赫赛汀（Herceptin,Trastuzumab Injection）

【Function and indications】
This product is suitable for metastatic breast cancer with HER2 overexpression; as a single drug for metastatic breast cancer that has received one or more chemotherapy regimens; combined with taxanes for metastatic breast cancer that has not received chemotherapy. Adjuvant therapy for breast cancer: This product is suitable for adjuvant therapy of HER2 overexpressing breast cancer after surgery, adjuvant chemotherapy containing anthracycline antibiotics and radiotherapy (if applicable).

【Model and specification】
Properties: Each bottle of this drug contains 440 mg of concentrated trastuzumab powder, which is a white to light yellow lyophilized powder, which can be used for intravenous infusion after being prepared into a solution. The concentration of trastuzumab after dissolution is 21 mg/mL.
Solvent: Sterile water for injection, containing 1.1% phenylethanol as a preservative, a colorless liquid.
Excipients: L-histidine hydrochloride, L-histidine, α,α-dicarboxy trehalose, polyoxyethylene sorbitan fatty acid ester 20.

[Usage and Dosage]
When used as a single drug or in combination with other chemotherapy drugs, the following initial loading and maintenance doses are recommended.
Initial loading dose: The recommended initial loading dose is 4 mg/kg, intravenously infused within 90 minutes. The patient should be observed for fever, chills or other infusion-related symptoms. Stopping the infusion can control these symptoms, and the infusion can be continued after the symptoms disappear.
Maintenance dose: The recommended weekly dose is 2 mg/kg. If the initial loading dose is tolerated, this dose can be infused within 30 minutes.
Do not push or pulse intravenously.

[Clinical Studies]
Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that selectively acts on the extracellular site of human epidermal growth factor receptor-2 (HER2). This antibody is of IgG1 type and contains human framework regions and complementary determining regions of mouse anti-p185 HER2 antibodies that can bind to HER-2.
Humanized anti-HER2 antibodies are produced by mammalian cells (Chinese Hamster Ovary cells, CHO) suspended in sterile culture and purified by affinity chromatography and ion exchange, including a special removal procedure for viral inactivation.
The HER2 proto-oncogene or C-erbB2 encodes a single receptor-like transmembrane protein of 185 kDa that 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, HER2 protein expression is increased on the surface of these tumor cells, leading to HER2 receptor activation.
Studies have shown that patients with tumors that overexpress HER2 have a shorter disease-free survival than those without overexpression. HER2 overexpression can be diagnosed by immunohistochemistry-based evaluation of tumor tissue blocks, ELISA or fluorescence in situ hybridization (FISH) of tissue or plasma samples.
Trastuzumab is a potential mediator of antibody-dependent cell-mediated cytotoxicity (ADCC). In in vitro studies, trastuzumab-mediated ADCC was shown to be preferentially produced in HER2-overexpressing cancer cells compared to HER2-non-overexpressing cancer cells.

[Precautions]
Cardiomyopathy
Trastuzumab can cause left ventricular dysfunction, arrhythmias, hypertension, symptomatic heart failure, cardiomyopathy, and cardiac death, and can also cause symptomatic left ventricular ejection fraction (LVEF) reduction. The incidence of symptomatic cardiac dysfunction was 4-6 times higher in patients receiving trastuzumab alone or in combination compared to patients not receiving trastuzumab. The absolute incidence of symptomatic cardiac dysfunction was highest when trastuzumab was used in combination with anthracyclines.
Trastuzumab treatment should be discontinued when the absolute decrease in LVEF relative to pre-treatment is ≥16% or when the LVEF is below the normal range of this parameter in the local medical institution and the absolute decrease is ≥10% relative to pre-treatment [see Dosage and Administration]. The safety of continuing trastuzumab therapy or resuming trastuzumab therapy after discontinuation in patients with trastuzumab-induced left ventricular dysfunction has not been studied.

Cardiac function monitoring
Before the first dose of trastuzumab is given, the patient’s cardiac function should be fully evaluated, including medical history, physical examination, and LVEF value measured by echocardiography or MUGA (radiovascular angiography) scan. In clinical trials, cardiac function monitoring was performed according to the following schedule:
1. Measure LVEF baseline value before starting trastuzumab treatment.
2. Measure LVEF every 3 months during trastuzumab treatment and once at the end of treatment.
3. Measure LVEF every 6 months for at least 2 years after the end of trastuzumab treatment.
4. Measure LVEF every 4 weeks after trastuzumab is discontinued due to severe left ventricular dysfunction [see Dosage and Administration].
In Study 1, 16% (136/844) of patients discontinued trastuzumab due to clinical evidence of cardiac dysfunction or severe LVEF (left ventricular ejection fraction) decline.
In Study 3, 2.6% (44/1678) of patients discontinued trastuzumab due to cardiac toxicity. Of the 32 patients who developed CHF with adjuvant chemotherapy (Studies 1 and 2), 1 patient died from cardiomyopathy, and all other patients received cardiac medications during subsequent follow-up. Surviving patients continued medical therapy, and approximately half had normalized LVEF (defined as ≥50%) at last follow-up. The safety of continuing or resuming trastuzumab in patients with trastuzumab-induced LV dysfunction has not been studied.

Infusion Reactions
Infusion reactions include a range of symptoms, manifested by fever, chills, and occasionally nausea, vomiting, pain (in some cases at the tumor site), headache, dizziness, dyspnea, hypotension, rash, and asthenia (see ADVERSE REACTIONS). Severe and fatal infusion reactions have been reported in postmarketing reports. Severe reactions include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, usually occurring during or immediately after the infusion. However, the onset and clinical course vary widely, including gradual worsening, initial improvement followed by worsening, or delayed post-infusion events with rapid clinical deterioration. Fatalities have occurred within hours or even days of severe infusion reactions.
For all patients who develop dyspnea or clinically significant hypotension, the trastuzumab infusion should be interrupted and medical therapy initiated. Medications include epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen. Patients should be evaluated and carefully monitored until symptoms and signs resolve. Permanent discontinuation of trastuzumab should be considered for all patients who experience severe infusion reactions.
There are currently no data on the most appropriate method for identifying patients who can safely be reintroduced with trastuzumab after experiencing a severe infusion reaction. Patients who experience severe infusion reactions should be treated with prophylactic antihistamines and/or glucocorticoids prior to reintroduction of trastuzumab. Some patients tolerated repeat trastuzumab therapy, while others had severe reactions despite prophylactic medication.

Worsening of chemotherapy-induced neutropenia
In a randomized, controlled clinical study of trastuzumab combined with chemotherapy for metastatic breast cancer, the incidence of NCIC CTG3-4 grade neutropenia and febrile neutropenia was higher in the combined myelosuppressive chemotherapy group than in the chemotherapy group alone. The incidence of death from sepsis was not significantly increased (see Adverse Reactions).

Pulmonary toxicity
The use of trastuzumab can cause severe, fatal pulmonary toxicity. Pulmonary toxicity includes dyspnea, pneumonia, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. These adverse reactions may occur due to infusion reactions (see Precautions). Patients with symptomatic lung disease or dyspnea at rest due to tumor involvement of the lungs may experience more severe toxicity.

HER2 Testing
Testing for HER2 protein overexpression is essential for selecting patients for trastuzumab therapy, as only patients with HER2 overexpression have been shown to benefit from treatment. Testing for HER2 overexpression and HER2 gene amplification should be performed by laboratories certified for this specific technique. Improper performance, including use of suboptimally fixed tissue, failure to use specific reagents, deviation from specific technical guidelines, and failure to include appropriate experimental controls, may lead to unreliable results.
Several commercially approved tests are available to assist in the selection of patients for trastuzumab therapy. These include the HercepTestTM, Pathway® HER-2/neu (IHC test), PathVysion®, and HER2FISH pharmDxTM (FISH test). Users should consult the package insert for specific test kits for information on the validation and performance of each test.
Limitations in test accuracy (particularly for IHC methods) and the direct relationship of test results to trastuzumab target overexpression (FISH methods) make it unacceptable to rely on only one test to exclude potential benefit from trastuzumab therapy. Negative FISH results do not exclude HER2 overexpression and potential benefit from trastuzumab treatment.

Detection of HER2 protein overexpression
HER2 protein overexpression can be determined by IHC. The HercepTest®, an approved IHC test, uses tumor specimens from women with metastatic breast cancer independent of trastuzumab clinical studies and has been evaluated to be consistent with CTA (clinical research test). Data are provided in the HerceptTest® package insert.

Detection of HER2 gene amplification
High HER2 protein expression and gene amplification are highly correlated, so FISH detection of gene amplification can be used to select patients for trastuzumab treatment. An approved test for this test, PathVysion®, was evaluated in an exploratory, retrospective manner using CTA 2+ or 3+ tumor specimens obtained from patient screening in metastatic breast cancer clinical studies (Studies 4 and 5).

[Adverse Reactions and Contraindications]
All adverse event data are obtained from clinical trials. This drug is used alone or in combination with chemotherapy drugs (anthracycline [doxorubicin or epirubicin] plus cyclophosphamide or paclitaxel) at the recommended dose.
Trastuzumab alone: ​​Patients with metastatic cancer with HER2 overexpression who have undergone one or more chemotherapy regimens and have failed to respond to this drug alone.
In 213 patients, the incidence of the following adverse reactions was ≥ (greater than or equal to) 5%:
Overall: abdominal pain, accidental injury, fatigue, back pain, chest pain, chills, fever, cold-like symptoms, headache, infection, neck pain, pain.
Cardiovascular: vasodilation.
Digestion: anorexia, constipation, diarrhea, dyspepsia, flatulence, vomiting and nausea.
Metabolism: peripheral edema, edema.
Musculoskeletal: joint pain, muscle pain.
Nervous system: anxiety, depression, dizziness, insomnia, paresthesia, drowsiness.
Respiratory: Asthma, increased cough, dyspnea, epistaxis, lung disease, pleural effusion, pharyngitis, rhinitis, sinusitis.
Skin: Itching, rash.
Infusion-related symptoms: During the first infusion of this drug, approximately 40% of patients will experience a syndrome that usually includes chills and/or fever. These symptoms are generally mild or moderate, rarely require discontinuation of treatment, and can be treated with antipyretics such as acetaminophen or antihistamines such as diphenhydramine. Other symptoms and/or signs include: nausea, vomiting, pain, chills, headache, dizziness, dyspnea, hypotension, rash and fatigue. These symptoms rarely occur during subsequent infusions of this drug.
Cardiac toxicity: Signs of cardiac insufficiency have been observed in patients treated with this drug in clinical trials. The incidence of moderate to severe cardiac insufficiency (NTHA grade III/IV) was 5% in patients treated with Herceptin alone.
Hematologic toxicity: Hematologic toxic reactions rarely occur in patients treated with this drug alone. The incidence of WHO grade III leukopenia, thrombocytopenia and anemia was <1%. No WHO grade IV hematological toxicity was observed.
Hepatotoxicity: WHO grade III or IV hepatotoxicity was observed in 12% of patients treated with this drug alone, and 60% of patients had hepatotoxicity related to the progression of liver metastases. No WHO grade III or IV renal toxicity was observed.
Diarrhea: Diarrhea occurred in 27% of patients treated with this drug alone.
Combination of trastuzumab with other chemotherapy drugs
Two chemotherapy regimens with or without Herceptin were used in patients with metastatic breast cancer with HER2 overexpression who had not received previous treatment for metastatic lesions. An anthracycline (doxorubicin or epirubicin) plus cyclophosphamide (AC); or paclitaxel, the incidence of adverse reactions of both chemotherapy regimens is ≥ (greater than or equal to) 10%, and the adverse reactions of the drug plus chemotherapy group are significantly higher than those of the chemotherapy group alone (P≤ (smaller than or equal to) 0.05), see the following table:
Cardiac toxicity: In clinical trials, patients treated with this drug were observed to have symptoms of heart failure.
In randomized clinical trials, the incidence of moderate to severe heart failure (NYHA III/IV grade) was 16% in patients treated with this drug plus an anthracycline (doxorubicin or epirubicin) plus cyclophosphamide, while the incidence was only 3% in patients treated with anthracycline/cyclophosphamide combination without Herceptin.
The incidence of moderate to severe heart failure (NYHA III/IV grade) was 2% in patients treated with Herceptin plus paclitaxel, while it was 1% in the paclitaxel alone group.
Hematologic toxicity: WHO grade III or IV hematologic toxicity occurred in 63% of patients treated with Herceptin plus anthracycline and cyclophosphamide and in 62% of patients treated with anthracycline/cyclophosphamide.
WHO grade III or IV hematologic toxicity was higher in the Herceptin plus paclitaxel group than in the paclitaxel group (34% vs. 21%). This finding is likely due to the longer time to tumor progression in the Herceptin plus paclitaxel group than in the paclitaxel group, resulting in higher total paclitaxel doses in this group).
Hepatotoxicity: WHO grade III or IV hepatotoxicity occurred in 6% of patients treated with Herceptin plus anthracycline plus cyclophosphamide and in 8% of patients treated with anthracycline/cyclophosphamide without Herceptin. No WHO grade III or IV nephrotoxicity was observed.
WHO grade III or IV hepatotoxicity was lower in the Herceptin plus paclitaxel group than in the paclitaxel group (7% vs. 15%). No WHO grade III or IV nephrotoxicity was observed.
Diarrhea: generally mild to moderate, with a higher incidence in the Herceptin plus chemotherapy group (an anthracycline plus cyclophosphamide or paclitaxel) than in the chemotherapy group alone.
Infection: generally mild with minimal clinical symptoms

Upper respiratory tract infection or catheter infection, which occurred more frequently with Herceptin plus chemotherapy (an anthracycline plus cyclophosphamide or paclitaxel) than with chemotherapy alone.
Serious adverse reactions: In both pivotal clinical trials, at least one adverse reaction occurred in patients treated with Herceptin alone or with Herceptin plus chemotherapy (an anthracycline [doxorubicin or epirubicin] plus cyclophosphamide, or paclitaxel).
Global: Allergic reaction, anaphylactoid reaction, ascites, malignancy, cellulitis, mucosal disease, reaction that cannot be evaluated, sepsis, sudden death.
Cardiovascular: Atrial fibrillation, cardiomyopathy, deep thrombophlebitis, heart failure, pulmonary embolism, thrombosis.
Digestive: Dysphagia, esophageal ulcer, hematemesis, hepatitis, liver failure, hepatomegaly, ileal or small bowel obstruction, jaundice, liver damage, tender liver.
Blood and Lymphatic: Acute leukemia, anemia, bone marrow suppression, myeloid cell maturation disorder, pancytopenia.
Metabolism: hypercalcemia, hyperglycemia.
Musculoskeletal: osteonecrosis, fractures.
Mental: anxiety, mental confusion, convulsions, neuropathy, abnormal thinking.
Respiratory: suffocation, asthma, lung disease, pneumothorax, pleural effusion, pneumonia.
Urogenital: acute renal failure, hydronephrosis.
Special senses: deafness, retinal artery occlusion.

[Contraindications]
Patients who are allergic to trastuzumab or other ingredients are prohibited from using it.

[Pregnant women use]
Teratogenic effect: Class D Pregnant women should avoid using trastuzumab during pregnancy. Trastuzumab treatment can only be used when the potential benefit to the mother far outweighs the potential risk to the fetus. After trastuzumab was marketed, oligohydramnios was reported in pregnant women treated with trastuzumab alone or in combination with chemotherapy. Half of these women had an increase in amniotic fluid index after stopping trastuzumab. In one patient, oligohydramnios recurred when trastuzumab treatment was resumed after the amniotic fluid index improved. Women treated with trastuzumab during pregnancy should be monitored for the development of oligohydramnios. If oligohydramnios occurs, fetal testing should be performed at an appropriate gestational age according to community health standards. Intravenous rehydration helps improve oligohydramnios that occurs after treatment with other chemotherapy drugs, but the efficacy of intravenous rehydration for oligohydramnios that occurs during trastuzumab treatment is uncertain. Reproduction studies were conducted in Cynomolgus monkeys, and no harm to the fetus was observed when the dose was 25 times the weekly maintenance dose in humans (2 mg/kg). However, HER2 protein is highly expressed in many embryonic tissues including heart and neural tissues; early embryonic death occurred in pregnant mice lacking HER2. In monkeys, placental transfer of trastuzumab was observed in early pregnancy (gestational age 20-50 days) and late pregnancy (gestational age 120-150 days). It is not known whether trastuzumab treatment in pregnant women will damage fertility or the fetus. Results of animal reproduction studies showed no evidence that trastuzumab damages fertility or the fetus. Lactating women It is not known whether trastuzumab is secreted into human milk, but human IgG is secreted into human milk. Published data indicate that antibodies in breast milk cannot enter the systemic circulation of newborns or fetuses in large quantities. After lactating macaques were given 12.5 times the human weekly dose (2 mg/kg) of trastuzumab, the mother macaques’ breast milk was positive for trastuzumab. The macaques with positive serum trastuzumab did not experience any adverse reactions during their growth and development within 3 months after birth; however, the level of trastuzumab in animal milk does not accurately reflect the level of trastuzumab in human milk. Since many drugs can be secreted into human milk and trastuzumab may cause serious adverse reactions in lactating infants, the decision to stop breastfeeding or cessation of trastuzumab treatment should be based on the half-life of trastuzumab and its importance to the mother. Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of trastuzumab has not been tested. In the standard Ames bacterial and human peripheral blood lymphocyte mutagenicity tests, no mutagenic reactions were observed at trastuzumab concentrations up to 5000 μg/mL. In the in vivo micronucleus test, no evidence of chromosomal damage in mouse bone marrow cells was observed after rapid intravenous injection of trastuzumab up to 118 mg/kg. Fertility studies were completed in female macaques, with weekly trastuzumab doses up to 25 times the human maintenance dose of 2 mg/kg, and no fertility impairment was found. The effect of trastuzumab on male fertility has not been studied.

[Pediatric Use]
The safety and efficacy of this drug for patients under 18 years of age have not been established.

[Drug Interactions]
In clinical studies, when trastuzumab was used in combination with paclitaxel, trastuzumab serum concentrations increased 1.5 times relative to baseline. In drug interaction studies, the pharmacokinetics of docetaxel and paclitaxel were not changed when used in combination with trastuzumab.

[Manufacturer]
Roche Pharmaceuticals, USA (Roche).