曲妥珠单抗注射液 通用产品

批准日期：2018年12月14日

公司：细胞精龙公司和特瓦制药工业有限公司。

治疗： 乳腺癌

Herzuma （trastuzumab-pkrb） 是 HER2/神经受体拮抗剂生物类似，指示用于治疗 HER2 过度表达乳腺癌。

Herzuma符合FDA严格的生物仿制药标准。此次批准，是基于对基础分析相似性数据、非临床数据、临床药理学、免疫原性、临床效果和不受威胁性数据的综合数据包的审查。Herzuma的临床开发项目结果表明，Herzuma和赫赛汀在治疗HER2高表达乳腺癌的纯度、效价、不受威胁性方面没有临床意义的差异。

具体而言，Herzuma适用于：（1）辅助治疗HER2过表达淋巴结阳性或淋巴结阴性（ER/PR阴性或具有一个高危特征）乳腺癌；（2）一线或多线治疗HER2过表达转移性乳腺癌。

Herzuma (trastuzumab-pkrb) for Injection

Herzuma

Generic Name: trastuzumab-pkrb
Dosage Form: injection

Medically reviewed by Drugs.com. Last updated on May 1, 2019.

WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY

Cardiomyopathy

Administration of trastuzumab products can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving trastuzumab with anthracycline-containing chemotherapy regimens.

Evaluate left ventricular function in all patients prior to and during treatment with Herzuma. Discontinue Herzuma treatment in patients receiving adjuvant therapy and withhold Herzuma in patients with metastatic disease for clinically significant decrease in left ventricular function [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

Infusion Reactions; Pulmonary Toxicity

Administration of trastuzumab products can result in serious and fatal infusion reactions and pulmonary toxicity. Symptoms usually occur during or within 24 hours of administration. Interrupt Herzuma infusion for dyspnea or clinically significant hypotension. Monitor patients until symptoms completely resolve. Discontinue Herzuma for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome [see Warnings and Precautions (5.2, 5.4)].

Embryo Fetal Toxicity

Exposure to trastuzumab products during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.3)].

Indications and Usage for Herzuma

Adjuvant Breast Cancer

Herzuma is indicated for adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature [see Clinical Studies (14.1)]) breast cancer

· as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel

· as part of a treatment regimen with docetaxel and carboplatin

· as a single agent following multi-modality anthracycline based therapy.

Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product [see Dosage and Administration (2.1)].

Metastatic Breast Cancer

Herzuma is indicated:

· In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer

· As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease.

Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product [see Dosage and Administration (2.1)].

Metastatic Gastric Cancer

Herzuma is indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease.

Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product [see Dosage and Administration (2.1)].

Herzuma Dosage and Administration

Patient Selection

Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens [see Indications and Usage (1) and Clinical Studies (14)]. Assessment of HER2 protein overexpression and HER2 gene amplification should be performed using FDA-approved tests specific for breast or gastric cancers by laboratories with demonstrated proficiency. Information on the FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at: http://www.fda.gov/CompanionDiagnostics.

Assessment of HER2 protein overexpression and HER2 gene amplification in metastatic gastric cancer should be performed using FDA-approved tests specifically for gastric cancers due to differences in gastric vs. breast histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers.

Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.

Recommended Doses and Schedules

· Do not administer as an intravenous push or bolus. Do not mix Herzuma with other drugs.

· Do not substitute Herzuma (trastuzumab-pkrb) for or with ado-trastuzumab emtansine.

Adjuvant Treatment, Breast Cancer:

Administer according to one of the following doses and schedules for a total of 52 weeks of Herzuma therapy:

During and following paclitaxel, docetaxel, or docetaxel and carboplatin:

· Initial dose of 4 mg/kg as an intravenous infusion over 90 minutes then at 2 mg/kg as an intravenous infusion over 30 minutes weekly during chemotherapy for the first 12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel and carboplatin).

· One week following the last weekly dose of Herzuma, administer Herzuma at 6 mg/kg as an intravenous infusion over 30–90 minutes every three weeks.

As a single agent within three weeks following completion of multi-modality, anthracycline-based chemotherapy regimens:

· Initial dose at 8 mg/kg as an intravenous infusion over 90 minutes

· Subsequent doses at 6 mg/kg as an intravenous infusion over 30–90 minutes every three weeks [see Dosage and Administration (2.3)].

· Extending adjuvant treatment beyond one year is not recommended [see Adverse Reactions (6.1)].

Metastatic Treatment, Breast Cancer:

· Administer Herzuma, alone or in combination with paclitaxel, at an initial dose of 4 mg/kg as a 90-minute intravenous infusion followed by subsequent once weekly doses of 2 mg/kg as 30-minute intravenous infusions until disease progression.

Metastatic Gastric Cancer:

· Administer Herzuma at an initial dose of 8 mg/kg as a 90-minute intravenous infusion followed by subsequent doses of 6 mg/kg as an intravenous infusion over 30–90 minutes every three weeks until disease progression [see Dosage and Administration (2.3)].

Important Dosing Considerations

If the patient has missed a dose of Herzuma by one week or less, then the usual maintenance dose (weekly schedule: 2 mg/kg; three-weekly schedule: 6 mg/kg) should be administered as soon as possible. Do not wait until the next planned cycle. Subsequent Herzuma maintenance doses should be administered 7 days or 21 days later according to the weekly or three-weekly schedules, respectively.

If the patient has missed a dose of Herzuma by more than one week, a re-loading dose of Herzuma should be administered over approximately 90 minutes (weekly schedule: 4 mg/kg; three-weekly schedule: 8 mg/kg) as soon as possible. Subsequent Herzuma maintenance doses (weekly schedule: 2 mg/kg; three-weekly schedule 6 mg/kg) should be administered 7 days or 21 days later according to the weekly or three-weekly schedules, respectively.

Infusion Reactions

[see Boxed Warning, Warnings and Precautions (5.2)]

· Decrease the rate of infusion for mild or moderate infusion reactions

· Interrupt the infusion in patients with dyspnea or clinically significant hypotension

· Discontinue Herzuma for severe or life-threatening infusion reactions.

Cardiomyopathy

[see Boxed Warning, Warnings and Precautions (5.1)]

Assess left ventricular ejection fraction (LVEF) prior to initiation of Herzuma and at regular intervals during treatment. Withhold Herzuma dosing for at least 4 weeks for either of the following:

· ≥ 16% absolute decrease in LVEF from pre-treatment values

· LVEF below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values.

Herzuma may be resumed if, within 4–8 weeks, the LVEF returns to normal limits and the absolute decrease from baseline is ≤ 15%.

Permanently discontinue Herzuma for a persistent (> 8 weeks) LVEF decline or for suspension of Herzuma dosing on more than 3 occasions for cardiomyopathy.

Preparation for Administration

To prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is Herzuma (trastuzumab-pkrb) and not ado-trastuzumab emtansine.

420 mg Multiple-dose vial

Reconstitution

Reconstitute each 420 mg vial of Herzuma with 20 mL of Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% benzyl alcohol as a preservative to yield a multiple-dose solution containing 21 mg/mL trastuzumab-pkrb that delivers 20 mL (420 mg trastuzumab-pkrb). In patients with known hypersensitivity to benzyl alcohol, reconstitute with 20 mL of Sterile Water for Injection (SWFI) without preservative to yield a single use solution.

Use appropriate aseptic technique when performing the following reconstitution steps:

· Using a sterile syringe, slowly inject the 20 mL of diluent into the vial containing the lyophilized powder of Herzuma, which has a cake-like appearance. The stream of diluent should be directed into the cake. The reconstituted vial yields a solution for multiple-dose use, containing 21 mg/mL trastuzumab-pkrb.

· Swirl the vial gently to aid reconstitution. DO NOT SHAKE.

· Slight foaming of the product may be present upon reconstitution. Allow the vial to stand undisturbed for approximately 5 minutes.

· Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect visually for particulates and discoloration. The solution should be free of visible particulates, clear to slightly opalescent and colorless to pale yellow.

· Store reconstituted Herzuma in the refrigerator at 2°C to 8°C (36°F to 46°F); discard unused Herzuma after 28 days. If Herzuma is reconstituted with SWFI without preservative, use immediately and discard any unused portion. Do not freeze.

Dilution

· Determine the dose (mg) of Herzuma [see Dosage and Administration (2.2)]. Calculate the volume of the 21 mg/mL reconstituted Herzuma solution needed, withdraw this amount from the vial and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP. DO NOT USE DEXTROSE (5%) SOLUTION.

· Gently invert the bag to mix the solution.

· The solution of Herzuma for infusion diluted in polyvinylchloride or polyethylene bags containing 0.9% Sodium Chloride Injection, USP, should be stored at 2°C to 8°C (36°F to 46°F) for no more than 24 hours prior to use. Do not freeze.

150 mg Single-dose vial

Reconstitution

Reconstitute each 150 mg vial of Herzuma with 7.4 mL of Sterile Water for Injection (SWFI) (not supplied) to yield a single-dose solution containing 21 mg/mL trastuzumab-pkrb that delivers 7.15 mL (150 mg trastuzumab-pkrb).

Use appropriate aseptic technique when performing the following reconstitution step:

· Using a sterile syringe, slowly inject the 7.4 mL of SWFI (not supplied) into the vial containing the lyophilized powder of Herzuma, which has a cake-like appearance. The stream of diluent should be directed into the cake. The reconstituted vial yields a solution for single-dose use, containing 21 mg/mL trastuzumab-pkrb.

· Swirl the vial gently to aid reconstitution. DO NOT SHAKE.

· Slight foaming of the product may be present upon reconstitution. Allow the vial to stand undisturbed for approximately 5 minutes.

· Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect visually for particulates and discoloration. The solution should be free of visible particulates, clear to slightly opalescent and colorless to pale yellow.

· Use the Herzuma solution immediately following reconstitution with SWFI, as it contains no preservative and is intended for single-dose only. If not used immediately, store the reconstituted Herzuma solution for up to 24 hours at 2°C to 8°C (36°F to 46°F); discard any unused Herzuma after 24 hours. Do not freeze.

Dilution

· Determine the dose (mg) of Herzuma [see Dosage and Administration (2.2)].

· Calculate the volume of the 21 mg/mL reconstituted Herzuma solution needed.

· Withdraw this amount from the vial and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP. DO NOT USE DEXTROSE (5%) SOLUTION.

· Gently invert the bag to mix the solution.

· The solution of Herzuma for infusion diluted in polyvinylchloride or polyethylene bags containing 0.9% Sodium Chloride Injection, USP, should be stored at 2°C to 8°C (36°F to 46°F) for no more than 24 hours prior to use. Discard after 24 hours. This storage time is additional to the time allowed for the reconstituted vials. Do not freeze.

Dosage Forms and Strengths

· For injection: 150 mg of Herzuma as a white to pale yellow lyophilized powder in a single-dose vial

· For injection: 420 mg of Herzuma as a white to pale yellow lyophilized powder in a multiple-dose vial.

Contraindications

None.

Warnings and Precautions

Cardiomyopathy

Trastuzumab products can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning: Cardiomyopathy]. Trastuzumab products can also cause asymptomatic decline in left ventricular ejection fraction (LVEF).

There is a 4–6 fold increase in the incidence of symptomatic myocardial dysfunction among patients receiving trastuzumab products as a single agent or in combination therapy compared with those not receiving trastuzumab products. The highest absolute incidence occurs when a trastuzumab product is administered with an anthracycline.

Withhold Herzuma for ≥ 16% absolute decrease in LVEF from pre-treatment values or an LVEF value below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values [see Dosage and Administration (2.3)]. The safety of continuation or resumption of Herzuma in patients with trastuzumab product-induced left ventricular cardiac dysfunction has not been studied.

Patients who receive anthracycline after stopping Herzuma may also be at increased risk of cardiac dysfunction [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

Cardiac Monitoring

Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. The following schedule is recommended:

· Baseline LVEF measurement immediately prior to initiation of Herzuma

· LVEF measurements every 3 months during and upon completion of Herzuma

· Repeat LVEF measurement at 4 week intervals if Herzuma is withheld for significant left ventricular cardiac dysfunction [see Dosage and Administration (2.3)]

· LVEF measurements every 6 months for at least 2 years following completion of Herzuma as a component of adjuvant therapy.

In Study 1, 15% (158/1031) of patients discontinued trastuzumab due to clinical evidence of myocardial dysfunction or significant decline in LVEF after a median follow-up duration of 8.7 years in the AC-TH (anthracycline, cyclophosphamide, paclitaxel, and trastuzumab) arm. In Study 3 (one-year trastuzumab treatment), the number of patients who discontinued trastuzumab due to cardiac toxicity at 12.6 months median duration of follow-up was 2.6% (44/1678). In Study 4, a total of 2.9% (31/1056) of patients in the TCH (docetaxel, carboplatin, trastuzumab) arm (1.5% during the chemotherapy phase and 1.4% during the monotherapy phase) and 5.7% (61/1068) of patients in the AC-TH arm (1.5% during the chemotherapy phase and 4.2% during the monotherapy phase) discontinued trastuzumab due to cardiac toxicity.

Among 64 patients receiving adjuvant chemotherapy (Studies 1 and 2) who developed congestive heart failure, one patient died of cardiomyopathy, one patient died suddenly without documented etiology and 33 patients were receiving cardiac medication at last follow-up. Approximately 24% of the surviving patients had recovery to a normal LVEF (defined as ≥ 50%) and no symptoms on continuing medical management at the time of last follow-up. Incidence of congestive heart failure (CHF) is presented in Table 1. The safety of continuation or resumption of Herzuma in patients with trastuzumab product-induced left ventricular cardiac dysfunction has not been studied.

In Study 3 (one-year trastuzumab treatment), at a median follow-up duration of 8 years, the incidence of severe CHF (NYHA III & IV) was 0.8%, and the rate of mild symptomatic and asymptomatic left ventricular dysfunction was 4.6%.

In Study 4, the incidence of NCI-CTC Grade 3/4 cardiac ischemia/infarction was higher in the trastuzumab containing regimens (AC-TH: 0.3% (3/1068) and TCH: 0.2% (2/1056)) as compared to none in AC-T.

Infusion Reactions

Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion included nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia [see Adverse Reactions (6.1)].

In post-marketing reports, serious and fatal infusion reactions have been reported. Severe reactions, which include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, were usually reported during or immediately following the initial infusion. However, the onset and clinical course were variable, including progressive worsening, initial improvement followed by clinical deterioration, or delayed post-infusion events with rapid clinical deterioration. For fatal events, death occurred within hours to days following a serious infusion reaction.

Interrupt Herzuma infusion in all patients experiencing dyspnea, clinically significant hypotension, and intervention of medical therapy administered (which may include epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen). Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation should be strongly considered in all patients with severe infusion reactions.

There are no data regarding the most appropriate method of identification of patients who may safely be retreated with trastuzumab products after experiencing a severe infusion reaction. Prior to resumption of trastuzumab infusion, the majority of patients who experienced a severe infusion reaction were pre-medicated with antihistamines and/or corticosteroids. While some patients tolerated trastuzumab infusions, others had recurrent severe infusion reactions despite pre-medications.

Embryo-Fetal Toxicity

Trastuzumab products can cause fetal harm when administered to a pregnant woman. In post marketing reports, use of trastuzumab during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death.

Verify the pregnancy status of females of reproductive potential prior to the initiation of Herzuma. Advise pregnant women and females of reproductive potential that exposure to Herzuma during pregnancy or within 7 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of Herzuma [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.3)].

Pulmonary Toxicity

Trastuzumab product use can result in serious and fatal pulmonary toxicity. Pulmonary toxicity includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions [see Warnings and Precautions (5.2)]. Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity.

Exacerbation of Chemotherapy-Induced Neutropenia

In randomized, controlled clinical trials, the per-patient incidences of NCI-CTC Grade 3 to 4 neutropenia and of febrile neutropenia were higher in patients receiving trastuzumab in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received trastuzumab and those who did not [see Adverse Reactions (6.1)].

Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the label:

· Cardiomyopathy [see Warnings and Precautions (5.1)]

· Infusion Reactions [see Warnings and Precautions (5.2)]

· Embryo-Fetal Toxicity [see Warnings and Precautions (5.3)]

· Pulmonary Toxicity [see Warnings and Precautions (5.4)]

· Exacerbation of Chemotherapy-induced Neutropenia [see Warnings and Precautions (5.5)]

The most common adverse reactions in patients receiving trastuzumab products in the adjuvant and metastatic breast cancer setting are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia. Adverse reactions requiring interruption or discontinuation of trastuzumab product treatment include CHF, significant decline in left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity [see Dosage and Administration (2.3)].

In the metastatic gastric cancer setting, the most common adverse reactions (≥ 10%) that were increased (≥ 5% difference) in patients receiving trastuzumab as compared to patients receiving chemotherapy alone were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia. The most common adverse reactions which resulted in discontinuation of trastuzumab treatment in the absence of disease progression were infection, diarrhea, and febrile neutropenia.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adjuvant Breast Cancer Studies

The data below reflect exposure to one-year trastuzumab therapy across three randomized, open-label studies, Studies 1, 2, and 3, with (n = 3678) or without (n = 3363) trastuzumab in the adjuvant treatment of breast cancer.

The data summarized in Table 3 below, from Study 3, reflect exposure to trastuzumab in 1678 patients; the median treatment duration was 51 weeks and median number of infusions was 18. Among the 3386 patients enrolled in the observation and one-year trastuzumab arms of Study 3 at a median duration of follow-up of 12.6 months in the trastuzumab arm, the median age was 49 years (range: 21 to 80 years), 83% of patients were Caucasian, and 13% were Asian.

In Study 3, a comparison of 3-weekly trastuzumab treatment for two years versus one year was also performed. The rate of asymptomatic cardiac dysfunction was increased in the 2-year trastuzumab treatment arm (8.1% versus 4.6% in the one-year trastuzumab treatment arm). More patients experienced at least one adverse reaction of Grade 3 or higher in the 2-year trastuzumab treatment arm (20.4%) compared with the one-year trastuzumab treatment arm (16.3%).

The safety data from Studies 1 and 2 were obtained from 3655 patients, of whom 2000 received trastuzumab; the median treatment duration was 51 weeks. The median age was 49 years (range: 24–80); 84% of patients were White, 7% Black, 4% Hispanic, and 3% Asian.

In Study 1, only Grade 3–5 adverse events, treatment-related Grade 2 events, and Grade 2–5 dyspnea were collected during and for up to 3 months following protocol-specified treatment. The following non-cardiac adverse reactions of Grade 2–5 occurred at an incidence of at least 2% greater