous expression. The ToGA trial demonstrated that the correlation between gene amplification and protein overexpression is not as good as in breast cancer. Table 16 shows the therapeutic effects of gastric cancer based on the results of HER2 gene amplification (FISH) and protein overexpression (IHC).
Detection of breast cancer HER2 overexpression or HER2 gene amplification Trastuzumab can only be used in patients who have identified HER2 overexpression or HER2 gene amplification using accurate and effective detection methods. HER2 overexpression was assessed using immunohistochemistry (IHC) -based fixed tumor tissue blocks. The HER2 gene was amplified by fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH). Patients with a HER2 overexpression intensity score of 3+ (IHC) or a positive FISH or CISH result are eligible for trastuzumab treatment.
In order to ensure the accuracy and reproducibility of the results, the test must be performed in a specialized laboratory to fully guarantee the effectiveness of the test procedures.
The recommended scoring system for evaluating IHC staining types is as follows:

Generally, if the ratio of HER2 gene copy number to chromosome 17 copy number of each tumor cell is greater than or equal to 2, or in the absence of chromosome 17, if the HER2 gene copy number of each tumor cell is greater than 4, it is considered FISH Positive.
In general, if more than 5 copies of the HER2 gene per nucleus are present in more than 50% of the tumor cells, they are considered CISH positive.
For detailed testing methods and explanations, please refer to the instructions of FISH and CISH effective testing methods, or you can use the official recommendations for HER2 testing.
If any other method is used to assess HER2 protein or gene expression, it must be performed in a laboratory that provides the most advanced and effective inspection methods. Such methods must be of sufficient precision and accuracy to detect HER2 overexpression, and must be able to distinguish the difference between moderately positive (2+) and strongly positive (3+) HER2 overexpression.
Detection of HER2 overexpression or HER2 gene amplification in gastric cancer must use accurate and effective methods to detect HER2 overexpression or HER2 gene amplification. IHC is recommended as the first detection method. If HER2 gene amplification is also required to be detected, silver enhancement In situ hybridization (SISH) or FISH detection. However, if parallel evaluation of tumor histology and morphology is required, SISH is recommended. In order to ensure the validity of the test method and obtain accurate and reproducible results, HER2 testing must be performed in a laboratory equipped with professional staff. For a detailed description of the test method and interpretation of the results, see the product information sheet provided with the HER2 test method kit used.
In the ToGA (BO18255) test, patients whose tumor test results were IHC3 + or FISH positive were classified as HER2 positive and included in the group test. Based on the results of this clinical trial, effectiveness is limited to patients with the highest levels of HER2 protein overexpression, ie, an IHC score of 3+, or an IHC score of 2+, and a positive FISH result.
In a method comparison study (Study D008548), the results of SISH and FISH tests for gastric cancer patients with HER2 gene amplification were highly consistent (95%).
Immunohistochemistry (IHC) -based assessment of fixed tumor tissue blocks should be used to detect HER2 overexpression; SISH or FISH in situ hybridization should be used to detect HER2 gene amplification of fixed tumor tissue blocks.
The recommended scoring system for evaluating IHC staining types is as follows:

In general, if the ratio between the number of copies of the HER2 gene and the number of copies of the chromosome 17 in each tumor cell is greater than or equal to 2, it is considered positive for SISH or FISH.
The ability to drive and operate machines has not yet been studied. Patients with infusion-related symptoms should not drive or operate machines until their symptoms have completely subsided.

Herceptin medication for pregnant and lactating women

Pregnant women should avoid trastuzumab during pregnancy. Trastuzumab should only be used when the potential benefit to the mother is far greater than the potential danger to the fetus.
In post-marketing clinical reports, pregnant women who used trastuzumab during pregnancy developed oligohydramnios, and in some cases also caused fatal fetal lung dysplasia. Women of childbearing age should take effective contraception during treatment with trastuzumab and for at least 6 months after treatment ends. Pregnant women should be informed that they may be harmful to the fetus. If pregnant women are being treated with trastuzumab, they need to be closely monitored by multidisciplinary professionals. It is unknown whether trastuzumab affects fertility. There is no evidence in animal reproduction experiments that this product impairs fertility or is harmful to the fetus.
After the introduction of trastuzumab, oligohydramnios was reported in pregnant women when treated with trastuzumab monotherapy or in combination with chemotherapy. Among these women, half of the patients had an elevated amniotic fluid index after trastuzumab was discontinued. In one patient, when trastuzumab was resumed after the amniotic fluid index improved, oligohydramnios relapsed.
For women treated with trastuzumab during pregnancy, monitor for oligohydramnios. If oligohydramnios occurs, it should be checked and monitored at the appropriate gestational age under the guidance of a specialist. Intravenous fluid replacement can help improve oligohydramnios after treatment with other chemotherapeutic drugs, but the efficacy of intravenous fluid replacement for oligohydramnios occurred during treatment with trastuzumab is uncertain.
Reproductive studies were performed in cynomolgus monkeys. When doses were given up to 25 times the human weekly maintenance dose (2 mg / kg), no harm to the fetus was seen. However, HER2 protein is highly expressed in many embryonic tissues including heart and neural tissues; early pregnancy embryo death occurs in pregnant mice lacking HER2. In macaque monkeys, placenta transfer was observed in trastuzumab during the first trimester (20-50 days of gestation) and late (120-150 days of gestation).

IgG
12.5 2mg/kg3

37765244 133 [4 5][1 2]3 65

1.5

BO15935 M77004 HER2-+
JP16003 HER2-JP19959 ToGA
+ +

]8 mg/kg

23752 [NSAPB B31 NCCTGN9831]HER2 3386 HERA (BO16348)
NSAPB B31 NCCTG N9831 HER2 IHC 3FISH HER2 NCCTG N9831NSAPB B31]100mmHg ]200mmHg
11ACAC+ 2 4 21 2260 mg/m600 mg/mNSAPB B31 822mg/m3175mg/m 12NCCTG N98314mg/kg 2mg/kg 52/ER /PR DFS
3752 NSAPB B31NCCTG N983149 2280 6 ]65 84 74 4 /9038 T191 27 66 53 ER /PR 53
HERA (BO16348)HER2IHC3+FISH T1c LVEF[55% ECG (] 180 mm Hg ] 100 mm Hg
41:1 (n = 1693)1 (n = 1693)ER /PgR 8 mg/kg36 mg/kg52NSAPB B31NCCTG N9831
3386 492180 83%13%94%50%ER/PgR57%32%11%96%(1055/1098 )109849%543 ER PgR 47% (512) ER /PgR2 cm23 [ 3594%
NSAPB B31NCCTG N9831 DFS3NSAPB B31NCCTG N9831 HERA (BO16348)DFS 10NSAPB B31 NCCTG N9831//HERA (BO16348)//65
10NSAPB B31NCCTG N9831 HERA

NCCTG N9831 HERA (BO16348)HER2DFS11NCCTG N9831 IHC 3+/FISH+81% HERA(BO16348)IHC 3+/FISH FISH +/IHC DFS

HERA(BO16348) 122 54 1 68 122 46 2667 92% 50%40% 10%41% 91% 26% HERA (BO16348)DFS 1 2 81.4%92.9%1 (HR 0.29, 95% CI 0.08-1.08, p=0.0489) HERA (BO16348)12

(H0648gn=469)H0649gn=2222HER2 2 3 HER2 03
H0648g
H0648g 469 IHC CTA01+2+3+,3+2+3+33 4mg/kg2mg/kg175mg/m[sup]2[/sup]321 16AC60 mg/m[sup]2[/sup]75mg/m[sup]2[/sup]600 mg/m[sup]2[/sup]211665 ORR13AC
13 H0648g:

H0648gHER2 314

H0649gHER2 1 2 22266 68 2 25 4mg/kg 2mg/kg
ORR142 12CTA 3+18CTA 2+6
(1:1)III ToGA 5-FU HER2 594 314 53% 351 184 62.2% 167 56.0%
vs.vs.ECOG 01 vs. 2vs. 5-HER2 FISH+HER2 IHC 3+LVEF ] 50%
8 mg/kg6mg/kg3 1
80mg/m2 IV 2 3 61000mg/m[sup]2[/sup]2000mg/m214 21615 CIV 5-800 mg/m2/3 6
60 2183 76%53%38%5%5%/91%ECOG PS0 182%18%23%7%/2%
log-rank OS 351 OS0.0193 OS154

See Table 16 for a summary of OS exploratory analysis based on the results of HER2 gene amplification (FISH) and protein overexpression (IHC) in this patient population.

a In this exploratory subgroup analysis, two patients with FISH + (but unknown IHC status) in the FC group were excluded.
b In this exploratory subgroup analysis, 5 patients with FISH + (but unknown IHC status) in the trastuzumab-containing drug treatment group were excluded.
c Includes 6 patients in the chemotherapy group, 10 patients with FISH- and IHC3 + in the trastuzumab group, 8 patients in the chemotherapy group, and 8 IHC 3+ patients with unknown FISH status in the trastuzumab group.
Effectiveness Results for Chinese Subgroup of Patients (Clinical Deadline: January 7, 2009)
Fifteen research centers in China participated in the study, and 614 patients were screened for HER2, and the HER2 positive rate was 22.7%. Of the HER2-positive Chinese patients, 85 met the inclusion criteria for inclusion in this study. There were 36 patients in the trastuzumab group and 49 patients in the chemotherapy group. Patient demographics, disease characteristics, and randomized stratification factors (range of disease, location of primary disease, measurability, ECOG performance status, and chemotherapy status) were well balanced in both treatment groups.
About 95% of patients have metastatic disease, with the primary site of origin being the stomach (about 80%). About 80% of patients have ECOG physical status of 0 to 1, and all patients except 1 patient have received capecitabine treatment.
The results showed that compared with chemotherapy alone, the addition of trastuzumab in chemotherapy (fluorouracil and cisplatin) for Chinese patients with HER2-positive metastatic gastric cancer improved overall survival (median survival 12.6 months vs 9.7 months ), The death risk of the FP + H group was reduced by 28% compared with the FP group (HR 0.72; 95% CI [0.40 1.29]), which was consistent with the results reported by the ToGA trial population (median survival 13.8 months vs 11.1 Month, HR 0.74; 95% CI [0.60 to 0.91]) (Table 17).
Table 17 Summary of total survival (FAS)

The Kaplan-Meier curve of overall survival is shown in Figure 5. The two curves remained basically separated after the 4-month observation period.
Figure 5 Kaplan-Meier curve (FAS) of overall survival in the Chinese subgroup

All other secondary efficacy endpoints (such as progression-free survival (PFS), time to disease progression (TTP), remission rate, clinical benefit rate, and duration of remission) were improved and also showed consistent results with the overall population analysis Trends (Table 18).

HER2 expression is the target of trastuzumab therapy. Among the patients in the Chinese subgroup, overexpression of HER2 was 34 in the FP group and 28 in the FP + H group. HER2 overexpression is defined as IHC 2 + / FISH + and IHC 3+. An exploratory analysis found that the median survival of the FP + H group and the FP group in patients with HER2 overexpression was 16 months and 9.7 months, respectively (HR 0.55; 95% CI [0.26; 1.18]). This result suggests that patients with overexpression of HER2 receiving trastuzumab may receive more clinical benefits. Similar results are described in the overall analysis report of the TOGA trial.

Herceptin Pharmacology and Toxicology

Mechanism of action <br /> Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that specifically acts on the extracellular site of human epidermal growth factor receptor-2 (HER2). This antibody contains a human IgG1 framework, and the complementarity determining region is derived from a murine anti-p185 HER2 antibody, capable of binding to HER2.
The HER2 proto-oncogene or C-erbB2 encodes a single receptor-like transmembrane protein with a molecular weight of 185 kDa and is structurally related to the epidermal growth factor receptor. HER2 overexpression is observed in 25% -30% of patients with primary breast cancer. As a result of HER2 gene amplification, the expression of HER2 protein on the surface of these tumor cells increased, leading to activation of the HER2 receptor.
Trastuzumab has been shown to inhibit tumor cell proliferation of HER2 overexpression in vitro and in animal experiments. In addition, trastuzumab is a potential mediator of antibody-dependent cell-mediated cytotoxicity (ADCC). In vitro studies, trastuzumab-mediated ADCC has been shown to be produced more preferentially in cancer cells that are overexpressed by HER2 than cancer cells that are not overexpressed by HER2.
The carcinogenic potential of trastuzumab was not tested for carcinogenesis, mutations, or damage to fertility.
In a standard Ames bacterial and human peripheral blood lymphocyte mutagenesis test, no mutagenic response was observed when trastuzumab reached a concentration of 5000 g / mL. In the in vivo micronucleus test, after rapid intravenous injection of trastuzumab reaching 118 mg / kg, no evidence of chromosomal damage in mouse bone marrow cells was observed.
Fertility studies were performed in female cynomolgus monkeys. Trastuzumab was administered at a dose up to 25 times the human maintenance dose of 2 mg / kg per week. No impaired fertility was found. The effect of trastuzumab on male fertility has not been studied.

Herceptin pharmacokinetics

Intravenous infusions of 10, 50, 100, 250, and 500 mg of trastuzumab once a week for breast cancer showed non-linear pharmacokinetics, and clearance decreased with increasing dose.
The half-life elimination half-life is 28 to 38 days, and the subsequent cleaning period is 25 weeks (175 days or 5 times the elimination half-life).
Steady-state pharmacokinetics reach steady state in approximately 25 weeks (175 days or 5 times the elimination half-life). Predicted median steady-state AUC for a 3-week course of pharmacokinetic evaluation in a phase I, II, and III clinical trial population of metastatic breast cancer (two-chamber, dependent model), in a weekly dosing regimen 1677 mg day / l, 1793 mg day / l in a three-week dosing regimen; estimated median peak concentrations are 104 mg / l and 189 mg / l, and trough concentrations are 64.9 mg / l And 47.3 mg / l. Early breast cancer patients received trastuzumab with an initial loading dose of 8 mg / kg and subsequent doses of 6 mg / kg every 3 weeks. The independent treatment model or non-atrial analysis (NCA) showed that the 13th course of treatment (No. 37 weeks) at an average steady state trough concentration of 63 mg / l, which is similar to the average steady state trough concentration reported by patients with previous metastatic breast cancer who received weekly treatment.
Clearance (CL)
The typical clearance of trastuzumab (body weight 68 kg) was 0.241 liters / day.
The effect of patient characteristics (such as age or serum creatinine) on the catabolism of trastuzumab was evaluated. The data showed no change in trastuzumab catabolism in each treatment group, but these study designs did not include a special study of The effect of damage on pharmacokinetics.
Distribution volume In all clinical studies, the central (Vc) and peripheral (Vp) compartment distribution volumes of typical patients are 3.02 liters and 2.68 liters, respectively.
Circulating shedding antigen In the serum of some breast cancer patients with HER2 overexpression, detectable concentrations of circulating HER2 receptors (shedding antigen) were found. The results of the detection of the shed antigen in the baseline serum samples showed that 64% (286/447) of the patients could detect shed antigen, up to 1880ng / ml (median = 11ng / ml). Patients with higher baseline shedding antigen levels are more likely to have lower trastuzumab serum trough concentrations. However, in weekly dosing treatment, the majority of patients with elevated levels of shedding antigen had serum trastuzumab serum concentrations reaching the target concentration at week 6, and there was no significant correlation between baseline shedding antigen levels and clinical efficacy.
Steady-state pharmacokinetics in patients with metastatic gastric cancer Based on data from the Phase III ToGA study, a two-compartment population pharmacokinetic study was performed to estimate patients with advanced gastric cancer receiving trastuzumab (initial loading dose) 8 mg / kg, followed by a maintenance dose of 6 mg / kg every 3 weeks). In these assessments, the total clearance was mainly linear, with a half-life of approximately 26 days in patients with advanced gastric cancer. The predicted median steady-state AUC value (3-week steady-state period) is equal to 1213 mg · day / L, the median steady-state Cmax value is equal to 128 mg / L, and the median steady-state Cmin value is equal to 27.6 mg / L.
There are no data on circulating extracellular domain HER2 receptor (shedding antigen) concentrations in patients with gastric cancer.

Herceptin storage

Store and transport at 2-8 ° C, protected from light. This product can be stably stored at 2 8 for 28 days after dissolving with the provided diluent. The prepared solution contains preservatives, so it can be used multiple times. The remaining solution should be discarded after 28 days.
Do not freeze the prepared solution with the trastuzumab infusion solution containing 0.9% sodium chloride solution. It can be stored stably for 24 hours at 2-8 ° C in polyvinyl chloride, polyethylene or polypropylene bags . At 30 , the diluted product can be stably stored for up to 24 hours. However, since trastuzumab after dilution does not contain an effective concentration of preservatives, it is best to store the solution after dilution and dilution at 2-8 ° C. To control microbial contamination, the infusion solution should be used immediately. The diluted solution cannot be stored unless the dilution is performed under strictly controlled and proven aseptic conditions.
Do not use this medicine after the expiry date shown behind the bottle.
Keep medicines out of the reach of children.

Herceptin packaging

1 bottle / box (including diluent). The diluent is 20ml of sterile water for injection containing 1.1% benzyl alcohol.

Herceptin validity

Store and transport at 2-8 ° C, protected from light, 36 months.

Herceptin Executive Standard

JS20090127

Herceptin approval number

Import Drug Registration Certificate Number: S20110007

Herceptin Manufacturing Enterprise

Shanghai Roche Pharmaceutical Co., Ltd.

Herceptin approval date

July 31, 2009

Herceptin Revision Date

October 27, 2006 September 05, 2007 December 31, 2008 March 03, 2009 April 03, 2009 November 04, 2009 November 24, 2011 October 27, 2011 2012 August 01, 2012 August 10, 2012