Trazimera

/ Pfizer

HER2 testing is mandatory prior to initiation of therapy. Treatment should only be initiated by a physician experienced in the administration of cytotoxic chemotherapy (see section 4.4) and should be administered by a healthcare professional only.
Metastatic breast cancer
Weekly schedule
The recommended initial loading dose of trastuzumab is 4 mg/kg body weight. The recommended weekly maintenance dose of trastuzumab is 2 mg/kg body weight, beginning one week after the loading dose.
Administration in combination with paclitaxel or docetaxel
In the pivotal trials (H0648g, M77001), paclitaxel or docetaxel was administered the day following the first dose of trastuzumab (for dose, see the prescribing information of paclitaxel or docetaxel) and immediately after the subsequent doses of trastuzumab if the preceding dose of trastuzumabwas well tolerated.
Administration in combination with an aromatase inhibitor
In the pivotal trial (BO16216) trastuzumab and anastrozole were administered from day 1. There were no restrictions on the relative timing of trastuzumab and anastrozole at administration (for dose, see the prescribing information of anastrozole or other aromatase inhibitors).
Early breast cancer
Three-weekly and weekly schedule
As a three-weekly regimen the recommended initial loading dose of trastuzumab is 8 mg/kg body weight. The recommended maintenance dose of trastuzumab at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose.
As a weekly regimen (initial loading dose of 4 mg/kg followed by 2 mg/kg every week) concomitantly with paclitaxel following chemotherapy with doxorubicin and cyclophosphamide.
Metastatic gastric cancer
Three-weekly schedule
The recommended initial loading dose is 8 mg/kg body weight. The recommended maintenance dose at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose.
Breast cancer and gastric cancer
Duration of treatment
Patients with MBC or MGC should be treated with trastuzumab until progression of disease. Patients with EBC should be treated with trastuzumab for 1 year or until disease recurrence, whichever occurs first, extending treatment in EBC beyond one year is not recommended (see section 5.1).
Dose reduction
No reductions in the dose of trastuzumab were made during clinical trials. Patients may continue therapy during periods of reversible, chemotherapy-induced myelosuppression but they should be monitored carefully for complications of neutropenia during this time. Refer to the prescribing information of paclitaxel, docetaxel or aromatase inhibitor for information on dose reduction or delays.
If left ventricular ejection fraction (LVEF) percentage drops ≥ 10 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 has declined further, or if symptomatic congestive heart failure (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.
Missed doses
If the patient has missed a dose of trastuzumab 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 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 by more than one week, a re-loading dose of trastuzumab should be administered over approximately 90 minutes (weekly regimen: 4 mg/kg; three-weekly regimen: 8 mg/kg) as soon as possible. Subsequent trastuzumab 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.
Special populations
Dedicated pharmacokinetic studies in the elderly and those with renal or hepatic impairment have not been carried out. In a population pharmacokinetic analysis, age and renal impairment were not shown to affect trastuzumab disposition.
Paediatric population
There is no relevant use of trastuzumab in the paediatric population.
Method of administration
trastuzumab loading dose should be administered as a 90-minute intravenous infusion. Do not administer as an intravenous push or bolus. trastuzumab intravenous infusion should be administered by a health- care provider prepared to manage anaphylaxis and an emergency kit should be available. Patients should be observed for at least six hours after the start of the first infusion and for two hours after the start of the subsequent infusions for symptoms like fever and chills or other infusion-related symptoms (see sections 4.4 and 4.8).
Interruption or slowing the rate of the infusion may help control such symptoms. The infusion may be resumed when symptoms abate.
If the initial loading dose was well tolerated, the subsequent doses can be administered as a 30-minute infusion.
See prescribing information for full details.

Metastatic Breast Cancer (MBC)
Indicated for the treatment of patients with metastatic breast cancer who have tumours that overexpress HER2;
1. As a single agent, for the treatment of those patients who have received one or more chemotherapy regimens for their metastatic disease.
2. In combination with Paclitaxel or Docetaxel for the treatment of those patients who have not received chemotherapy for their metastatic disease.
3. In combination with an aromatase inhibitor for the treatment of postmenopausal patient with hormone-receptor positive metastatic breast cancer.
Early Breast Cancer (EBC)
Indicated to treat patients with HER2 positive early breast cancer following surgery and chemotherapy (neoadjuvant or adjuvant) either alone or in combination with chemotherapy excluding anthracyclines.
The drug should only be used in patients whose tumours have either HER2 overexpression or HER2 gene amplification as determined by an accurate and validated assay.
HER2 Metastatic Gastric Cancer (MGC)
In combination with capecitabine or 5-fluorouracil and cisplatin is indicated for the treatment of patients with HER2 positive metastatic adenocarcinoma of the stomach or gastro-esophageal junction who have not received prior anti-cancer treatment for their metastatic disease.
The drug should only be used in patients with metastatic gastric cancer whose tumours have HER2 overexpression as defined by IHC2+ and a confirmatory FISH+ result, or IHC 3+, as determined by an accurate and validated assay.

-Hypersensitivity to trastuzumab, murine proteins, or to any of the excipients
-Severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy.  

Traceability
In order to improve the traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded.
HER2 testing must be performed in a specialised laboratory which can ensure adequate validation of the testing procedures (see section 5.1).
Currently no data from clinical trials are available on re-treatment of patients with previous exposure to trastuzumab in the adjuvant setting.
Cardiac dysfunction
General considerations
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 section 4.8). 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.
Trastuzumab may persist in the circulation for up to 7 months after stopping trastuzumab treatment based on population pharmacokinetic analysis of all available data (see section 5.2). 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 7 months after stopping trastuzumab. If 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 percentage drops ≥10 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.
If symptomatic cardiac failure develops during trastuzumab therapy, 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 Class 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.
In patients with EBC 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 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 (BCIRG006) 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 ).
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.
Benzyl alcohol as a preservative in Bacteriostatic Water for Injection has been associated with toxicity in neonates and children up to 3 years old. When administering the drug to a patient with a known sensitivity to benzyl alcohol, the drug should be reconstituted with Water for Injection, and only one dose per vial should be used. Any unused portion must be discarded.
Neoadjuvant-adjuvant treatment
In patients with EBC eligible for neoadjuvant-adjuvant treatment, 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.
If patients have been treated concurrently with a full course of low-dose anthracyclines and trastuzumab in the neoadjuvant setting, no additional cytotoxic chemotherapy should be given after surgery. In other situations, the decision on the need for additional cytotoxic chemotherapy is determined based on individual factors.
Experience of concurrent administration of trastuzumab with low dose anthracycline regimens is currently limited to the trial (MO16432).
In the pivotal trial MO16432, trastuzumab 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 arm.
Clinical experience is limited in patients above 65 years of age. Infusion-related reactions (IRRs) and hypersensitivity
Serious IRRs to trastuzumab infusion including dyspnoea, hypotension, wheezing, hypertension, bronchospasm, supraventricular tachyarrhythmia, reduced oxygen saturation, anaphylaxis, respiratory distress, urticaria and angioedema have been reported (see section 4.8). Pre-medication 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 (see section 4.2). 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.
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
Severe pulmonary events have been reported with the use of trastuzumab in the post-marketing setting. 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. Caution should be exercised for pneumonitis, especially in patients being treated concomitantly with taxanes.
See prescribing information for full details.

Very common: Infection, nasopharyngitis, febrile neutropenia, anaemia, neutropenia, white blood cell count decreased/leukopenia, thrombocytopenia, weight decreased/weight loss, anorexia, insomnia, tremor, dizziness, headache, paraesthesia, dysgeusia, conjunctivitis, lacrimation increased, blood pressure decreased, blood pressure increased, heart beat irregular, cardiac flutter, ejection fraction decreased, hot flush, dyspnoea, cough, epistaxis, rhinorrhoea, diarrhoea, vomiting, nausea, lip swelling, abdominal pain, dyspepsia, constipation, stomatitis, erythema, rash, swelling face, alopecia, nail disorder, palmar-plantar erythrodysaesthesia syndrome, arthralgia, muscle tightness, myalgia, asthenia, chest pain, chills, fatigue, influenza-like symptoms, infusion related reaction, pain, pyrexia, mucosal inflammation, peripheral oedema
Common: Neutropenic sepsis, cystitis, influenza, sinusitis, skin infection, rhinitis, upper respiratory tract infection, urinary tract infection, pharyngitis, hypersensitivity, anxiety, depression, peripheral neuropathy, hypertonia, somnolence, dry eye, cardiac failure (congestive), supraventricular tachyarrhythmia, cardiomyopathy, palpitation, hypotension, vasodilatation, pneumonia, asthma, lung disorder, pleural effusion, haemorrhoids, dry mouth, hepatocellular injury, hepatitis, liver tenderness, acne, dry skin, ecchymosis, hyperhydrosis, maculopapular rash, pruritus, onychoclasis, dermatitis, arthritis, back pain, bone pain, muscle spasms, neck pain, pain in extremity, renal disorder, breast inflammation/mastitis, malaise, oedema, contusion
See prescribing information for full details.

No formal drug interaction studies have been performed. Clinically significant interactions between trastuzumab and the concomitant medicinal products used in clinical trials have not been observed.
Effect of trastuzumab on the pharmacokinetics of other antineoplastic agents
Pharmacokinetic data from studies BO15935 and M77004 in women with HER2-positive MBC suggested that exposure to paclitaxel and doxorubicin (and their major metabolites 6-α hydroxyl- paclitaxel, POH, and doxorubicinol, DOL) was not altered in the presence of trastuzumab (8 mg/kg or 4 mg/kg IV loading dose followed by 6 mg/kg q3w or 2 mg/kg q1w IV, respectively).
However, trastuzumab may elevate the overall exposure of one doxorubicin metabolite, (7-deoxy-13 dihydro-doxorubicinone, D7D). The bioactivity of D7D and the clinical impact of the elevation of this metabolite was unclear.
Data from study JP16003, a single-arm study of trastuzumab (4 mg/kg IV loading dose and 2 mg/kg IV weekly) and docetaxel (60 mg/m2 IV) in Japanese women with HER2- positive MBC, suggested that concomitant administration of trastuzumab had no effect on the single dose pharmacokinetics of docetaxel. Study JP19959 was a substudy of BO18255 (ToGA) performed in male and female Japanese patients with advanced gastric cancer to study the pharmacokinetics of capecitabine and cisplatin when used with or without trastuzumab . The results of this substudy suggested that the exposure to the bioactive metabolites (e.g. 5-FU) of capecitabine was not affected by concurrent use of cisplatin or by concurrent use of cisplatin plus trastuzumab . However, capecitabine itself showed higher concentrations and a longer half-life when combined with trastuzumab. The data also suggested that the pharmacokinetics of cisplatin were not affected by concurrent use of capecitabine or by concurrent use of capecitabine plus trastuzumab .
Pharmacokinetic data from Study H4613g/GO01305 in patients with metastatic or locally advanced inoperable HER2-positive cancer suggested that trastuzumab had no impact on the PK of carboplatin.
Effect of antineoplastic agents on trastuzumab pharmacokinetics
By comparison of simulated serum trastuzumab concentrations after trastuzumab monotherapy (4 mg/kg loading/2 mg/kg q1w IV) and observed serum concentrations in Japanese women with HER2- positive MBC (study JP16003) no evidence of a PK effect of concurrent administration of docetaxel on the pharmacokinetics of trastuzumab was found.
Comparison of PK results from two Phase II studies (BO15935 and M77004) and one Phase III study (H0648g) in which patients were treated concomitantly with trastuzumab and paclitaxel and two Phase II studies in which trastuzumab was administered as monotherapy (W016229 and MO16982), in women with HER2-positive MBC indicates that individual and mean trastuzumab trough serum concentrations varied within and across studies but there was no clear effect of the concomitant administration of paclitaxel on the pharmacokinetics of trastuzumab. Comparison of trastuzumab PK data from Study M77004 in which women with HER2-positive MBC were treated concomitantly with trastuzumab, paclitaxel and doxorubicin to trastuzumab PK data in studies where trastuzumab was administered as monotherapy (H0649g) or in combination with anthracycline plus cyclophosphamide or paclitaxel (Study H0648g), suggested no effect of doxorubicin and paclitaxel on the pharmacokinetics of trastuzumab.
Pharmacokinetic data from Study H4613g/GO01305 suggested that carboplatin had no impact on the PK of trastuzumab.
The administration of concomitant anastrozole did not appear to influence the pharmacokinetics of trastuzumab.

Women of childbearing potential
Women of childbearing potential should be advised to use effective contraception during treatment with trastuzumab and for 7 months after treatment has concluded.
Pregnancy
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.
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, or if a patient becomes pregnant while receiving trastuzumab or within 7 months following the last dose of trastuzumab, close monitoring by a multidisciplinary team is desirable.
Breast-feeding
A study conducted in Cynomolgus monkeys at doses 25 times that of the weekly human maintenance dose of 2 mg/kg trastuzumab intravenous formulation from days 120 to 150 of pregnancy demonstrated that trastuzumab is secreted in the milk postpartum. The exposure to trastuzumab in utero and 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.  

There is no experience with overdose in human clinical trials. Single doses of trastuzumab alone greater than 10 mg/kg have not been administered in the clinical trials; a maintenance dose of 10 mg/kg q3w following a loading dose of 8 mg/kg has been studied in a clinical trial with metastatic gastric cancer patients. Doses up to this level were well tolerated.

Patients experiencing infusion-related symptoms should be advised not to drive and use machines until symptoms abate.