Hertraz Special Precautions

HER2 testing must be performed in a specialised laboratory having trained and qualified personnel which can ensure adequate validation of the testing procedures.
The narrated data as follows is from published literature.
Cardiac Dysfunction: General considerations: As per the published literature, patients treated with trastuzumab are at increased risk for developing CHF (New York Heart Association [NYHA] class II-IV) or asymptomatic cardiac dysfunction. These events have been observed in patients receiving trastuzumab therapy alone or in combination with paclitaxel or docetaxel, particularly following anthracycline (doxorubicin or epirubicin)-containing chemotherapy. These may be moderate to severe and have 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, LVEF of <55%, older age.
All candidates for treatment with trastuzumab, but especially those with prior anthracycline and cyclophosphamide (AC) exposure, should undergo baseline cardiac assessment including history and physical examination, electrocardiogram (ECG), echocardiogram, and/or multigated acquisition (MUGA) scan or magnetic resonance imaging. Monitoring may help to identify patients who develop cardiac dysfunction. 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. A careful risk-benefit assessment should be made before deciding to treat with trastuzumab.
Because the half-life of trastuzumab is approximately 28-38 days, trastuzumab may persist in the circulation for up to 27 weeks after stopping the treatment. Patients who receive anthracyclines after stopping trastuzumab may possibly be at increased risk of cardiac dysfunction. If possible, physicians should avoid anthracycline-based therapy for up to 27 weeks after stopping trastuzumab. In case anthracyclines are used, the patient's cardiac function should be monitored carefully.
Formal cardiological assessment should be considered in patients in whom there are cardiovascular concerns following baseline screening. In all patients cardiac function should be monitored during treatment (e.g. every 12 weeks). Monitoring may help to identify patients who develop cardiac dysfunction. 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 if no clinical benefit of trastuzumab therapy has been seen. The safety of continuation or resumption of trastuzumab in patients who experience cardiac dysfunction has not been prospectively studied. If LVEF drops ≥10 ejection fraction (EF) points from baseline AND to below 50%, treatment should be suspended and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has not improved, or declined further, or symptomatic CHF has developed, discontinuation of trastuzumab should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks. All such patients should be referred for assessment by a cardiologist and followed up.
During trastuzumab therapy if symptomatic cardiac failure develops, it should be treated with standard medicinal products for CHF. Most patients who developed CHF or asymptomatic cardiac dysfunction in pivotal trials improved with standard CHF treatment consisting of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and a beta-blocker. The majority of patients with cardiac symptoms and evidence of a clinical benefit of trastuzumab treatment continued on therapy without additional clinical cardiac events.
Metastatic Breast Cancer: Trastuzumab and anthracyclines should not be given concurrently in combination in the MBC setting. Patients with MBC who have previously received anthracyclines are also at risk of cardiac dysfunction with trastuzumab treatment, although the risk is lower than with concurrent use of trastuzumab and anthracyclines.
Early Breast Cancer: 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. 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, or longer if a continuous decrease of LVEF is observed.
Patients with history of myocardial infarction (MI), angina pectoris requiring medical treatment, history of or existing CHF (NYHA II-IV), LVEF of < 55%, other cardiomyopathy, cardiac arrhythmia requiring medical treatment, clinically significant cardiac valvular disease, poorly controlled hypertension (hypertension controlled by standard medical treatment eligible), and hemodynamic effective pericardial effusion were excluded from adjuvant and neoadjuvant EBC pivotal trials with trastuzumab and therefore treatment cannot be recommended in such patients.
Adjuvant Treatment: Trastuzumab and anthracyclines should not be given concurrently in combination in the adjuvant treatment setting.
As per the published literature on another trastuzumab product, an increase in the incidence of symptomatic and asymptomatic cardiac events was observed in patients with EBC when trastuzumab was administered after anthracycline-containing chemotherapy compared to administration with a non-anthracycline regimen of docetaxel and carboplatin and was more marked when trastuzumab 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. In one of the 3 pivotal studies conducted in which a median follow-up of 5.5 years was available a continuous increase in the cumulative rate of symptomatic cardiac or LVEF events was observed in patients who were administered trastuzumab concurrently with a taxane following anthracycline therapy up to 2.37% compared to approximately 1% in the two comparator arms (anthracycline plus cyclophosphamide followed by taxane and taxane, carboplatin and trastuzumab).
As per the published literature on another trastuzumab product, risk factors for a cardiac event identified in four large adjuvant studies included advanced age (> 50 years), low LVEF (<55%) at baseline, prior to or following the initiation of paclitaxel treatment, decline in LVEF by 10-15 points, and prior or concurrent use of anti-hypertensive medicinal products. In patients receiving trastuzumab 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 and a body mass index (BMI) >25 kg/m².
Neoadjuvant-Adjuvant Treatment: In patients with EBC eligible for neoadjuvant-adjuvant treatment, trastuzumab should be used concurrently with anthracyclines only in chemotherapy-naive patients and only with low-dose anthracycline regimens i.e. maximum cumulative doses: of doxorubicin 180 mg/m² or epirubicin 360 mg/m².
No additional cytotoxic chemotherapy should be given after surgery if patients have been treated concurrently with a full course of low-dose anthracyclines and trastuzumab in the neoadjuvant setting. In other situations, the decision on the need for additional cytotoxic chemotherapy is determined based on individual factors.
As per the published literature on another trastuzumab product, experience of concurrent administration of trastuzumab with low dose anthracycline regimens is currently limited to two trials. Trastuzumab was administered concurrently with neoadjuvant chemotherapy that contained three to four cycles of an anthracycline (cumulative doxorubicin dose 180 mg/m² or epirubicin dose 300 mg/m²). The incidence of symptomatic cardiac dysfunction was low in the Trastuzumab arms (up to 1.7 %).
In patients above 65 years of age clinical experience is limited.
Infusion Reactions, Allergic-Like Reactions and Hypersensitivity: As per the published literature, serious adverse reactions to trastuzumab infusion that have been reported infrequently include dyspnoea, hypotension, wheezing, hypertension, bronchospasm, supraventricular tachyarrhythmia, reduced oxygen saturation, anaphylaxis, respiratory distress, urticaria and angioedema (see Adverse Reactions). Premedication may be used to reduce risk of occurrence of these events. The majority of these events occur during or within 2.5 hours of the start of the first infusion. Should an infusion reaction occur the infusion should be discontinued or the rate of infusion slowed and the patient should be monitored until resolution of all observed symptoms. These symptoms can be treated with an analgesic/antipyretic such as meperidine or paracetamol, or an antihistamine such as diphenhydramine. The majority of patients experienced resolution of symptoms and subsequently received further infusions of trastuzumab.
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 fatal outcome. Patients experiencing dyspnoea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of a fatal infusion reaction. Therefore, these patients should not be treated with trastuzumab, (see Contraindications).
Initial improvement followed by clinical deterioration and delayed reactions with rapid clinical deterioration have also been reported. Fatalities have occurred within hours and up to one week following infusion. On very rare occasions, patients have experienced the onset of infusion symptoms and pulmonary symptoms more than six hours after the start of the trastuzumab infusion. Patients should be warned of the possibility of such a late onset and should be instructed to contact their physician if these symptoms occur.
Pulmonary Events: As per the published literature on another trastuzumab product, with the use of trastuzumab in the post-marketing setting severe pulmonary events have been reported (see Adverse Reactions). These events have occasionally been fatal. In addition, cases of interstitial lung disease including lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary oedema 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. These events may occur as part of an infusion-related reaction or with a delayed onset. Patients experiencing dyspnoea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of pulmonary events. Therefore, these patients should not be treated with trastuzumab (see Contraindications). Caution should be exercised for pneumonitis, especially in patients being treated concomitantly with taxanes.
Effects on Ability to Drive and Use Machines: As per the published literature, trastuzumab has no or negligible influence on the ability to drive or use machines. However, patients experiencing infusion-related symptoms (see Precautions) should be advised not to drive and use machines until symptoms abate.
Women of Childbearing Potential: Women of childbearing potential should be advised to use effective contraception during treatment with trastuzumab and for at least 7 months after treatment has concluded.
Use in Pregnancy: As per the published literature on another trastuzumab product, reproduction studies have been conducted in cynomolgus monkeys at doses up to 25 times that of the weekly human maintenance dose of 2 mg/kg trastuzumab intravenous formulation and have revealed no evidence of impaired fertility or harm to the foetus. Placental transfer of trastuzumab during the early (days 20-50 of gestation) and late (days 120-150 of gestation) foetal development period was observed. It is not known whether trastuzumab can affect reproductive capacity. As animal reproduction studies are not always predictive of human response, trastuzumab should be avoided during pregnancy unless the potential benefit for the mother outweighs the potential risk to the foetus. As per the published literature on another trastuzumab product, in the post-marketing setting, cases of foetal renal growth and/or function impairment in association with oligohydramnios, some associated with fatal pulmonary hypoplasia of the foetus, have been reported in pregnant women receiving trastuzumab. Women who become pregnant should be advised of the possibility of harm to the foetus. If a pregnant woman is treated with trastuzumab, close monitoring by a multidisciplinary team is desirable.
Use in Lactation: As per the published literature on another trastuzumab product, a study conducted in lactating cynomolgus monkeys at doses 25 times that of the weekly human maintenance dose of 2 mg/kg Trastuzumab intravenous formulation demonstrated that trastuzumab is secreted in the milk. The presence of trastuzumab in the serum of infant monkeys was not associated with any adverse effects on their growth or development from birth to 1 month of age. It is not known whether trastuzumab is secreted in human milk. As human IgG1 is secreted into human milk, and the potential for harm to the infant is unknown, women should not breast-feed during trastuzumab therapy and for 7 months after the last dose.
Fertility: There is no fertility data available in public literature.