Zuhera Special Precautions

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.
Initiate Zuhera therapy under the supervision of a physician experienced in cancer treatment.
Clinical Trials and Post-Marketing Data of for Herceptin: Infusion/Administration-related reactions (IRRs/ARRs): IRRs/ARRs are known to occur with the administration of Trastuzumab (see Adverse Reactions).
IRRs/ARRs may be clinically difficult to distinguish from hypersensitivity reactions.
Pre-medication may be used to reduce the risk of occurrence of IRRs.
Serious IRRs/ARRs to Trastuzumab including dyspnoea, 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 paracetamol and an antihistamine. 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 who are experiencing dyspnea at rest due to complications of advanced malignancy or co-morbidities may be at increased risk of a fatal infusion reaction. Therefore, these patients should be treated with extreme caution and the risk versus benefit should be considered for each patient.
Pulmonary Reactions: Severe pulmonary events leading to death have been reported with the use of Trastuzumab in the post-marketing setting. These events have occasionally resulted in fatal 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 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. Patients with dyspnoea 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.
Cardiac Dysfunction: General Considerations: Patients treated with Trastuzumab 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 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 treatment (see Pharmacology: Pharmacokinetics under Actions). Patients who receive anthracycline after stopping Trastuzumab 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. If anthracyclines are used, the patient's cardiac function should be monitored carefully.
Candidates for treatment with Trastuzumab, especially those with prior exposure to anthracycline, should undergo baseline cardiac assessment including history and physical examination, electrocardiogram (ECG), echocardiogram, and/or multigated acquisition (MUGA) scanning. 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 treatments until 24 months from the last administration of Trastuzumab.
If Left Ventricular Ejection Fraction (LVEF) percentage drops 10 points from baseline and to below 50%, Trastuzumab should be withheld and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has not improved, or has declined further, or clinically significant CHF has developed, discontinuation of Trastuzumab 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 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 symptomatic cardiac failure develops during Trastuzumab therapy, it should be treated with the standard medications for heart failure. In the pivotal trials, most patients who developed heart failure or asymptomatic cardiac dysfunction improved with standard heart failure treatment consisting of 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 treatment continued with Trastuzumab without additional clinical cardiac events.
Metastatic Breast Cancer: Trastuzumab and anthracycline should not be given concurrently in the metastatic breast cancer setting.
Early Breast Cancer: For patients with early breast cancer, 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 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 haemodynamic effective pericardial effusion were excluded from adjuvant breast cancer clinical trials with Trastuzumab.
Adjuvant Treatment: Trastuzumab and anthracyclines should not be given concurrently in the adjuvant treatment setting.
In patients with early breast cancer, an increase in the incidence of symptomatic and asymptomatic cardiac events was observed when Trastuzumab 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 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 treatment, and prior or concurrent use of anti-hypertensive medications. 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 high body mass index (BMI) (>25 kg/m²).
Neoadjuvant-adjuvant treatment: In patients with early breast cancer eligible for neoadjuvant-adjuvant treatment, Trastuzumab should only be used concurrently with anthracyclines in chemotherapy-naive patients and only with low-dose anthracycline regimens, i.e. with maximum cumulative doses of doxorubicin 180 mg/m² or epirubicin 360 mg/m².
If patients have been treated concurrently with low-dose anthracyclines and Trastuzumab 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 is used as a preservative in bacteriostatic water for injection in the 440 mg ZUHERA multidose vials, has been associated with toxicity in neonates and children up to 3 years old. When administering Trastuzumab to a patient with a known hypersensitivity to benzyl alcohol, Trastuzumab should be reconstituted with water for injection, and only one dose per Trastuzumab vial should be used. Any unused portion must be discarded. Sterile water for injection, used to reconstitute the 150 mg single dose vials, does not contain benzyl alcohol.
Ability to drive and use machines: No studies on the effects on the ability to drive and to use machines have been performed. Patients experiencing infusion-related symptoms should be advised not to drive or use machines until symptoms resolve completely.
Use in Special Populations: From available data, disposition of Trastuzumab is not altered with increasing age, renal impairment or serum creatinine levels. Elderly patients in reported clinical trials did not receive reduced doses.
Use in Children: The safety and efficacy of Trastuzumab has not been established in paediatric patients (below 18 years of age). Zuhera should not be used in these patients.