Herity

/ Unipharm

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 trastuzumab was 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
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.

Metastatic Breast Cancer (MBC)
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 patients with hormone-receptor positive metastatic breast cancer.
Early Breast Cancer (EBC)
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 the active substance, 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.
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. 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 treatment based on population pharmacokinetic analysis of all available data. 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 to a patient with a known sensitivity to benzyl alcohol, it 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, 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.
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.

Very common: infection, nasopharyngitis, febrile neutropenia, anaemia , neutropenia, white blood cell count decreased/leukopenia, thrombocytopenia, weight decreased/weight loss, anorexia, nsomnia, 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.

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.
Please see prescribing information for full details.

Women of childbearing potential
Women of childbearing potential should be advised to use effective contraception during treatment 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 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.

There is no experience with overdose in human clinical trials.
See prescribing information for full details.

HER2 testing is mandatory prior to initiation of therapy. Treatment should only be initiated by a physician experienced in the administration of cytotoxic chemotherapy, and should be administered by a healthcare professional only.
the intravenous formulation is not intended for subcutaneous administration and should be administered via an intravenous infusion only.
If an alternate route of administration is required, other trastuzumab products offering such an option should be used.
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 and not trastuzumab emtansine.
Dizziness and somnolence may occur during treatment. Patients experiencing infusion-related symptoms should be advised not to drive and use machines until symptoms abate.