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说明书

 

　　通用名称：注射用曲妥珠单抗
　　商品名称：赫赛汀
　　英文名称：Trastuzumab Injection
　　

　　【成分】
　　本品主要成分为曲妥珠单抗。

　　【性状】
　　本药每瓶含浓缩曲妥珠单抗粉末440 mg，为白色至淡黄色冻干粉剂。

　　【药理作用】
　　赫赛汀是一种重组DNA衍生的人源化单克隆抗体，选择性地作用于人表皮生长因子受体-2(HER2)的细胞外部位。在原发性乳腺癌患者中观察到有25%-30%的患者HER2过度表达。研究表明，HER2过度表达的肿瘤患者较无过度表达的无病生存期短。赫赛汀?在体外及动物实验中均显示可抑制HER2过度表达的肿瘤细胞的增殖。另外，赫赛汀是抗体依赖的细胞介导的细胞毒反应(ADCC)的潜在介质。在体外研究中，赫赛汀介导的ADCC被证明在HER2过度表达的癌细胞中比HER2非过度表达的癌细胞中更优先产生。

　　【药代动力学】
　　药物清除 对转移性乳腺癌的研究表明，短时间静脉输入10，50，100，250和500mg曲妥珠单抗每周1次的药代动力学呈剂量依赖性。随剂量水平的提高，平均半衰期延长，清除率下降。在临床试验中，使用了曲妥珠单抗4mg/kg的首次负荷量和2mg/kg每周维持量，观察到其平均半衰期为5.8天（1-32天），在16-32周之间，曲妥珠单抗的血浆浓度达到稳定状态，平均谷浓度约75ug/mL。特殊临床情况下的药物动力学,病人特性（如年龄，血浆肌酐浓度）对曲妥珠单抗分布的影响也进行了评价。数据显示，曲妥珠单抗的体内分布在不同亚群病人中均无变化。

　　【适应症】
　　赫赛汀适用于治疗HER2过度表达的转移性乳腺癌。
　　a) 作为单一药物治疗已接受过1个或多个化疗方案的转移性.乳腺癌.
　　b) 与紫杉类药物合用治疗未接受过化疗的转移性乳腺癌.

　　【用法用量】
　　初次负荷剂量：建议赫赛汀初次负荷量为4mg/kg。90分钟内静脉输入。维持剂量：建议每周赫赛汀用量为2mg/kg。如初次负荷量可耐受，则此剂量可于30分钟内输完赫赛汀可一直用到疾病进展。根据国外市场调查资料显示：接受治疗的患者平均约连续使用24至26周。

　　【不良反应】
　　所有不良事件的数据均由临床试验得到，本药均按推荐剂量单药或与化疗药（蒽环类[阿霉素或表阿霉素]加环磷酰胺或紫杉醇）合用。单独使用赫赛汀,有HER2过度表达的转移癌患者，已对进行过1或多个方案化疗无效者单独使用本药。213例患者，下列不良反应发生率≥ (greater than or equal to) 5% ：整体 ：腹痛，意外损伤，乏力，背痛，胸痛，寒战，发热，感冒样症状，头痛，感染，颈痛，疼痛。心血管 ：血管扩张。消化 ：厌食，便秘，腹泻，消化不良，胃肠胀气，呕吐和恶心。代谢 ：周围水肿，水肿。肌肉骨骼 ：关节痛，肌肉疼痛。神经系统 ：焦虑，抑郁，眩晕，失眠，感觉异常，嗜睡。呼吸 ：哮喘，咳嗽增多，呼吸困难，鼻出血，肺部疾病，胸腔积液，咽炎，鼻炎，鼻窦炎。皮肤 ：瘙痒，皮疹。

　　【禁 忌】
　　对曲妥珠单抗或其它成分过敏的患者禁止使用。

　　【注意事项】
　　本药治疗必须在治疗癌症方面很有经验的内科医生的监测下开始进行。在使用本药治疗的患者中观察到有心脏功能减退的症状和体征，如呼吸困难，咳嗽增加，夜间阵发性呼吸困难，周围性水肿，S3奔马律或射血分数减低。与赫赛汀治疗相关的充血性心衰可能相当严重，并可引起致命性心衰、死亡、粘液栓子脑栓塞。特别在赫赛汀与蒽环类药（阿霉素或表阿霉素）和环磷酰胺合用治疗转移乳腺癌的患者中，观察到中至重度的心功能减退（纽约心脏学会（NYHA）分级的III/IV）。在治疗前就有心功能不全的患者需特别小心。选择使用本药治疗的患者应进行全面的基础心脏评价，包括病史，物理检查和以下一或多项检查：EKG，超声心动图，MUGA扫描。目前尚无数据显示有合适的评价方法可确定病人有发生心脏毒性危险。在本药治疗过程中，左室功能应经常评估。若患者出现临床显著的左室功能减退应考虑停用赫赛汀。监测并不能全部发现将发生心功能减退的患者。约2/3有心功能减退的患者因有症状被治疗，大多数治疗后症状好转。治疗通常包括利尿药，强心苷类药和/或血管紧张素转换酶抑制剂类药。绝大多数用本药治疗临床有效的有心脏症状和表现的患者继续每周使用赫赛汀，并未产生更多的临床心脏情况。在灭菌注射水中，苯乙醇作为防腐剂，它对新生儿和3岁以下的儿童有毒性。当本药用于已知对苯乙醇过敏的病人时，应用注射用水重新配制。

　　【孕妇及哺乳期妇女用药】
　　在发育早期（孕20-50天）和晚期（孕120-150天）均观察到曲妥珠单抗经胎盘传送入胎儿。鉴于动物生殖研究结果并不能预示人类的反应，赫赛汀应不用于孕期妇女，除非对孕妇的潜在好处远大于对胎儿的潜在危险。
　　哺乳期妇女 ：哺乳期cynomolgus猴子用25倍人每周维持量赫赛汀（2 mg/kg）进行研究，显示曲妥珠单抗可分泌到乳汁里。出生3月内，幼猴血中存在曲妥珠单抗对其生长发育无任何不利影响。

　　【儿童用药】
　　小于18岁患者使用本药的安全性和疗效尚未确立

 Pronunciation

(tras TU zoo mab)

      Index Terms

anti-c-erB-2

anti-ERB-2

Conventional Trastuzumab

MOAB HER2

rhuMAb HER2

Trastuzumab (Conventional)

 

      Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Herceptin: 440 mg (1 ea) [contains benzyl alcohol, mouse (murine) and/or hamster protein]

Solution Reconstituted, Intravenous [preservative free]:

Herceptin: 150 mg (1 ea)

Brand Names: U.S.HerceptinPharmacologic CategoryAntineoplastic Agent, Anti-HER2Antineoplastic Agent, Monoclonal AntibodyPharmacology

Trastuzumab is a monoclonal antibody which binds to the extracellular domain of the human epidermal growth factor receptor 2 protein (HER-2); it mediates antibody-dependent cellular cytotoxicity by inhibiting proliferation of cells which overexpress HER-2 protein.

Excretion

In most patients, trastuzumab concentrations will decrease to ~3% (~97% washout) by 7 months following discontinuation.

Use: Labeled Indications

Breast cancer, adjuvant treatment: Treatment (adjuvant) of human epidermal growth receptor 2 (HER2)-overexpressing node positive or node negative (estrogen receptor/progesterone receptor negative or with 1 high risk feature) breast cancer as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; with docetaxel and carboplatin; or as a single agent following multimodality anthracycline-based therapy.

Breast cancer, metastatic: First-line treatment of HER2-overexpressing metastatic breast cancer (in combination with paclitaxel); single agent treatment of HER2-overexpressing breast cancer in patients who have received 1 or more chemotherapy regimens for metastatic disease.

Gastric cancer, metastatic: Treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma (in combination with cisplatin and either capecitabine or 5-fluorouracil) in patients who have not received prior treatment for metastatic disease.

Limitations of use: Patients should be selected for breast and gastric cancer therapy based on an approved companion diagnostic test for tumor specimen for HER2 overexpression or HER2 gene amplification.

Off Label UsesHER2-positive metastatic breast cancer (in combination with pertuzumab and docetaxel) in patients who have not received prior anti-HER2 therapy or chemotherapy to treat metastatic disease

Data from a large, randomized, controlled phase III study supports the use of trastuzumab in combination with pertuzumab and docetaxel in the management of metastatic breast cancer [Baselga 2012].

Based on the American Society of Clinical Oncology (ASCO), Systemic Therapy for Patients with Advanced HER2-Positive Breast Cancer guidelines, trastuzumab in combination with pertuzumab and a taxane is recommended as first-line treatment, unless there are contraindications to taxanes.

HER2-positive metastatic breast cancer (in combination with pertuzumab and weekly paclitaxel)

Data from a small phase II study supports the use of trastuzumab in combination with pertuzumab and weekly paclitaxel in the management of metastatic breast cancer [Dang 2015]. Based on the American Society of Clinical Oncology (ASCO), Systemic Therapy for Patients with Advanced HER2-Positive Breast Cancer guidelines, trastuzumab in combination with pertuzumab and a taxane is recommended as first-line treatment, unless there are contraindications to taxanes; paclitaxel is a reasonable alternative in patients who are not good candidates for docetaxel [Giordano 2014].

HER2-positive metastatic breast cancer (in combination with either docetaxel or vinorelbine)

Data from a large phase III study supports the use of trastuzumab (in combination with either docetaxel or vinorelbine) for the treatment of metastatic or locally advanced HER2-positive breast cancer [Andersson 2011]. Additionally, a large randomized phase II trial supports the combination of trastuzumab and docetaxel for the management of metastatic HER2-positive disease [Marty 2005].

HER2 overexpressing metastatic breast cancer (in combination with lapatinib) which had progressed on prior trastuzumab containing therapy

Data from a phase III randomized controlled study supports the use of trastuzumab in combination with lapatinib in the management of metastatic breast cancer which has progressed on prior trastuzumab therapy [Blackwell 2012].

Based on the American Society of Clinical Oncology (ASCO), Systemic Therapy for Patients with Advanced HER2-Positive Breast Cancer guidelines, trastuzumab in combination with lapatinib is a third-line treatment option in patients whose disease has progressed during or after second line or greater HER2-targeted therapy.

Neoadjuvant treatment of HER2-positive locally advanced, inflammatory or early breast cancer

Data from a large randomized phase II study supports the use of trastuzumab in combination with pertuzumab and docetaxel in the neoadjuvant management of HER2-positive locally advanced, inflammatory or early breast cancer [Gianni 2012].

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to trastuzumab, Chinese hamster ovary (CHO) cell proteins, or any component of the formulation

Dosing: Adult

Note: Do NOT substitute conventional trastuzumab for or with ado-trastuzumab emtansine; products are different and are NOT interchangeable.

Breast cancer, adjuvant treatment, HER2+: IV: Note: Extending adjuvant treatment beyond 1 year is not recommended

With concurrent paclitaxel or docetaxel:

Initial loading dose: 4 mg/kg infused over 90 minutes, followed by

Maintenance dose: 2 mg/kg infused over 30 minutes weekly for total of 12 weeks, followed 1 week later (when concurrent chemotherapy completed) by 6 mg/kg infused over 30 to 90 minutes every 3 weeks for total therapy duration of 52 weeks

With concurrent docetaxel/carboplatin:

Initial loading dose: 4 mg/kg infused over 90 minutes, followed by

Maintenance dose: 2 mg/kg infused over 30 minutes weekly for total of 18 weeks, followed 1 week later (when concurrent chemotherapy completed) by 6 mg/kg infused over 30 to 90 minutes every 3 weeks for total therapy duration of 52 weeks

Following completion of multi-modality anthracycline-based chemotherapy:

Initial loading dose: 8 mg/kg infused over 90 minutes, followed by

Maintenance dose: 6 mg/kg infused over 30 to 90 minutes every 3 weeks for total therapy duration of 52 weeks

Breast cancer, metastatic, HER2+ (either as a single agent or in combination with paclitaxel): IV:

Initial loading dose: 4 mg/kg infused over 90 minutes, followed by

Maintenance dose: 2 mg/kg infused over 30 minutes weekly until disease progression

Gastric cancer, metastatic, HER2+ (in combination with cisplatin and either capecitabine or fluorouracil for 6 cycles followed by trastuzumab monotherapy; Bang 2010): IV:

Initial loading dose: 8 mg/kg infused over 90 minutes, followed by

Maintenance dose: 6 mg/kg infused over 30 to 90 minutes every 3 weeks until disease progression

Missed doses: If a dose is missed by ≤1 week, the usual maintenance dose should be administered as soon as possible (do not wait until the next planned cycle) and subsequent maintenance doses should be administered 7 or 21 days later (based on patient's maintenance dose/schedule); if a dose is missed by >1 week, then a re-loading dose (4 mg/kg if patient receives trastuzumab weekly; 8 mg/kg if on an every-3-week schedule) should be administered, followed by the usual maintenance dose administered 7 or 21 days later (based on patient's maintenance dose/schedule).

Breast cancer (early stage, locally advanced, or inflammatory), neoadjuvant treatment, HER2+ (off-label use): IV: Trastuzumab, pertuzumab, and docetaxel (in patients with operable disease who had received no prior chemotherapy): Initial: 8 mg/kg (cycle 1) followed by 6 mg/kg every 3 weeks for a total of 4 neoadjuvant cycles; postoperatively, administer 3 cycles of adjuvant FEC [fluorouracil, epirubicin, and cyclophosphamide] chemotherapy and continue trastuzumab to complete 1 year of treatment (Gianni 2012)

Breast cancer, metastatic, HER2+ (off-label combinations): IV: Note: There are multiple trastuzumab-containing regimens for the treatment of HER2+ metastatic breast cancer; commonly used regimens are listed below:

Trastuzumab, pertuzumab, and docetaxel (in patients with no prior anti-HER2 therapy or chemotherapy to treat metastatic disease): Initial: 8 mg/kg followed by a maintenance dose of 6 mg/kg every 3 weeks until disease progression or unacceptable toxicity (Baselga 2012)

Trastuzumab, pertuzumab, and weekly paclitaxel: Initial: 8 mg/kg followed by a maintenance dose of 6 mg/kg every 3 weeks until disease progression (Dang 2015)

Trastuzumab and lapatinib (in patients with progression on prior trastuzumab containing therapy): Initial: 4 mg/kg followed by a maintenance dose of 2 mg/kg every week (Blackwell 2010; Blackwell 2012)

Other trastuzumab combinations: Initial: 8 mg/kg followed by a maintenance dose of 6 mg/kg every 3 weeks until disease progression or unacceptable toxicity (in combination with docetaxel or vinorelbine) (Andersson 2011) or 4 mg/kg loading dose followed by a maintenance dose of 2 mg/kg weekly until disease progression (in combination with docetaxel) (Marty 2005)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl 30 to 90 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling, although no clinically significant pharmacokinetic differences have been observed.

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

End-stage renal disease (ESRD) (with or without hemodialysis): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Adjustment for Toxicity

Cardiotoxicity: LVEF ≥16% decrease from baseline or LVEF below normal limits and ≥10% decrease from baseline: Withhold treatment for at least 4 weeks and repeat LVEF every 4 weeks. May resume trastuzumab treatment if LVEF returns to normal limits within 4 to 8 weeks and remains at ≤15% decrease from baseline value. Discontinue permanently for persistent (>8 weeks) LVEF decline or for >3 incidents of treatment interruptions for cardiomyopathy.

Infusion-related events:

Mild-moderate infusion reactions: Decrease infusion rate.

Dyspnea, clinically significant hypotension: Interrupt infusion.

Severe or life-threatening infusion reactions: Discontinue.

Reconstitution

Check vial labels to assure appropriate product is being reconstituted (conventional trastuzumab and ado-trastuzumab emtansine are different products and are NOT interchangeable).

Reconstitute each 420 mg vial (multidose vial) with 20 mL of bacteriostatic sterile water for injection (sterile water for injection may be used if a patient has a known hypersensitivity to benzyl alcohol). Reconstitute each 150 mg vial (single use vial) with 7.4 mL of sterile water for injection. Direct the stream of diluent into the lyophilized cake. The reconstituted solutions (in the vial) will have a concentration of 21 mg/mL. Swirl gently; do not shake. Slight foaming may occur during reconstitution. Allow vial to rest undisturbed for ~5 minutes. Solutions reconstituted with sterile water for injection must be used immediately. Further dilute the appropriate volume for the trastuzumab dose in 250 mL NS prior to administration; do not use D5W. Gently invert bag to mix.

440 mg vial [Canadian product]: Reconstitute each 440 mg vial with 20 mL bacteriostatic sterile water for injection (sterile water for injection may be used if a patient has a known hypersensitivity to benzyl alcohol) to a concentration of 21 mg/mL, then follow above for further instructions.

Administration

Check label to ensure appropriate product is being administered (conventional trastuzumab and ado-trastuzumab emtansine are different products and are NOT interchangeable).

Administered by IV infusion; loading doses are infused over 90 minutes; maintenance doses may be infused over 30 minutes if tolerated. Do not administer with D5W. Do not administer IV push or by rapid bolus. Do not mix with any other medications.

Observe patients closely during the infusion for fever, chills, or other infusion-related symptoms. Treatment with acetaminophen, diphenhydramine, and/or meperidine is usually effective for managing infusion-related events.

Storage

Prior to reconstitution, store intact vials at 2°C to 8°C (36°F to 46°F). Following reconstitution with bacteriostatic SWFI, the solution in the vial is stable refrigerated for 28 days from the date of reconstitution; do not freeze. Solutions reconstituted with sterile water for injection without preservatives must be used immediately. The solution diluted in polyvinylchloride or polyethylene bags containing 250 mL NS for infusion may be stored refrigerated for up to 24 hours prior to use; do not freeze.

Drug Interactions

Anthracyclines: Trastuzumab may enhance the cardiotoxic effect of Anthracyclines. Management: When possible, patients treated with trastuzumab should avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab. Monitor closely for cardiac dysfunction in patients receiving anthracyclines with trastuzumab. Consider therapy modification

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

Immunosuppressants: Trastuzumab may enhance the neutropenic effect of Immunosuppressants.Exceptions: Cytarabine (Liposomal). Monitor therapy

PACLitaxel (Conventional): Trastuzumab may decrease the serum concentration of PACLitaxel (Conventional). PACLitaxel (Conventional) may increase the serum concentration of Trastuzumab.Monitor therapy

Adverse Reactions

Percentages reported with single-agent therapy.

>10%:

Cardiovascular: Decreased left ventricular ejection fraction (4% to 22%)

Central nervous system: Pain (47%), chills (5% to 32%), headache (10% to 26%), insomnia (14%), dizziness (4% to 13%)

Dermatologic: Skin rash (4% to 18%)

Gastrointestinal: Nausea (6% to 33%), diarrhea (7% to 25%), vomiting (4% to 23%), abdominal pain (2% to 22%), anorexia (14%)

Infection: Infection (20%)

Neuromuscular & skeletal: Weakness (4% to 42%), back pain (5% to 22%)

Respiratory: Cough (5% to 26%), dyspnea (3% to 22%), rhinitis (2% to 14%), pharyngitis (12%)

Miscellaneous: Infusion related reaction (21% to 40%, chills and fever most common; severe: 1%), fever (6% to 36%)

1% to 10%:

Cardiovascular: Peripheral edema (5% to 10%), edema (8%), cardiac failure (2% to 7%; severe: <1%), tachycardia (5%), hypertension (4%), arrhythmia (3%), palpitations (3%)

Central nervous system: Paresthesia (2% to 9%), depression (6%), peripheral neuritis (2%), neuropathy (1%)

Dermatologic: Acne vulgaris (2%), nail disease (2%), pruritus (2%)

Gastrointestinal: Constipation (2%), dyspepsia (2%)

Genitourinary: Urinary tract infection (3% to 5%)

Hematologic & oncologic: Anemia (4%; grade 3: <1%), leukopenia (3%)

Hypersensitivity: Hypersensitivity reaction (3%)

Infection: Influenza (4%), herpes simplex infection (2%)

Neuromuscular & skeletal: Arthralgia (6% to 8%), ostealgia (3% to 7%), myalgia (4%), muscle spasm (3%)

Respiratory: Flu-like symptoms (2% to 10%), sinusitis (2% to 9%), nasopharyngitis (8%), upper respiratory tract infection (3%), epistaxis (2%), pharyngolaryngeal pain (2%)

Miscellaneous: Accidental injury (6%)

<1% (Limited to important or life-threatening; as a single-agent or with combination chemotherapy): Adult respiratory distress syndrome, amblyopia, anaphylaxis, apnea, ascites, asthma, ataxia, blood coagulation disorder, bronchitis, cardiogenic shock, cardiomyopathy, cellulitis, cerebrovascular accident, colitis, coma, confusion, deafness, dermal ulcer, dyspnea on exertion, erysipelas, esophageal ulcer, febrile neutropenia, gastroenteritis, glomerulopathy, hematemesis, hemorrhage, hemorrhagic cystitis, hepatic failure, hepatitis, herpes zoster, hydrocephalus, hydronephrosis, hypercalcemia, hypotension, hypothyroidism, hypoxia, immune thrombocytopenia, intestinal obstruction, interstitial pneumonitis, interstitial pulmonary disease, leukemia (acute), lymphangitis, madarosis, mania, meningitis, myopathy, neutropenia, neutropenic sepsis, oligohydramnios, onychoclasis, osteonecrosis, pancreatitis, pancytopenia, paresis, paroxysmal nocturnal dyspnea, pathological fracture, pericardial effusion, pleural effusion, pneumonitis, pneumothorax, pulmonary edema (noncardiogenic), pulmonary fibrosis, pulmonary hypertension, pyelonephritis, radiation injury, renal failure, respiratory failure, seizure, sepsis, syncope, stomatitis, thyroiditis (autoimmune), ventricular dysfunction

ALERT: U.S. Boxed Warning

Cardiomyopathy:

Trastuzumab can result in subclinical and clinical cardiac failure. The incidence and severity was highest in patients who received trastuzumab concurrently with anthracycline-containing chemotherapy regimens.

Evaluate left ventricular function in all patients prior to and during treatment with trastuzumab. Discontinue trastuzumab treatment in patients receiving adjuvant therapy, and withhold trastuzumab in patients with metastatic disease for clinically significant decrease in left ventricular function.

Infusion reactions and pulmonary toxicity:

Trastuzumab administration can result in serious and fatal infusion reactions and pulmonary toxicity. Symptoms usually occur during or within 24 hours of administration of trastuzumab. Interrupt trastuzumab infusion for patients experiencing dyspnea or clinically significant hypotension. Monitor patients until signs and symptoms resolve completely. Discontinue trastuzumab for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.

Pregnancy:

Exposure to trastuzumab 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.

Warnings/Precautions

Concerns related to adverse effects:

• Cardiomyopathy: [US Boxed Warning]: Trastuzumab is associated with symptomatic and asymptomatic reductions in left ventricular ejection fraction (LVEF) and heart failure (HF); the incidence is highest in patients receiving trastuzumab with an anthracycline-containing chemotherapy regimen. Evaluate LVEF in all patients prior to and during treatment; discontinue for cardiomyopathy. Extreme caution should be used in patients with pre-existing cardiac disease or dysfunction. Prior or concurrent exposure to anthracyclines or radiation therapy significantly increases the risk of cardiomyopathy; other potential risk factors include advanced age, high or low body mass index, smoking, diabetes, hypertension, and hyper-/hypothyroidism. Patients who receive anthracyclines after completion or discontinuation of trastuzumab are at increased risk of cardiac dysfunction (anthracyclines should be avoided for at least 7 months after the last trastuzumab dose, and then monitor cardiac function closely if anthracyclines are used. Discontinuation should be strongly considered in patients who develop a clinically significant reduction in LVEF during therapy; treatment with HF medications (eg, ACE inhibitors, beta-blockers) should be initiated. Withhold treatment for ≥16% decrease from pretreatment levels or LVEF below normal limits and ≥10% decrease from baseline (see Dosage Adjustment for Cardiotoxicity). Cardiomyopathy due to trastuzumab is generally reversible over a period of 1 to 3 months after discontinuation. Long-term (8 years) follow-up in the adjuvant setting (trastuzumab for 1 or 2 years administered sequentially following chemotherapy and radiation therapy) has demonstrated a low incidence of cardiac events, which were generally reversible in most patients (de Azambuja 2014). Trastuzumab is also associated with arrhythmias, hypertension, mural thrombus formation, stroke, and even cardiac death.

• Infusion reactions: [US Boxed Warning]: Infusion reactions (including fatalities) have been associated with use; discontinue for anaphylaxis or angioedema. Most reactions occur during or within 24 hours of the first infusion; interrupt infusion for dyspnea or significant hypotension; monitor until symptoms resolve. Infusion reactions may consist of fever and chills, and may also include nausea, vomiting, pain, headache, dizziness, dyspnea, hypotension, rash, and weakness. Re-treatment of patients who experienced severe hypersensitivity reactions has been attempted (with premedication). Some patients tolerated re-treatment, while others experienced a second severe reaction.

• Pulmonary toxicity: [US Boxed Warning]: May cause serious pulmonary toxicity (dyspnea, hypoxia, interstitial pneumonitis, pulmonary infiltrates, pleural effusion, noncardiogenic pulmonary edema, pulmonary insufficiency, acute respiratory distress syndrome [ARDS], and/or pulmonary fibrosis); discontinue for ARDS or interstitial pneumonitis. Use caution in patients with pre-existing pulmonary disease or patients with extensive pulmonary tumor involvement; these patient populations may have more severe toxicity. Pulmonary events may occur during or within 24 hours of administration; delayed reactions have occurred.

• Renal toxicity: Rare cases of nephrotic syndrome with evidence of glomerulopathy have been reported, with an onset of 4 to 18 months from trastuzumab initiation; complications may include volume overload and HF. The incidence of renal impairment was increased in metastatic gastric cancer patients when trastuzumab is added to chemotherapy.

Concurrent drug therapy issues:

• Chemotherapy: When used in combination with myelosuppressive chemotherapy, trastuzumab may increase the incidence of neutropenia (moderate-to-severe) and febrile neutropenia. The incidence of anemia may be higher when trastuzumab is added to chemotherapy.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pregnancy: [US Boxed Warning]: Trastuzumab exposure during pregnancy may result in oligohydramnios and oligohydramnios sequence (pulmonary hypoplasia, skeletal malformations and neonatal death). Advise patients of these risks and the need for effective contraception. Effective contraception is recommended in women of childbearing potential during treatment and for at least 7 months after the last trastuzumab dose.

Dosage form specific issues:

• Do not interchange: Conventional trastuzumab and ado-trastuzumab emtansine are notinterchangeable. Verify product label prior to reconstitution and administration to prevent medication errors. Dosing and treatment schedules between conventional trastuzumab (Herceptin) and ado-trastuzumab emtansine (Kadcyla) are different; confusion between the products may potentially cause harm to the patient.

Other warnings/precautions:

• HER2 expression: Establish HER2 status prior to treatment with an approved test, either HER2 protein overexpression by validated immunohistochemistry (IHC) assay or gene amplification by fluorescence in situ hybridization (FISH) assay. Due to differences in disease histopathology (eg, incomplete membrane staining and more frequent heterogeneous HER2 expression in gastric cancer), tests appropriate for the specific tumor type (breast or gastric) should be used to assess HER2 status. Unreliable results may occur from improper assay performance, such as use of suboptimally fixed tissue, failure to utilize specified reagents or to include appropriate controls for assay validation, or incorrectly following specific assay instructions. Information regarding HER2 diagnostic testing may be found at http://www.fda.gov/CompanionDiagnostics.

Monitoring Parameters

Assessment for HER2 overexpression and HER2 gene amplification by validated immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) methodology (pretherapy); test should be specific for cancer type (breast vs gastric cancer). Pregnancy test (prior to treatment in women of reproductive potential). Monitor vital signs during infusion; signs and symptoms of cardiac dysfunction; LVEF (baseline, every 3 months during treatment, upon therapy completion and if component of adjuvant therapy, every 6 months for at least 2 years; if treatment is withheld for significant LVEF dysfunction, monitor LVEF at 4-week intervals); signs and symptoms of infusion reaction or pulmonary toxicity; if pregnancy inadvertently occurs during treatment, monitor amniotic fluid volume

Pregnancy Considerations

Trastuzumab inhibits HER2 protein, which has a role in embryonic development. [US Boxed Warning]: Trastuzumab exposure during pregnancy may result in oligohydramnios and oligohydramnios sequence (pulmonary hypoplasia, skeletal malformations and neonatal death). Advise patients of these risks and the need for effective contraception. Oligohydramnios (reversible in some cases) has been reported with trastuzumab use alone or with combination chemotherapy. Monitor for oligohydramnios if trastuzumab exposure occurs during pregnancy or within 7 months prior to conception; conduct appropriate fetal testing if oligohydramnios occurs. Verify pregnancy status in women of reproductive potential prior to initiation of therapy. Women of reproductive potential should use effective contraception during treatment and for at least 7 months after the last trastuzumab dose. If trastuzumab is administered during pregnancy, or if a patient becomes pregnant during or within 7 months after treatment, report exposure to Genentech Adverse Events at 1-888-835-2555. Women exposed to trastuzumab during pregnancy (or within 7 months prior to conception) are encouraged to enroll in MotHER (the Herceptin Pregnancy Registry; 1-800-690-6720 or http://www.motherpregnancyregistry.com).

European Society for Medical Oncology (ESMO) guidelines for cancer during pregnancy recommend delaying treatment with trastuzumab (and other HER-2 targeted agents) until after delivery in pregnant patients with HER-2 positive disease (Peccatori 2013).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience flu-like symptoms, lack of appetite, abdominal pain, weight loss, change in taste, bone pain, joint pain, back pain, insomnia, rhinitis, rhinorrhea, muscle pain, or pharyngitis. Have patient report immediately to prescriber infusion reaction, signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), signs of infection, abnormal heartbeat, angina, tachycardia, shortness of breath, excessive weight gain, swelling of arms or legs, severe dizziness, passing out, vision changes, severe headache, severe nausea, vomiting, severe diarrhea, bruising, bleeding, severe loss of strength and energy, burning or numbness feeling, or depression (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.