HERCEPTIN Trastuzumab 600mg / 5mL (120mg / mL) Solution for SC Injection 5mL

Trastuzumab (Herceptin) IV and Trastuzumab (Herceptin) SC: Breast Cancer: Metastatic Breast Cancer (MBC): Trastuzumab (Herceptin) is indicated for the treatment of patients with metastatic breast cancer who have tumors that overexpress HER2: as monotherapy for the treatment of those patients who have received one or more chemotherapy regimens for their metastatic disease; in combination with paclitaxel or docetaxel for the treatment of those patients who have not received chemotherapy for their metastatic disease; in combination with an aromatase inhibitor for the treatment of patients with hormone-receptor positive metastatic breast cancer.
Early Breast Cancer (EBC): Trastuzumab (Herceptin) is indicated for the treatment of patients with HER2-positive early breast cancer: following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable); following adjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel; in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin; in combination with neoadjuvant chemotherapy followed by adjuvant Trastuzumab (Herceptin), for locally advanced (including inflammatory) breast cancer or tumors > 2 cm in diameter.
Trastuzumab (Herceptin) IV only: Advanced Gastric Cancer (AGC): Trastuzumab (Herceptin) in combination with capecitabine or intravenous 5-fluorouracil and a platinum agent is indicated for the treatment of patients with HER2-positive advanced adenocarcinoma of the stomach or gastro-esophageal junction who have not received prior anti-cancer treatment for their metastatic disease.

General: HER2 testing is mandatory prior to initiation of Trastuzumab (Herceptin) therapy.
Substitution by any other biological medicinal product requires the consent of the prescribing physician. The benefit-risk of alternating or switching between Trastuzumab (Herceptin) and products that are biosimilar but not deemed interchangeable needs to be carefully considered when the safety and efficacy of alternating or switching has not been established.
Trastuzumab (Herceptin) should be administered by a qualified health care professional.
It is important to check the product labels to ensure that the correct formulation (Trastuzumab (Herceptin) IV or Trastuzumab (Herceptin) SC) is being administered to the patient as prescribed.
Switching treatment between Trastuzumab (Herceptin) IV and Trastuzumab (Herceptin) SC and vice versa, using a three-weekly (q3w) dosing regimen, was investigated in study MO22982 (see Clinical Trials under Adverse Reactions).
In order to prevent medication errors it is important to check the vial labels to ensure that the drug being prepared and administered is Trastuzumab (Herceptin) and not Trastuzumab emtansine (Kadcyla).
Trastuzumab (Herceptin) IV (see Cautions for Usage):Trastuzumab (Herceptin) IV is not to be used for subcutaneous administration and should be administered as intravenous infusion.
Do not administer as an intravenous push or bolus.
Weekly schedule: Loading dose: The recommended initial loading dose is 4 mg/kg body weight Trastuzumab (Herceptin) IV administered as a 90-minute IV infusion.
Subsequent doses: The recommended weekly dose of Trastuzumab (Herceptin) IV is 2 mg/kg body weight. If the prior dose was well tolerated, the dose can be administered as a 30-minute infusion.
Alternative 3-weekly schedule: Initial Trastuzumab (Herceptin) IV loading dose of 8 mg/kg body weight, followed by 6 mg/kg body weight 3 weeks later and then 6 mg/kg repeated at 3-weekly intervals administered as infusions over approximately 90 minutes. If the prior dose was well tolerated, the dose can be administered as a 30-minute infusion.
Trastuzumab (Herceptin) SC (see Cautions for Usage):Trastuzumab (Herceptin) SC is not to be used for intravenous administration and must be administered as a subcutaneous injection only.
No loading dose is required.
The recommended fixed dose of Trastuzumab (Herceptin) SC is 600 mg every three weeks irrespective of the patient's body weight.
The injection site should be alternated between the left and right thigh. New injections should be given at least 1 inch/2.5 cm from the previous site on healthy skin and never into areas where the skin is red, bruised, tender, or hard. During the treatment course with Trastuzumab (Herceptin) SC, other medications for SC administration should preferably be injected at different sites.
When administering Trastuzumab (Herceptin) SC Vial, the dose should be administered over 2-5 minutes every three weeks.
Duration of Treatment: Patients with MBC should be treated with Trastuzumab (Herceptin) until progression of disease or unmanageable toxicity.
Patients with EBC should be treated for 1 year or until disease recurrence or unmanageable toxicity, whichever occurs first. Extending treatment in EBC beyond one year is not recommended (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
Patients with advanced gastric cancer should be treated with Trastuzumab (Herceptin) IV until progression of disease or unmanageable toxicity.
Missed doses: Trastuzumab Herceptin IV:If the patient has missed a dose of Trastuzumab (Herceptin) IV by one week or less, then the usual maintenance dose (weekly regimen: 2 mg/kg; three-weekly regimen: 6 mg/kg) should be administered as soon as possible. Do not wait until the next planned cycle. Subsequent Trastuzumab (Herceptin) IV 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 Trastuzumab (Herceptin) IV by more than one week, a re-loading dose of Trastuzumab (Herceptin) IV should be administered over approximately 90 minutes (weekly regimen: 4 mg/kg; three-weekly regimen: 8 mg/kg) as soon as possible. Subsequent Trastuzumab (Herceptin) IV maintenance doses (weekly regimen: 2 mg/kg; three-weekly regimen 6 mg/kg respectively) should be administered 7 days or 21 days later according to the weekly or three-weekly schedules respectively.
Trastuzumab (Herceptin) SC:If one dose of Trastuzumab (Herceptin) SC is missed, it is recommended to administer the next 600 mg dose (i.e. the missed dose) as soon as possible. The interval between subsequent Trastuzumab (Herceptin) SC doses should not be less than three weeks.
Dose Modification: If the patient develops an infusion-related reaction (IRR), the infusion rate of Trastuzumab (Herceptin) IV may be slowed or interrupted (see Precautions).
No reductions in the dose of Trastuzumab (Herceptin) were made during clinical trials. Patients may continue Trastuzumab (Herceptin) therapy during periods of reversible, chemotherapy-induced myelosuppression, but they should be monitored carefully for complications of neutropenia during this time. The specific instructions to reduce or hold the dose of chemotherapy should be followed.
Special Dosage Instructions: Geriatric use: Data suggest that the disposition of Trastuzumab (Herceptin) is not altered based on age (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions). In clinical trials, patients ≥ 65 years of age did not receive reduced doses of Trastuzumab (Herceptin).
Pediatric Use: The safety and efficacy of Trastuzumab (Herceptin) in pediatric patients < 18 years of age have not been established.

Trastuzumab (Herceptin) is contraindicated in patients with known hypersensitivity to trastuzumab or to any of its excipients.

General:In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded (or stated) in the patient file.
Trastuzumab (Herceptin) therapy should only be initiated under supervision of a physician experienced in the treatment of cancer patients.
Infusion/Administration-related reactions (IRRs/ARRs): IRRs/ARRs are known to occur with the administration of Trastuzumab Herceptin (see Adverse Reactions).
IRRs/ARRs may be clinically difficult to distinguish from hypersensitivity reactions. Pre-medication may be used to reduce risk of occurrence of IRRs/ARRs.
Serious IRRs/ARRs to Trastuzumab (Herceptin) including dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress, supraventricular tachyarrhythmia and urticaria have been reported (see Adverse Reactions). Patients should be observed for IRRs/ARRs. Interruption of an IV infusion may help control such symptoms and the infusion may be resumed when symptoms abate. These symptoms can be treated with an analgesic/antipyretic such as meperidine or paracetamol, or an antihistamine such as diphenhydramine. Serious reactions have been treated successfully with supportive therapy such as oxygen, beta-agonists and corticosteroids. In rare cases, these reactions are associated with a clinical course culminating in a fetal outcome. Patients who are experiencing dyspnea at rest due to complications of advanced malignancy or co-morbidities may be at increased risk of a fetal infusion reaction. Therefore, these patients should not be treated with Trastuzumab (Herceptin).
Pulmonary Reactions: Severe pulmonary events have been reported with the use of Trastuzumab (Herceptin) IV in the post-marketing setting. These events have occasionally resulted in fetal outcome and may occur as part of an IRR or with a delayed onset. In addition, cases of interstitial lung disease including lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary edema and respiratory insufficiency have been reported.
Risk factors associated with interstitial lung disease include prior or concomitant therapy with other anti-neoplastic therapies known to be associated with it such as taxanes, gemcitabine, vinorelbine and radiation therapy. Patients with dyspnea at rest due to complications of advanced malignancy and co-morbidities may be at increased risk of pulmonary events. Therefore, these patients should not be treated with Trastuzumab (Herceptin).
Cardiac Dysfunction: General considerations: Patients treated with Trastuzumab (Herceptin) are at increased risk of developing congestive heart failure (CHF) (New York Heart Association [NYHA] Class II-IV) or asymptomatic cardiac dysfunction. These events have been observed in patients receiving Trastuzumab (Herceptin) therapy alone or in combination with taxane following anthracycline (doxorubicin or epirubicin)–containing chemotherapy. This may be moderate to severe and has been associated with death (see Adverse Reactions). In addition, caution should be exercised in treating patients with increased cardiac risk, e.g. hypertension, documented coronary artery disease, CHF, diastolic dysfunction, older age.
Population pharmacokinetic model simulations indicate that trastuzumab may persist in the circulation for up to 7 months after stopping Trastuzumab (Herceptin) IV or Trastuzumab (Herceptin) SC treatment (see Pharmacology: Pharmacokinetics under Actions). Patients who receive anthracycline after stopping Trastuzumab (Herceptin) may also be at increased risk of cardiac dysfunction.
If possible, physicians should avoid anthracycline-based therapy for up to 7 months after stopping Trastuzumab (Herceptin). If anthracyclines are used, the patient’s cardiac function should be monitored carefully.
Candidates for treatment with Trastuzumab (Herceptin), especially those with prior exposure to an anthracycline, should undergo baseline cardiac assessment including history and physical examination, electrocardiogram (ECG), and echocardiogram or multigated acquisition scanning (MUGA) scan. Monitoring may help to identify patients who develop cardiac dysfunction, including signs and symptoms of CHF. Cardiac assessments, as performed at baseline, should be repeated every 3 months during treatment and every 6 months following discontinuation of treatment until 24 months from the last administration of Trastuzumab (Herceptin).
If LVEF percentage drops 10 points from baseline and to below 50%, Trastuzumab (Herceptin) should be withheld and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has not improved, or has declined further, or if clinically significant CHF has developed, discontinuation of Trastuzumab (Herceptin) should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks.
Patients who develop asymptomatic cardiac dysfunction may benefit from more frequent monitoring (e.g. every 6 - 8 weeks). If patients have a continued decrease in left ventricular function, but remain asymptomatic, the physician should consider discontinuing therapy unless the benefits for the individual patient are deemed to outweigh the risks.
The safety of continuation or resumption of Trastuzumab (Herceptin) in patients who experience cardiac dysfunction has not been prospectively studied. If symptomatic cardiac failure develops during Trastuzumab (Herceptin) therapy, it should be treated with standard medications for heart failure (HF). In the pivotal trials, most patients who developed HF or asymptomatic cardiac dysfunction improved with standard HF treatment consisting of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and a β-blocker. The majority of patients with cardiac symptoms and evidence of a clinical benefit of Trastuzumab (Herceptin) treatment continued with Trastuzumab (Herceptin) without additional clinical cardiac events.
Metastatic breast cancer (MBC):Trastuzumab (Herceptin) and anthracyclines should not be given concurrently in the metastatic breast cancer setting.
Early breast cancer (EBC):For patients with EBC, cardiac assessments, as performed at baseline, should be repeated every 3 months during treatment and every 6 months following discontinuation of treatment until 24 months from the last administration of Trastuzumab (Herceptin). In patients who receive anthracycline- containing chemotherapy, further monitoring is recommended and should occur yearly up to 5 years from the last administration of Trastuzumab (Herceptin), or longer if a continuous decrease of LVEF is observed.
Patients with history of myocardial infarction (MI), angina pectoris requiring medication, history of or present CHF (NYHA Class II –IV), other cardiomyopathy, cardiac arrhythmia requiring medication, clinically significant cardiac valvular disease, poorly controlled hypertension (hypertension controlled by standard medication eligible), and hemodynamic effective pericardial effusion were excluded from adjuvant breast cancer clinical trials with Trastuzumab (Herceptin).
Adjuvant treatment:Trastuzumab (Herceptin) and anthracyclines should not be given concurrently in the adjuvant treatment setting. In patients with EBC an increase in the incidence of symptomatic and asymptomatic cardiac events was observed when Trastuzumab (Herceptin) IV was administered after anthracycline-containing chemotherapy compared to administration with a non-anthracycline regimen of docetaxel and carboplatin. The incidence was more marked when Trastuzumab (Herceptin) IV was administered concurrently with taxanes than when administered sequentially to taxanes. Regardless of the regimen used, most symptomatic cardiac events occurred within the first 18 months.
Risk factors for a cardiac event identified in four large adjuvant studies included advanced age (> 50 years), low level of baseline and declining LVEF (< 55%), low LVEF prior to or following the initiation of paclitaxel treatment, Trastuzumab (Herceptin) treatment, and prior or concurrent use of anti- hypertensive medications. In patients receiving Trastuzumab (Herceptin) after completion of adjuvant chemotherapy, the risk of cardiac dysfunction was associated with a higher cumulative dose of anthracycline given prior to initiation of Trastuzumab (Herceptin) and a high body mass index (BMI >25 kg/m²).
Neoadjuvant-adjuvant treatment:In patients with EBC eligible for neoadjuvant-adjuvant treatment, Trastuzumab (Herceptin) concurrently with anthracyclines should be used with caution and only in chemotherapynaive patients. The maximum cumulative doses of the low-dose anthracycline regimens should not exceed 180 mg/m² (doxorubicin) or 360 mg/m² (epirubicin).
If patients have been treated concurrently with low-dose anthracyclines and Trastuzumab (Herceptin) in the neoadjuvant setting, no additional cytotoxic chemotherapy should be given after surgery.
Clinical experience in the neoadjuvant-adjuvant setting is limited in patients above 65 years of age.
Benzyl alcohol: Benzyl alcohol, used as a preservative in bacteriostatic water for injection in the 440 mg multidose vial, has been associated with toxicity in neonates and children up to 3 years old. When administering Trastuzumab (Herceptin) to a patient with a known hypersensitivity to benzyl alcohol, Trastuzumab (Herceptin) should be reconstituted with water for injection, and only one dose per Trastuzumab (Herceptin) vial should be used. Any unused portion must be discarded. Sterile water for injection, used to reconstitute the 60 mg and 150 mg single dose vials, does not contain benzyl alcohol.
Drug Abuse and Dependence: No data to report.
Ability to Drive and Use Machines: No studies on the effects on the ability to drive and to use machines have been preformed. Patients experiencing infusion-related symptoms should be advised not to drive or use machines until symptoms resolve completely.
Renal Impairment: In a population pharmacokinetic analysis, renal impairment was shown not to affect trastuzumab disposition.
Hepatic Impairment: No data to report.
Use in Children: The safety and efficacy of Trastuzumab (Herceptin) in pediatric patients below the age of 18 have not been established.
Use in Elderly: Data suggest that the disposition of Trastuzumab (Herceptin) is not altered based on age (see Pharmacology: Pharmacokinetics: Special Populations under Actions).

Clinical Trials: Table 12 summarizes the adverse drug reactions (ADRs) that have been reported in association with the use of Trastuzumab (Herceptin) alone or in combination with chemotherapy in pivotal clinical trials. All the terms included are based on the highest percentage seen in pivotal clinical trials.
As Trastuzumab (Herceptin) is commonly used with other chemotherapeutic agents and radiotherapy it is often difficult to ascertain the causal relationship of an adverse event to a particular drug/radiotherapy.
The corresponding frequency category for each adverse drug reaction is based on the following convention: 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), very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions should be presented in order of decreasing seriousness. (See Table 12.)

 

Additional information for selected adverse drug reactions: Infusion/Administration- related reactions (IRRs/ARRs) and Hypersensitivity: IRRs/ARRs such as chills and/or fever, dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress were seen in all trastuzumab clinical trials and for the IV and the SC formulation (see Precautions).
IRRs/ARRs may be clinically difficult to distinguish from hypersensitivity reactions.
The rate of IRRs/ARRs of all grades varied between studies depending on the indication, whether trastuzumab was given concurrently with chemotherapy or as monotherapy and data collection methodology.
In MBC, the rate of IRRs ranged from 49% to 54% in the trastuzumab containing arm compared to 36% to 58% in the comparator arm (which may have contained other chemotherapy). Severe (grade 3 and above) ranged from 5% to 7% in the trastuzumab containing arm compared to 5 to 6% in the comparator arm.
In EBC, the rate of IRRs/ARRs ranged from 18% to 54% in the trastuzumab containing arm compared to 6% to 50% in the comparator arm (which may have contained other chemotherapy). Severe (grade 3 and above) ranged from 0.5% to 6% in the trastuzumab containing arm compared to 0.3 to 5% in the comparator arm.
In the neoadjuvant-adjuvant EBC treatment setting (BO22227), the rates of IRRs/ARRs were in line with the above and were 37.2% in the Trastuzumab (Herceptin) IV arm to 47.8% in the Trastuzumab (Herceptin) SC arm. Severe (grade 3) IRRs/ARRs were 2.0% and 1.7% in the Trastuzumab (Herceptin) IV and Trastuzumab (Herceptin) SC arms, respectively during the treatment phase. There were no grade 4 or 5 IRRs/ARRs.
Anaphylactoid reactions were observed in isolated cases.
Cardiac dysfunction:Congestive heart failure (NYHA Class II-IV) is a common adverse reaction to Trastuzumab (Herceptin). It has been associated with fetal outcome. Signs and symptoms of cardiac dysfunction such as dyspnea, orthopnea, increased cough, pulmonary edema, S₃ gallop, or reduced ventricular ejection fraction, have been observed in patients treated with Trastuzumab (Herceptin) (see Precautions).
Metastatic Breast Cancer: Depending on the criteria used to define cardiac dysfunction, the incidence in the pivotal metastatic trials varied between 9% and 12% in the Trastuzumab (Herceptin) + paclitaxel group, compared with 1% – 4% in the paclitaxel-alone group. For Trastuzumab (Herceptin) monotherapy, the rate was 6% – 9%. The highest rate of cardiac dysfunction was seen in patients receiving concurrent Trastuzumab (Herceptin) + anthracycline/cyclophosphamide (27%), and was significantly higher than in the anthracycline/cyclophosphamide-alone group (7% – 10%). In a subsequent trial with prospective monitoring of cardiac function, the incidence of symptomatic heart failure was 2.2% in patients receiving Trastuzumab (Herceptin) and docetaxel, compared with 0% in patients receiving docetaxel alone. Most of the patients (79%) who developed cardiac dysfunction in these trials experienced an improvement after receiving standard treatment for CHF.
Early Breast Cancer (adjuvant setting): In three pivotal clinical trials of adjuvant trastuzumab given in combination with chemotherapy, the incidence of grade 3/4 cardiac dysfunction (symptomatic CHF) was similar in patients who were administered chemotherapy alone and in patients who were administered Trastuzumab (Herceptin) sequentially after a taxane (0.3 - 0.4%). The rate was highest in patients who were administered Trastuzumab (Herceptin) concurrently with a taxane (2.0%). At 3 years, the cardiac event rate in patients receiving AC→P (doxorubicin plus cyclophosphamide followed by paclitaxel) + H (trastuzumab) was estimated at 3.2%, compared with 0.8% in AC→P treated patients. No increase in the cumulative incidence of cardiac events was seen with further follow-up at 5 years.
At 5.5 years, the rates of symptomatic cardiac or LVEF events were 1.0%, 2.3%, and 1.1% in the AC→D (doxorubicin plus cyclophosphamide, followed by docetaxel), AC→DH (doxorubicin plus cyclophosphamide, followed by docetaxel plus trastuzumab), and DCarbH (docetaxel, carboplatin and trastuzumab) treatment arms, respectively. For symptomatic CHF (NCI-CTC Grade 3-4), the 5-year rates were 0.6%, 1.9%, and 0.4% in the AC→D, AC→DH, and DCarbH treatment arms, respectively. The overall risk of developing symptomatic cardiac events was low and similar for patients in the AC→D and DCarbH arms; relative to both the AC→D and DCarbH, arms there was an increased risk of developing a symptomatic cardiac event for patients in the AC→DH arm, being discernable by a continuous increase in the cumulative rate of symptomatic cardiac or LVEF events up to 2.3% compared to approximately 1% in the two comparator arms (AC→D and DCarbH).
When Trastuzumab (Herceptin) was administered after completion of adjuvant chemotherapy NYHA Class III-IV heart failure was observed in 0.6% of patients in the one-year arm after a median follow-up of 12 months. After a median follow-up of 3.6 years the incidence of severe CHF and left ventricular dysfunction after 1 year Trastuzumab (Herceptin) therapy remained low at 0.8% and 9.8%, respectively.
In study BO16348, after a median follow-up of 8 years the incidence of severe CHF (NYHA Class III-IV) in the Trastuzumab (Herceptin) 1-year treatment arm was 0.8%, and the rate of mild symptomatic and asymptomatic left ventricular dysfunction was 4.6%.
Reversibility of severe CHF (defined as a sequence of at least two consecutive LVEF values ≥ 50% after the event) was evident for 71.4% of Trastuzumab (Herceptin)-treated patients. Reversibility of mild symptomatic and asymptomatic left ventricular dysfunction was demonstrated for 79.5% of patients. Approximately 17% of cardiac-dysfunction related events occurred after completion of Trastuzumab (Herceptin).
In the joint analysis of studies NSABP B-31 and NCCTG N9831, with a median follow-up of 8.1 years for the AC→PH group (doxorubicin plus cyclophosphamide, followed by paclitaxel plus trastuzumab), the per-patient incidence of new onset cardiac dysfunction, as determined by LVEF, remained unchanged compared to the analysis performed at a median follow up of 2.0 years in the AC→PH group: 18.5% of AC→PH patients with an LVEF decrease of ≥10% to below 50%.
Reversibility of left ventricular dysfunction was reported in 64.5% of patients who experienced a symptomatic CHF in the AC→PH group being asymptomatic at latest follow up, and 90.3% having full or partial LVEF recovery.
Early Breast Cancer (neoadjuvant-adjuvant setting):In the pivotal trial MO16432, Trastuzumab (Herceptin) was administered concurrently with neoadjuvant chemotherapy containing three cycles of doxorubicin (cumulative dose 180 mg/m²). The incidence of symptomatic cardiac dysfunction was 1.7 % in the Trastuzumab (Herceptin) arm.
In the pivotal trial BO22227, Trastuzumab (Herceptin) was administered concurrently with neoadjuvant chemotherapy that contained four cycles of epirubicin (cumulative dose 300 mg/m²); at a median follow-up exceeding 70 months, the incidence of cardiac failure / congestive cardiac failure was 0.3% in the Trastuzumab (Herceptin) IV arm and 0.7% in the Trastuzumab (Herceptin) SC arm. In patients with lower body weights (<59 kg, the lowest body weight quartile) the fixed dose used in the Trastuzumab (Herceptin) SC arm was not associated with an increased risk of cardiac events or significant drop in LVEF.
Advanced Gastric Cancer:In the BO18255 study, at screening, the median LVEF value was 64% (range 48%-90%) in the Fluoropyrimidine/Cisplatin arm (FP) arm and 65% (range 50%-86%) in the Trastuzumab (Herceptin) IV plus Fluoropyrimidine/Cisplatin arm (H+FP) arm.
The majority of the LVEF decreases noted in BO18255 study were asymptomatic, with the exception of one patient in the Trastuzumab (Herceptin)-containing arm whose LVEF decrease coincided with cardiac failure. (See Tables 13 and 14.)

 

Overall, there were no significant differences in cardiac dysfunction between the treatment arm and the comparator arm.
Haematological toxicity: Breast Cancer:Hematological toxicity is infrequent following the administration of Trastuzumab (Herceptin) IV monotherapy in the metastatic setting, WHO Grade 3 leukopenia, thrombocytopenia and anemia occurring in < 1% of patients. No WHO Grade 4 toxicities were observed. There was an increase in WHO Grade 3 or 4 hematological toxicity in patients treated with the combination of Trastuzumab (Herceptin) and paclitaxel compared with patients receiving paclitaxel alone (34% versus 21%). Hematological toxicity was also increased in patients receiving Trastuzumab (Herceptin) and docetaxel, compared with docetaxel alone (32% grade 3/4 neutropenia versus 22%, using NCI-CTC criteria). The incidence of febrile neutropenia/neutropenic sepsis was also increased in patients treated with Trastuzumab (Herceptin) plus docetaxel (23% versus 17% for patients treated with docetaxel alone).
Using NCI-CTC criteria, in the BO16348 study, 0.4% of Trastuzumab (Herceptin)-treated patients experienced a shift of 3 or 4 grades from baseline, compared with 0.6% in the observation arm.
Advanced Gastric Cancer: The most frequently reported AEs, of Grade ≥ 3 occurring with an incidence rate of at least 1% by trial treatment, that were categorized under the Blood and Lymphatic System Disorders SOC are shown below: see Table 15.

Overall, there were no significant differences in hematoxicity between the treatment arm and the comparator arm.
Hepatic and renal toxicity: Breast Cancer:WHO Grade 3 or 4 hepatic toxicity was observed in 12% of patients following administration of Trastuzumab (Herceptin) IV as single agent, in the metastatic setting. This toxicity was associated with progression of disease in the liver in 60% of these patients.
WHO Grade 3 or 4 hepatic toxicity was less frequently observed among patients receiving Trastuzumab (Herceptin) IV and paclitaxel than among patients receiving paclitaxel alone (7% compared with 15%). No WHO Grade 3 or 4 renal toxicity was observed.
Advanced Gastric Cancer: In the BO18255 study no significant differences in hepatic and renal toxicity were observed between the two treatment arms.
NCI-CTCAE (version 3.0) grade ≥3 renal toxicity was not significantly higher in patients receiving Trastuzumab (Herceptin) IV than those in the F+P arm (3% and 2% respectively).
NCI-CTCAE (version 3.0) grade ≥3 adverse event in the Hepatobiliary Disorders SOC: Hyperbilirubinemia was the only reported AE and was not significantly higher in patients receiving Trastuzumab (Herceptin) IV than those in the F+P arm (1% and < 1% respectively).
Diarrhea: Breast Cancer:Of patients treated with Trastuzumab (Herceptin) IV monotherapy in the metastatic setting 27% experienced diarrhea. An increase in the incidence of diarrhea, primarily mild to moderate in severity, has also been observed in patients receiving Trastuzumab (Herceptin) in combination with paclitaxel compared with patients receiving paclitaxel alone.
In the BO16348 study, 8% of Trastuzumab (Herceptin)-treated patients experienced diarrhea during the first year of treatment.
Advanced Gastric Cancer:In the BO18255 study, 109 patients (37%) participating in the Trastuzumab (Herceptin)-containing treatment arm versus 80 patients (28%) in the comparator arm experienced any grade diarrhea. Using NCI-CTCAE v3.0 severity criteria, the percentage of patients experiencing grade ≥ 3 diarrhea was 4% in the FP arm versus 9% in the FP+H arm.
Infection:An increased incidence of infections, primarily mild upper respiratory infections of minor clinical significance or catheter infections has been observed in patients treated with Trastuzumab (Herceptin).
Switching treatment from Trastuzumab (Herceptin) IV to Trastuzumab (Herceptin) SC and vice versa: Study MO22982 investigated switching from Trastuzumab (Herceptin) IV to Trastuzumab (Herceptin) SC, and vice versa, in patients with HER2 positive EBC, with a primary objective to evaluate patient preference for either Trastuzumab (Herceptin) IV infusion or Trastuzumab (Herceptin) SC injection. In this trial, 2 cohorts (one using Trastuzumab (Herceptin) SC Vial and one using Trastuzumab (Herceptin) SC SID) were investigated using a 2-arm, cross-over design with patients being randomized to one of two different q3w Trastuzumab (Herceptin) treatment sequences (Trastuzumab (Herceptin) IV (Cycles 1-4) → Trastuzumab (Herceptin) SC (Cycles 5-8), or Trastuzumab (Herceptin) SC (Cycles 1-4) → Trastuzumab (Herceptin) IV (Cycles 5-8)). Patients were either naïve to Trastuzumab (Herceptin) IV treatment (20.3%) or pre-exposed to Trastuzumab (Herceptin) IV (79.7%) as part of ongoing adjuvant treatment for HER2 positive EBC. Overall, switches from Trastuzumab (Herceptin) IV to Trastuzumab (Herceptin) SC and vice versa were well tolerated. Pre-switch rates (Cycles 1-4) for SAEs, Grade 3 AEs and treatment discontinuations due to AEs were low (<5%) and similar to post-switch rates (Cycles 5-8). No Grade 4 or Grade 5 AEs were reported.
Trastuzumab (Herceptin) SC safety and tolerability in EBC patients: Study MO28048 investigating the safety and tolerability of Trastuzumab (Herceptin) SC as adjuvant therapy enrolled HER2 positive EBC patients in either a Trastuzumab (Herceptin) SC Vial cohort (N=1868 patients, including 20 patients receiving neoadjuvant therapy) or a Trastuzumab (Herceptin) SC SID cohort (N=710 patients, including 21 patients receiving neoadjuvant therapy). The primary analysis included patients with a median follow-up of up to 23.7 months. No new safety signals were observed and results were consistent with the known safety profile for Trastuzumab (Herceptin) IV and Trastuzumab (Herceptin) SC. In addition, treatment of lower body weight patients with Trastuzumab (Herceptin) SC fixed dose in adjuvant EBC was not associated with increased safety risk, AEs and SAEs, compared to the higher body weight patients. The final results of study BO22227 at a median follow-up exceeding 70 months (see Pharmacology: Pharmacodynamics: Clinical/Efficacy studies under Actions) were also consistent with the known safety profile for Trastuzumab (Herceptin) IV and Trastuzumab (Herceptin) SC, and no new safety signals were observed.
Postmarketing Experience: The following adverse drug reactions have been identified from postmarketing experience with Trastuzumab (Herceptin)(see Table 16).

 

Adverse Events: Table 17 as follows indicates adverse events that historically have been reported in patients who have received Trastuzumab (Herceptin). As no evidence of a causal association has been found between Trastuzumab (Herceptin) and these events, these events are not considered expected for the purposes of regulatory reporting. (See Table 17.)

Targeted Cancer Therapy