Consumer medicine information

Trazimera

Trastuzumab

BRAND INFORMATION

Brand name

Trazimera

Active ingredient

Trastuzumab

Schedule

What is in this leaflet

This leaflet answers some common questions about TRAZIMERA. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking TRAZIMERA against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What TRAZIMERA is used for

TRAZIMERA contains an active ingredient called trastuzumab.

TRAZIMERA belongs to a group of medicines known as anti-neoplastic (or anti-cancer) agents. There are many different classes of antineoplastic agents. TRAZIMERA belongs to a class called monoclonal antibodies.

Monoclonal antibodies are proteins made in a laboratory. These proteins are designed to recognise and bind to other unique proteins in the body.

TRAZIMERA binds selectively to a protein called human epidermal growth factor receptor 2 (HER2).

HER2 is found in large amounts on the surface of some cancer cells.

When TRAZIMERA binds to HER2 it stops the growth and spread of the cancer cells.

TRAZIMERA is used to treat breast and gastric cancer. It is only used in patients whose tumour has tested positive to HER2.

TRAZIMERA may be used alone or with other medicines that treat breast cancer, such as an aromatase inhibitor (hormone receptor positive breast cancer) or a taxane (e.g. paclitaxel or docetaxel).

For the treatment of gastric cancer TRAZIMERA is used with chemotherapy medicines cisplatin and capecitabine (or 5FU).

For further information about the other medicines you are receiving with TRAZIMERA, please ask your doctor, nurse or pharmacist for the Consumer Medicine Information (CMI) leaflet.

Ask your doctor if you have any questions about why TRAZIMERA has been prescribed for you.

This medicine is available only with a doctor's prescription.

Before you are given TRAZIMERA

When you must not be given it

Do not use TRAZIMERA if:

you have had an allergic reaction to;
- any medicine containing trastuzumab
- any of the ingredients listed at the end of this leaflet.
- any protein of Chinese hamster origin
Some of the symptoms of an allergic reaction may include: shortness of breath; wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.
you have breast cancer that has not spread (non-metastatic) and
- you have had an LVEF test result (which measures how well your heart can pump blood) of less than 45% or
- you have symptoms of heart failure

Symptoms of heart failure may include:

shortness of breath or tire easily after light physical activity (such as walking)
shortness of breath at night, especially when lying flat
swelling of the hands or feet due to fluid build up
abnormal or irregular heartbeat

If you are not sure whether you should start receiving this medicine, talk to your doctor.

Before you are given it

Tell your doctor if:

you have a history of heart disease with:
- angina (chest pain)
- cardiac arrhythmias (abnormal beating of the heart)
- heart failure (where the heart cannot pump blood normally)
- coronary artery disease (also known as CAD, a condition where plaque builds up inside the arteries)
- poorly controlled high blood pressure
you have previously been treated with chemotherapy medicines known as anthracyclines (e.g. doxorubicin); these medicines can damage heart muscle and increase the risk of heart problems with TRAZIMERA
Your doctor will monitor your heart function closely before and during your treatment with TRAZIMERA. Your heart function may also be monitored for years after ceasing TRAZIMERA treatment.
if you have any breathing or lung problems
you are allergic to any other medicines or any other substances such as foods, preservatives or dyes
Allergic or anaphylactic reactions can occur with TRAZIMERA treatment (known as infusion or administration related reactions). Your doctor or nurse will monitor you for side effects during treatment. See "side effects" for symptoms to look out for.
you are pregnant or intend to become pregnant
TRAZIMERA may be harmful to an unborn baby. If there is a need for TRAZIMERA treatment when you are pregnant your doctor will discuss the risks and benefits to you and the unborn baby.
You should use effective contraception to avoid becoming pregnant while you are being treated with TRAZIMERA and for 7 months after stopping treatment.
you are breast-feeding or plan to breast-feed
It is not known if TRAZIMERA passes into breast milk. It is recommended that you discontinue breast-feeding while you are being treated with TRAZIMERA and not restart breast-feeding until 7 months after completing TRAZIMERA treatment.

If you have not told your doctor about any of the above, tell him/her before you start taking TRAZIMERA.

Use in children

The safety and effectiveness of TRAZIMERA in children under 18 years of age have not been established.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

TRAZIMERA treatment with gemcitabine, vinorelbine, a taxane or radiation therapy can increase the chance of lung problems (interstitial lung disease).

Your doctor and pharmacist have more information on medicines to be careful with or avoid while receiving TRAZIMERA.

Tell your doctor or pharmacist that you have had TRAZIMERA if you start any new medication in the seven months after stopping treatment. It may take up to seven months for TRAZIMERA to be removed from your body

How TRAZIMERA is given

Follow all directions given to you by your doctor or nurse carefully. They may differ from the information contained in this leaflet.

TRAZIMERA must be prepared by a healthcare professional and will be given in a hospital or clinic by a doctor or nurse.

TRAZIMERA is given by "drip" into a vein (intravenous (IV) infusion).

The first TRAZIMERA infusion is given over 90 minutes. If the first infusion is well tolerated, your drip time may be shortened to 30 minutes.

For the treatment of breast cancer, TRAZIMERA is given either once a week or once every three weeks. It may be given alone or in combination with other medicines used to treat breast cancer.

For the treatment of gastric cancer TRAZIMERA is given every three weeks in combination with other medicines used to treat gastric cancer.

Your doctor will decide how long you should receive TRAZIMERA, this will depend on your response to the medicine and the state of your disease.

If you miss a dose

As TRAZIMERA is given under the supervision of your doctor, you are unlikely to miss a dose. However, if you forget or miss your appointment to receive TRAZIMERA, make another appointment as soon as possible.

Your doctor will decide when and how much your next dose of TRAZIMERA will be.

If you are given too much (overdose)

As TRAZIMERA is given to you under the supervision of your doctor it is unlikely that you will be given too much. However, if you experience any side effects after being given TRAZIMERA, tell your doctor immediately.

While you are receiving TRAZIMERA

Things you must do

Tell your doctor or nurse immediately if you have any signs and symptoms of an allergic or anaphylactic reaction

Some signs and symptoms include;

swelling of your face, lips, tongue or throat with difficulty breathing,
swelling of other parts of your body
shortness of breath, wheezing or trouble breathing
rash, itching or hives on the skin
feeling sick (nausea)
fever, chills
feeling tired
headache

Tell your doctor or nurse immediately if you have any signs and symptoms of heart problems.

Some signs and symptoms of heart problems are

shortness of breath or getting tired easily after light physical activity (such as walking)
shortness of breath at night, especially when lying flat
swelling of the hands or feet due to fluid build up
cough
abnormal or irregular heartbeat

Please follow all your doctors' instructions if any of these symptoms require medication.

Tell any other doctors, dentists, and pharmacists who treat you that you are receiving TRAZIMERA.

Tell your doctor if you become pregnant or intend to start a family while receiving TRAZIMERA.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may perform regular tests.

Things you must not do

Do not stop your TRAZIMERA treatment without checking with your doctor.

Tell your doctor if you feel that TRAZIMERA is not helping your condition.

Do not take any other medicines, whether they require a prescription or not, without first telling your doctor or consulting with a pharmacist.

Things to be careful of

Be careful driving or operating machinery until you know how TRAZIMERA affects you. If you have experienced symptoms during your treatment with TRAZIMERA you should not drive or operate machinery.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking TRAZIMERA.

This medicine helps most people with HER2 positive breast and gastric cancer but it may have unwanted side effects in some people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have. Because TRAZIMERA may be used with other medicines that treat breast and gastric cancer, it may be difficult for your doctor to tell whether the side effects are due to TRAZIMERA or due to the other medicines.

For further information about the side effects of any other medicines you are receiving, please ask your doctor, nurse or pharmacist for the Consumer Medicine Information (CMI) leaflets for these medicines

During an infusion

Tell your doctor or nurse immediately if you notice any of the following while receiving an infusion (particularly during the first infusion):

swelling of your face, lips, tongue or throat with difficulty breathing
swelling of other parts of your body such as your hands or feet
shortness of breath, wheezing or trouble breathing
abnormal or irregular heartbeat
rash, itching or hives on the skin
feeling sick (nausea) or vomiting, diarrhoea
pain or discomfort (including stomach pain, back pain, chest or neck pain)
fever or chills
headache
fatigue or tiredness
cough

These may be serious side effects. You may require urgent medical attention.

Your doctor may prescribe medication to stop the side effects from occurring.

After an infusion

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

swelling of your face, lips, tongue or throat with difficulty breathing
severe shortness of breath, wheezing or trouble breathing
severe chest pain spreading out to the arms, neck, shoulder and/or back
rash, itching or hives on the skin
fever or chills
abnormal or irregular beating of the heart
severe swelling of the hands, feet or legs
severe coughing

These are serious side effects. You may need urgent medical attention.

Tell your doctor or nurse as soon as possible if you notice any of the following:

any of the side effects listed above
getting tired more easily after light physical activity, such as walking
shortness of breath, especially when lying down or being woken from your sleep with shortness of breath
runny or blocked nose, or nosebleeds
insomnia (difficulty sleeping)
weakness, soreness in muscles and/or joints
increased cough
feeling dizzy, tired, looking pale
flu and/or cold like symptoms, frequent infections such as fever, severe chills, sore throat or mouth ulcers
hot flushes
diarrhoea
changes in weight (gain or loss)
redness, dryness or peeling of the hands or feet (hand-foot syndrome)
pain in hands or feet
unusual hair loss or thinning
nail problems
eye problems such as producing more tears, swollen runny eyes or conjunctivitis (discharge with itching of the eyes and crusty eyelids)

This is not a complete list of all possible side effects. Your doctor or pharmacist has a more complete list.

Others may occur in some people and there may be some side effects not yet known.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

Ask your doctor or pharmacist if you don't understand anything in this list.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Product description

Storage

TRAZIMERA will be stored in the pharmacy or on the hospital ward in a refrigerator at a temperature between 2°C and 8°C.

Availability

TRAZIMERA is a powder for intravenous infusion (drip into the vein) and supplied as a single dose vial and available in two strengths, 60 mg and 150 mg.

It is important to check the product labels to ensure that the medicine is being given as prescribed.

What it looks like

TRAZIMERA is a white powder which is dissolved in sterile water before use.

After dissolving, the TRAZIMERA solution should appear as a clear, colourless to pale yellow-brown solution.

Ingredients

Each vial of TRAZIMERA contains 60 mg or 150 mg of the active ingredient trastuzumab.

It also contains;

histidine hydrochloride
histidine
polysorbate 20
sucrose

The trastuzumab protein is made using Chinese hamster ovary cells.

Supplier

TRAZIMERA is supplied in Australia by:

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free number: 1800 675 229
www.pfizer.com.au

Australian registration numbers

60mg: AUST R 304049

150mg: AUST R 304050

This leaflet was prepared in August 2019.

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Trazimera

Active ingredient

Trastuzumab

Schedule

1 Name of Medicine

Trastuzumab.
Trazimera is a biosimilar medicine to the reference biological medicine Herceptin.

2 Qualitative and Quantitative Composition

Each vial contains 60 mg or 150 mg trastuzumab.
The humanized antibody against HER2 is produced by recombinant mammalian cells (Chinese hamster ovary (rch)) in suspension culture in a nutrient medium and purified by affinity chromatography and ion exchange, including specific viral inactivation and removal procedures.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for injection for infusion.
Trazimera is a sterile, white preservative-free lyophilized powder or cake for IV infusion.

4 Clinical Particulars

4.1 Therapeutic Indications

Early breast cancer.

Trazimera is indicated for the treatment of HER2-positive early breast cancer following surgery, and in association with chemotherapy and, if applicable, radiotherapy.

Locally advanced breast cancer.

Trazimera is indicated for the treatment of HER2-positive locally advanced breast cancer in combination with neoadjuvant chemotherapy followed by adjuvant Trazimera.

Metastatic breast cancer.

Trazimera is indicated for the treatment of patients with metastatic breast cancer who have tumours that overexpress HER2:
a) as monotherapy for the treatment of those patients who have received one or more chemotherapy regimens for their metastatic disease;
b) in combination with taxanes for the treatment of those patients who have not received chemotherapy for their metastatic disease; or
c) in combination with an aromatase inhibitor for the treatment of post-menopausal patients with hormone-receptor positive metastatic breast cancer.

Advanced gastric cancer.

Trazimera is indicated in combination with cisplatin and either capecitabine or 5-FU for the treatment of patients with HER2 positive advanced adenocarcinoma of the stomach or gastro-oesophageal junction who have not received prior anti-cancer treatment for their metastatic disease.

4.2 Dose and Method of Administration

HER2 testing is mandatory prior to initiation of Trazimera therapy (see Section 4.2 Dose and Method of Administration, Detection of HER2 protein overexpression or HER2 gene amplification).
In order to prevent medication errors it is important to check the vial labels to ensure the medicine being prepared and administered is Trazimera (trastuzumab) and not Kadcyla (trastuzumab emtansine).
In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded in the patient medical record.

Dose.

Early breast cancer.

Three-weekly schedule.

The recommended initial loading dose is 8 mg/kg body weight, followed by a maintenance dose of 6 mg/kg body weight administered at 3 weekly intervals.

Weekly schedule.

The recommended initial loading dose is 4 mg/kg body weight, followed by a maintenance dose of 2 mg/kg body weight administered at weekly intervals.
Locally advanced breast cancer.

Three-weekly schedule.

The recommended initial loading dose is 8 mg/kg body weight, followed by a maintenance dose of 6 mg/kg body weight administered at 3 weekly intervals.
Metastatic breast cancer.

Three-weekly schedule.

The recommended initial loading dose is 8 mg/kg body weight, followed by a maintenance dose of 6 mg/kg body weight administered at 3 weekly intervals.

Weekly schedule.

The recommended initial loading dose is 4 mg/kg body weight, followed by a maintenance dose of 2 mg/kg body weight administered at weekly intervals.
Advanced gastric cancer.

Three-weekly schedule.

The recommended initial loading dose is 8 mg/kg body weight, followed by a maintenance dose of 6 mg/kg body weight administered at 3-weekly intervals.
See Section 5.1 Pharmacodynamic Properties, Clinical trials (including Table 5 for early breast cancer) for the sequence and dosing of chemotherapy medicines used in the supporting pivotal trials. Refer also to the currently approved product information for the chemotherapy partners.

Administration.

Trazimera IV solution is not to be used for subcutaneous administration and must be administered as an IV infusion. Do not administer as an IV push or bolus.
Trazimera IV loading doses should be administered over approximately 90 minutes. If the loading dose was well tolerated, subsequent doses can be administered as a 30 minute infusion.
Patients should be observed for fever and chills or other infusion-associated symptoms (see Section 4.8 Adverse Effects (Undesirable Effects)). Interruption of the infusion and/or medication may help to control such symptoms. The infusion may be resumed when symptoms abate.

Duration of treatment.

Patients with early or locally advanced breast cancer should be treated for 1 year or until disease recurrence, whichever occurs first. However, extending adjuvant treatment beyond one year is not recommended (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Early breast cancer).
Patients with metastatic breast cancer and advanced gastric cancer should be treated until progression of disease.

Missed doses.

If the patient has missed a dose of Trazimera by one week or less, then the usual maintenance dose of Trazimera (weekly regimen: 2 mg/kg; 3-weekly: 6 mg/kg) should be administered as soon as possible (do not wait until the next planned cycle). Subsequent maintenance doses should then 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 Trazimera by more than one week, a re-loading dose of Trazimera should be administered over approximately 90 minutes (weekly regimen: 4 mg/kg; 3-weekly: 8 mg/kg) as soon as possible. Subsequent maintenance doses (weekly regimen: 2 mg/kg; 3-weekly: 6 mg/kg) should be administered 7 days or 21 days later according to the weekly or three-weekly schedules, respectively.

Dose modification.

If the patient develops an infusion-related reaction (IRR), the infusion rate of Trazimera IV may be slowed or interrupted (see Section 4.4 Special Warnings and Precautions for Use).
No reductions in the dose of Trazimera were made during clinical trials. Patients may continue Trazimera therapy during periods of reversible, chemotherapy-induced myelosuppression, but they should be carefully monitored for complications of neutropenia during this time. The specific instructions to reduce or hold the dose of chemotherapy should be followed.

Use in elderly.

In clinical trials, elderly patients did not receive reduced doses of trastuzumab. Age has been shown to have no effect on the disposition of trastuzumab (see Section 5.2 Pharmacokinetic Properties).

Detection of HER2 protein overexpression or HER2 gene amplification.

Trazimera should only be used in patients whose tumours have HER2 protein overexpression or HER2 gene amplification.
To ensure accurate and reproducible results, testing must be performed in a specialized laboratory, which can ensure validation of the testing procedures.
HER2 protein overexpression should be detected using an immunohistochemistry (IHC)-based assessment of fixed tumour blocks. HER2 gene amplification should be detected using in situ hybridization (ISH) of fixed tumour blocks. Examples of ISH include fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH) and silver in situ hybridization (SISH).
For any other method to be used for the assessment of HER2 protein or gene expression, the test method must be precise and accurate enough to demonstrate overexpression of HER2 (it must be able to distinguish between moderate (congruent with 2+) and strong (congruent with 3+) HER2 overexpression).
For full instructions on the use of these assays and interpretation of the results please refer to the package inserts of validated FISH, CISH and SISH assays. Official recommendations on HER2 testing may also apply.

Breast cancer.

Trazimera treatment is only appropriate if there is strong HER2 overexpression, as described by a 3+ score by IHC or a positive ISH result. For patients with an intensity score of 2+ on IHC, confirmation of HER2 positive status by ISH is mandatory.

Advanced gastric cancer.

Trazimera treatment is only appropriate if there is HER2 overexpression, as described by a 3+ IHC score. For cases with a score of less than 3+ by IHC, confirmation of HER2 positive status by ISH is mandatory.
Bright-field ISH technology is recommended for advanced gastric cancer samples to enable evaluation of tumour histology and morphology in parallel. Either FISH or SISH are recommended for detecting HER2 gene amplification in advanced gastric cancer tissue.

Preparation for IV infusion.

Reconstituting the powder. Appropriate aseptic technique should be used.
Trazimera should be carefully handled during reconstitution. Causing excessive foaming during reconstitution or shaking the reconstituted Trazimera may result in problems with the amount of Trazimera that can be withdrawn from the vial.
Each 60 mg vial should be reconstituted with 3.0 mL of sterile water for injections as the solvent. The use of other solvents should be avoided. The resultant solution is 3.1 mL of approximately 21 mg/mL trastuzumab. A 7.5% overage is included to ensure withdrawal of the labelled dose of 60 mg.
Each 150 mg vial should be reconstituted with 7.2 mL of sterile water for injections as the solvent. The use of other solvents should be avoided. The resultant solution is 7.4 mL of approximately 21 mg/mL trastuzumab. A 4% overage is included to ensure withdrawal of the labelled dose of 150 mg.
Instructions for reconstitution. 1) Using a sterile syringe, slowly inject 7.2 mL (for 150 mg vial) or 3.0 mL (for 60 mg vial) of sterile water for injections in the vial containing the lyophilized Trazimera, directing the stream into the lyophilized cake.
2) Swirl vial gently to aid reconstitution. Trazimera may be sensitive to shear-induced stress, e.g. agitation or rapid expulsion from a syringe. Do not shake.
Slight foaming of the product upon reconstitution is not unusual. Allow the vial to stand undisturbed for approximately 5 minutes. The reconstituted preparation results in a clear to slightly opalescent and colourless to pale yellow-brown solution and should be essentially free of visible particulates.
Instructions for dilution.

Weekly regimen.

Determine the volume of the reconstituted solution required based on a loading dose of trastuzumab 4 mg/kg body weight, or a maintenance dose of trastuzumab 2 mg/kg body weight. See Equation 1.

Three-weekly regimen.

Determine the volume of the reconstituted solution required based on a loading dose of trastuzumab 8 mg/kg body weight, or subsequent every 3 weeks dose of 6 mg/kg body weight. See Equation 2.

Preparation and stability of the admixture. The appropriate amount of the reconstituted solution should be withdrawn from the vial using a sterile needle and syringe and added to an infusion bag containing 250 mL of 0.9% sodium chloride.
Dextrose (5%) solution should not be used since it causes aggregation of the protein.
Trazimera should not be mixed or diluted with other medicines.
No incompatibilities between Trazimera and polyvinylchloride, polyethylene, polypropylene, or ethylene vinyl acetate bags or glass IV bottles have been observed.
The infusion bag should be gently inverted to mix the solution in order to avoid foaming. Parenteral drug products should be inspected visually for particulates and discoloration prior to administration.

4.3 Contraindications

Trazimera is contraindicated in patients with known hypersensitivity to trastuzumab, Chinese hamster ovary cell proteins or to any of its excipients.
In the treatment of early or locally advanced breast cancer, Trazimera is contraindicated in patients with a left ventricular ejection fraction of less than 45% and those with symptomatic heart failure.

4.4 Special Warnings and Precautions for Use

General.

Trazimera therapy should only be initiated under the supervision of a physician experienced in the treatment of cancer patients. Usual clinical care should be taken to prevent microbial contamination of the intravenous access sites used to deliver Trazimera therapy. Trazimera should be administered by a healthcare professional prepared to manage anaphylaxis and adequate life support facilities should be available. Treatment may be administered in an outpatient setting.
If Trazimera is used concurrently with cytotoxic chemotherapy, the specific guidelines used to reduce or hold the dose of chemotherapy should be followed. Patients may continue Trazimera therapy during periods of reversible chemotherapy-induced myelosuppression, renal toxicity or hepatic toxicity.

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 product therapy alone or in combination with a taxane following anthracycline (doxorubicin or epirubicin)-containing chemotherapy. This may be moderate to severe and has 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, 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 Section 5.2 Pharmacokinetic Properties). 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 Trazimera, especially those with prior anthracycline and cyclophosphamide (AC) exposure, should undergo baseline cardiac assessment including history and physical examination, ECG echocardiogram, and/or 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 Trazimera.
If left ventricular ejection fraction (LVEF) drops 10 percentage points from baseline and to below 50%, Trazimera should be withheld and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has not improved, or declined further, or clinically significant CHF has developed, discontinuation of Trazimera 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 Trazimera 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 this purpose. 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 on weekly therapy with trastuzumab without additional clinical cardiac events.
Early and locally advanced 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.
All patients should have a determination of LVEF prior to treatment. Use of trastuzumab is contraindicated in patients with early or locally advanced disease and a LVEF of less than 45% and those with symptomatic heart failure (see Section 4.3 Contraindications). Patients with a LVEF of 45 - 55% at baseline should be monitored regularly for symptoms of heart failure during trastuzumab treatment.
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 and neoadjuvant breast cancer clinical trials with trastuzumab.

Adjuvant treatment.

Trazimera and anthracyclines should not be given concurrently in the adjuvant treatment setting.
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 4 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 (> 25 kg/m²).

Neoadjuvant-adjuvant treatment.

Trazimera neoadjuvant-adjuvant treatment concurrent with anthracyclines should be used with caution and only in chemotherapy-naive 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 Trazimera in the neoadjuvant setting, no additional cytotoxic chemotherapy should be given after surgery.
Metastatic breast cancer. Trazimera and anthracyclines should be given concurrently in the metastatic breast cancer setting.
Advanced gastric cancer. In advanced gastric cancer, patients with a history of documented congestive heart failure, angina pectoris requiring medication, evidence of transmural myocardial infarction on ECG, poorly controlled hypertension (systolic BP > 180 mmHg or diastolic BP > 100 mmHg), clinically significant valvular heart disease, high risk uncontrollable arrhythmias, and baseline LVEF < 50% (measured by echocardiography or MUGA) were excluded from Study BO18255 (ToGA) according to the study protocol.

Hypersensitivity reactions including anaphylaxis.

Severe hypersensitivity reactions have been infrequently reported in patients treated with trastuzumab products. Signs and symptoms include anaphylaxis, urticaria, bronchospasm, angioedema, and/or hypotension. In some cases, the reactions have been fatal. The onset of symptoms generally occurred during an infusion, but there have also been reports of symptom onset after the completion of an infusion. Reactions were most commonly reported in association with the initial infusion.
Patients should be observed closely for hypersensitivity reactions, Trazimera infusion should be interrupted in all patients with severe hypersensitivity reactions. In the event of a hypersensitivity reaction, appropriate medical therapy should be administered, which may include adrenaline, corticosteroids, antihistamines, bronchodilators and oxygen. Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms.

Infusion-related reactions (IRRs).

IRRs are known to occur with the administration of trastuzumab (see Section 4.8 Adverse Effects (Undesirable Effects)).
Pre-medication may be used to reduce risk of occurrence of IRRs.
Serious IRRs to trastuzumab infusion including dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress and supraventricular tachyarrhythmia have been reported (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients should be observed for IRRs. 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, intravenous fluids, beta-agonists and corticosteroids. In rare cases, these reactions are associated with a clinical course culminating in a fatal outcome. In other patients with acute onset of signs and symptoms, initial improvement was followed by clinical deterioration and delayed reactions with rapid clinical deterioration have also been reported. Fatalities have occurred within hours or up to one week following an infusion.
Patients who are experiencing dyspnoea 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 the benefit considered for each patient (see Pulmonary reactions).

Pulmonary reactions.

Severe pulmonary events leading to death have been reported with the use of trastuzumab in the post-marketing setting. These events may occur as part of an infusion-related reaction (see Infusion-related reactions) 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, pulmonary hypertension, pulmonary fibrosis 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 Trazimera.

Use in hepatic impairment.

The use of trastuzumab in patients with hepatic impairment has not been studied.

Use in renal impairment.

Formal PK studies have not been conducted in patients with renal impairment. Based on population PK analysis, renal impairment is not expected to influence trastuzumab exposure, however, limited data from patients with moderate to severe renal impairment were included in the population PK analysis (see Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

Clinical experience is limited in patients above 65 years of age. The risk of cardiac dysfunction may be increased in elderly patients. The reported clinical experience is not adequate to determine whether older patients respond differently from younger patients. Elderly patients did not receive reduced doses of trastuzumab in clinical trials. However, greater sensitivity to trastuzumab in some older patients cannot be ruled out.

Paediatric use.

The safety and efficacy of trastuzumab in patients under the age of 18 years have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal drug interaction studies have been performed with trastuzumab in humans. Clinically significant interactions with concomitant medication used in clinical trials have not been observed. A comparison of serum levels of trastuzumab given in combination with cisplatin, doxorubicin or epirubicin-plus-cyclophosphamide has not suggested the possibility of any interaction.
Administration of paclitaxel in combination with trastuzumab resulted in a slightly less than two-fold decrease in trastuzumab clearance in a non-human primate study and a 1.5-fold increase in trastuzumab serum levels in clinical studies. Paclitaxel pharmacokinetics determined during the fourth cycle of the alternative 3-weekly trastuzumab regimen (n = 25) were not altered appreciably, relative to parameters determined during the initiation of paclitaxel, prior to introduction of trastuzumab. Similarly, docetaxel pharmacokinetics determined during the first dose of trastuzumab in the standard weekly regimen (n = 10) were not altered appreciably relative to those determined 2 weeks earlier for docetaxel-alone.
A pharmacokinetic interaction substudy of BO18255 (ToGA) performed in male and female Japanese patients with advanced gastric cancer showed that co-administration of trastuzumab and capecitabine and cisplatin had no significant effects on the pharmacokinetics of the two chemotherapy agents compared with co-administration of the two agents without trastuzumab. The pharmacokinetics of trastuzumab were not evaluated in this study.
The administration of concomitant chemotherapy (either anthracycline or cyclophosphamide) did not appear to influence the pharmacokinetics of trastuzumab.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

A study in female cynomolgus monkeys revealed no evidence of impaired fertility at IV trastuzumab doses up to 25 mg/kg twice weekly, corresponding to serum trough levels (serum C_min) about 15 times higher than that in humans receiving the recommended weekly dose of 2 mg/kg.
(Category D)
Trazimera should be avoided during pregnancy and since trastuzumab may persist in the circulation for up to 7 months, pregnancy should be avoided for 7 months after the last dose of Trazimera, unless the anticipated benefit for the mother outweighs the unknown 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 of childbearing potential should be advised to use effective contraception during treatment with Trazimera and for at least 7 months after treatment has concluded. Women who become pregnant should be advised of the possibility of harm to the foetus. If a pregnant woman is treated with Trazimera, or becomes pregnant within 7 months following the last dose of Trazimera, close monitoring by a multidisciplinary team is desirable.
A study conducted in lactating cynomolgus monkeys dosed intravenously with trastuzumab at 25 mg/kg twice weekly (serum C_min about 15 times higher than that in humans receiving the recommended weekly dose of 2 mg/kg) demonstrated that trastuzumab is excreted in the milk. The presence of trastuzumab in the serum of infant monkeys was not associated with adverse effects on their growth or development from birth to 1 month of age. However, the binding affinity of trastuzumab to epidermal growth factor receptor 2 protein in cynomolgus monkeys is unclear.
It is not known whether trastuzumab is excreted in human milk. As human immunoglobulin G (IgG) is secreted into human milk and the potential for harm to the infant is unknown, breast-feeding should be avoided during Trazimera therapy and for 7 months after the last dose of Trazimera.

4.7 Effects on 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.

4.8 Adverse Effects (Undesirable Effects)

The adverse drug reactions listed in this section fall into the following categories: 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 are presented in order of decreasing seriousness.
Presented in Table 1 are adverse reactions that have been reported in association with the use of trastuzumab alone, or in combination with chemotherapy in the below pivotal clinical trials as well as in the post-marketing setting.

Early breast cancer.

BO16348 (HERA): trastuzumab arm (n=1678). Control arm (n=1708).
B-31/N9831 joint analysis: trastuzumab arms (n=2345). Control arm (n=1673).
BCIRG 006: trastuzumab arm (n=2133). Control arm (n=1041).
BO16216 (TanDEM): trastuzumab arm (n=161). Control arm (n=161).

Locally advanced breast cancer.

MO16432 (NOAH): trastuzumab arm (n=115). Control arm (n=116).

Metastatic breast cancer (MBC).

H0648g/H0649g: trastuzumab arms (n=469 and n=222 respectively).
M77001: trastuzumab arm (n=92). Control arm (n=94).

Advanced gastric cancer.

BO18255 (ToGA): trastuzumab arm (n=294). Control arm (n=290).
All terms included are based on the highest percentage seen in pivotal clinical trials.

Additional information for selected adverse drug reactions.

The following information is relevant to all indications.

Infusion-related reactions (IRRs) and hypersensitivity.

IRRs such as chills and/or fever, dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress were seen in all trastuzumab clinical trials (see Section 4.4 Special Warnings and Precautions for Use).
IRRS may be clinically difficult to distinguish from hypersensitivity reactions.
The rate of IRRs 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 early breast cancer, the rate of IRRs 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 reactions (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 metastatic breast cancer, 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 reactions (grade 3 and above) ranged from 5% to 7% in the trastuzumab containing arm compared to 5% to 6% in the comparator arm.
Anaphylactoid reactions were observed in isolated cases (see Section 4.4 Special Warnings and Precautions for Use).

Cardiac dysfunction.

Congestive heart failure (NYHA Class II-IV) is a common adverse reaction to trastuzumab. It has been associated with fatal outcome. Signs and symptoms of heart failure, such as dyspnoea, orthopnoea, increased cough, pulmonary oedema, pulmonary hypertension and S3 gallop or reduced ventricular ejection fraction, have been observed in patients treated with trastuzumab (see Section 4.4 Special Warnings and Precautions for Use).

Locally advanced breast cancer (neoadjuvant-adjuvant setting).

In the clinical trial setting, when trastuzumab was administered concurrently with neoadjuvant chemotherapy containing 3-4 cycles of a neoadjuvant anthracycline (cumulative doxorubicin dose 180 mg/m² or epirubicin dose 360 mg/m²) overall, the incidence of symptomatic cardiac dysfunction was up to 1.7% in the trastuzumab arm.

Early breast cancer (adjuvant setting).

In 3 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 sequentially to a taxane (0.3 - 0.4%). The rate was highest in patients who were administered trastuzumab 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 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 discernible 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 was administered after completion of adjuvant chemotherapy, NYHA class III-IV heart failure was observed in 0.6% of patients in the 1 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 therapy remained low at 0.8% and 9.8%, respectively.
After a median follow-up of 8 years the incidence of severe CHF (NYHA Class III and IV) following 1 year of trastuzumab therapy (combined analysis of the two trastuzumab treatment arms) 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-treated patients. Reversibility of mild symptomatic and asymptomatic left ventricular dysfunction was demonstrated for 79.5% of trastuzumab-treated patients. Approximately 17% of cardiac dysfunction related events occurred after completion of trastuzumab.
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): in patients with a symptomatic CHF event, while data are missing for 22.6%, 64.5% were known to recover, and 12.9% experienced no recovery. The median time to first recovery by LVEF status occurred at 8.3 months (range 1-104 months); 90.3% experienced a full or partial LVEF recovery.

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 + paclitaxel subgroup, compared with 1% - 4% for the paclitaxel-alone subgroup. For trastuzumab monotherapy, the rate was 6 - 9%. The highest rate of cardiac dysfunction was seen in patients receiving concurrent trastuzumab + anthracycline/cyclophosphamide (27%), significantly higher than in the anthracycline/cyclophosphamide-alone subgroup (7 - 10%). In study M77001 with prospective monitoring of cardiac function, the incidence of symptomatic heart failure was 2.2% in patients receiving trastuzumab 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 heart failure.

Advanced gastric cancer.

In Study BO18255 (ToGA), at screening, the median LVEF value was 64% (range 48% - 90%) in the fluoropyrimidine/cisplatin (FP) arm and 65% (range 50% - 86%) in the trastuzumab + FP arm.
The majority of the LVEF decreases noted in Study BO18255 (ToGA) were asymptomatic, with the exception of 1 patient in the trastuzumab arm whose LVEF decrease coincided with cardiac failure. See Tables 2 and 3.

Overall, there were no significant differences in cardiotoxicity between the treatment arm and the comparator arm.

Haematological toxicity.

Breast cancer.

Monotherapy - study H0649g.

Haematological toxicity is infrequent following the administration of trastuzumab as monotherapy in the metastatic setting, WHO Grade 3 leukopenia, thrombocytopenia and anaemia occurring in < 1% of patients. No WHO Grade 4 toxicities were observed.

Combination therapy - studies H0648g and M77001.

WHO Grade 3 or 4 haematological toxicity was observed in 63% of patients treated with trastuzumab and an anthracycline/cyclophosphamide compared to an incidence of 62% in patients treated with the anthracycline/cyclophosphamide combination without trastuzumab.
There was an increase in WHO Grade 3 or 4 haematological toxicity in patients treated with the combination of trastuzumab and paclitaxel compared with patients receiving paclitaxel-alone (34% vs. 21%). Haematological toxicity was also increased in patients receiving trastuzumab and docetaxel, compared with docetaxel-alone (32% grade 3/4 neutropenia vs. 22%, using NCI-CTC criteria). The incidence of febrile neutropenia/neutropenic sepsis was also increased in patients treated with trastuzumab + docetaxel (23% vs. 17% for patients treated with docetaxel-alone).

Early setting - HERA trial.

Using NCI-CTC criteria, in the BO16348 (HERA) trial, 0.4% of trastuzumab 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 adverse events categorized under the blood and lymphatic system disorders SOC (Grade ≥ 3) are shown in Table 4 by trial treatment.

The total percentage of patients who experienced an adverse event of ≥ Grade 3 NCI CTCAE v3.0 categorized under this SOC were 38% in the FP arm and 40% in the FP + H arm.
Overall, there were no significant differences in haematotoxicity between the treatment arm and the comparator arm.

Hepatic and renal toxicity.

Breast cancer.

Monotherapy - study H0649g.

WHO Grade 3 or 4 hepatic toxicity was observed in 12% of patients following administration of trastuzumab as monotherapy in the metastatic setting. This toxicity was associated with progression of disease in the liver in 60% of these patients. No WHO Grade 3 or 4 renal toxicity was observed.

Combination therapy - study H0648g.

WHO Grade 3 or 4 hepatic toxicity was observed in 6% of patients treated with trastuzumab and an anthracycline/cyclophosphamide compared with an incidence of 8% in patients treated with the anthracycline/cyclophosphamide combination without trastuzumab. No WHO Grade 3 or 4 renal toxicity was observed.
WHO Grade 3 or 4 hepatic toxicity was less frequently observed among patients receiving trastuzumab and paclitaxel than among patients receiving paclitaxel-alone (7% vs.15%). No WHO Grade 3 or 4 renal toxicity was observed.
Advanced gastric cancer. In Study BO18255 (ToGA) no significant differences in hepatic and renal toxicity were observed between the two treatment arms.
NCI-CTCAE (v3.0) grade ≥ 3 renal toxicity was not significantly higher in patients receiving trastuzumab than those in the fluoropyrimidine/cisplatin arm (3% and 2% respectively).
NCI-CTCAE (v3.0) grade ≥ 3 adverse events in the Hepatobiliary Disorders SOC: Hyperbilirubinaemia was the only reported adverse event and was not significantly higher in patients receiving trastuzumab than those in the fluoropyrimidine/cisplatin arm (1% and < 1% respectively).

Diarrhoea.

Breast cancer.

Monotherapy - study H0649g.

Of patients treated with trastuzumab monotherapy in the metastatic setting, 27% experienced diarrhoea.

Combination therapy - studies H0648g and M77001.

An increase in the incidence of diarrhoea, primarily mild to moderate in severity, has been observed in patients receiving trastuzumab in combination with chemotherapy compared with patients receiving chemotherapy-alone or trastuzumab-alone.

Early setting - HERA study.

In the HERA trial, 8% of trastuzumab treated patients experienced diarrhoea during the first year of treatment.
Advanced gastric cancer. In Study BO18255 (ToGA), 109 patients (37%) in the trastuzumab treatment arm versus 80 patients (28%) in the comparator arm experienced any grade diarrhoea. Four percent (4%) of patients in the fluoropyrimidine/cisplatin arm experienced Grade ≥ 3 diarrhoea vs. 9% in the trastuzumab arm.

Infection.

An increased incidence of infections, primarily mild upper respiratory infections of minor clinical significance or catheter infections, has been observed primarily in patients treated with trastuzumab + chemotherapy compared with patients receiving chemotherapy-alone or trastuzumab-alone.

Laboratory abnormalities.

Febrile neutropenia occurs very commonly. Commonly occurring adverse reactions include anaemia, leukopenia, thrombocytopenia and neutropenia. The frequency of occurrence of hypoprothrombinemia is not known.

Immunogenicity.

Immunogenicity of Herceptin.

In a neoadjuvant-adjuvant breast cancer trial (BO22227), at a median follow-up exceeding 70 months, 10.1% (30/296) of patients treated with intravenous Herceptin developed antibodies against trastuzumab. Neutralizing anti-trastuzumab antibodies were detected in post-baseline samples in 2 of 30 patients in the intravenous Herceptin arm.
The clinical relevance of these antibodies is not known. The presence of anti-trastuzumab antibodies had no impact on the pharmacokinetics, efficacy [determined by pathological complete response (pCR) and event free survival (EFS)] and safety [determined by the occurrence of administration related reaction (ARRs)] of intravenous Herceptin.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no experience with overdosage in human clinical trials. Single doses higher than 10 mg/kg have not been tested.
Treatment of overdose should consist of general supportive measures.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 in Australia. Contact the National Poisons Centre on 0800 POISON (0800 764766) in New Zealand.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC03.

Mechanism of action.

Trazimera (trastuzumab) is a recombinant DNA-derived humanized monoclonal antibody that selectively targets the extracellular domain of the human epidermal growth factor receptor 2 protein (HER2). The antibody is an IgG1 kappa that contains human framework regions with the complementarity-determining regions of a murine anti-p185 HER2 antibody that binds to HER2. Trastuzumab is composed of 1,328 amino acids and has a molecular weight of ~148 kDa.
The HER2 (or c-erbB2) proto-oncogene encodes for a single transmembrane spanning, receptor-like protein of 185 kDa, which is structurally related to the epidermal growth factor receptor.
Trastuzumab has been shown, both in in vitro assays and in animals, to inhibit the proliferation of human tumour cells that overexpress HER2. In vitro, trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2. In animal models in vivo, murine anti-HER2 antibody inhibited the growth of human tumours overexpressing HER2, indicating that the humanized antibody (trastuzumab) is likely also to have anti-proliferative activity in vivo against human breast tumours expressing high levels of HER2.

Clinical trials.

Early breast cancer. Early breast cancer is defined as non-metastatic, primary, invasive carcinoma of the breast.

Trastuzumab in combination with adjuvant chemotherapy.

The use of trastuzumab in the setting of early breast cancer (after surgery and in association with chemotherapy and, if applicable, radiotherapy) has been studied in four multicentre randomized phase III trials of patients with HER2 positive breast cancer who have completed surgery. In these clinical trials, early breast cancer was limited to operable, primary adenocarcinoma of the breast with positive axillary nodes or node negative disease with additional indicators of a higher degree of risk. The design of these studies is summarized in Table 5 and efficacy results are presented in Tables 6-10.

The HERA trial was designed to compare 1 and 2 years of 3-weekly trastuzumab treatment vs. observation in patients with HER2 positive breast cancer following surgery, established chemotherapy and radiotherapy (if applicable). In addition, a comparison of 2 years trastuzumab treatment vs. 1 year trastuzumab treatment was performed. Patients assigned to receive trastuzumab were given an initial loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for either 1 or 2 years. The efficacy results from the HERA trial are summarized in Table 6.

The HERA trial included a subgroup of patients (n = 602) with small tumours (< 2 cm) and node-negative disease. In this subgroup, the relative risk reduction was similar to the overall trial population (HR = 0.50; 95% CI: 0.21 - 1.15). However, the benefit in terms of absolute difference in rate of recurrence after 1 year of follow-up was smaller (2.7% recurrence rate with trastuzumab vs. 5.5% with observation).
In the final analysis (8 year median follow-up) extending trastuzumab treatment for a duration of 2 years did not show additional benefit over treatment for 1 year [DFS HR in the intent to treat (ITT) population of 2 years vs. 1 year = 0.99 (95% CI: 0.87, 1.13); p-value = 0.90 and OS HR = 0.98 (0.83, 1.15); p-value = 0.78]. The rate of asymptomatic cardiac dysfunction was increased in the 2-year treatment arm (8.1% vs. 4.6% in the 1-year treatment arm). More patients experienced at least one grade 3 or 4 adverse event in the 2-year treatment arm (20.4%) compared with the 1-year treatment arm (16.3%).
The efficacy results from the joint analysis of the NCCTG 9831 and NSABP B-31 trials are summarized in Tables 7 and 8.

The pre-planned final analysis of OS from the joint analysis of studies NSABP B-31 and NCCTG N9831 was performed when 707 deaths had occurred (median follow-up 8.3 years in the AC → P H group). At 8 years, the survival rate was estimated to be 86.9% in the AC → P H arm and 79.4% in the AC → P arm, an absolute benefit of 7.4% (95% CI: 4.9%, 10.0%. The final OS results from the joint analysis of studies NSABP B-31 and NCCTG N9831 are summarized in Table 8.

The efficacy results from the BCIRG 006 are summarized in Tables 9 and 10.

Based on studies to date, the optimal duration of adjuvant trastuzumab therapy is 1 year and may be clarified in further randomized trials. However, extending adjuvant treatment beyond 1 year is not recommended (see Section 4.2 Dose and Method of Administration).
Locally advanced breast cancer. Locally advanced breast cancer is defined as the absence of metastatic disease and meeting one or more of the following criteria: inflammatory breast cancer, a primary tumour that extends to the chest wall or skin, tumour > 5 cm with any positive lymph node(s), any tumour with disease in supraclavicular nodes, infraclavicular nodes or internal mammary nodes, any tumour with axillary lymph nodes fixed to one another or other structures.

Trastuzumab in combination with neoadjuvant-adjuvant chemotherapy.

The use of trastuzumab for the neoadjuvant-adjuvant treatment of locally advanced breast cancer has been studied in Study MO16432 (NOAH), a multicentre randomized trial, designed to investigate the concurrent administration of trastuzumab with neoadjuvant chemotherapy, including both an anthracycline and a taxane, followed by adjuvant trastuzumab, up to a total treatment duration of 1 year. The trial recruited patients with newly diagnosed locally advanced (Stage III) or inflammatory breast cancer. Patients with HER2+ tumours were randomized to receive either neoadjuvant chemotherapy concurrently with neoadjuvant-adjuvant trastuzumab (n = 116), or neoadjuvant chemotherapy alone (n = 118).
Trastuzumab was administered concurrently with 10 cycles of neoadjuvant chemotherapy as follows:
doxorubicin (60 mg/m²) and paclitaxel (150 mg/m²) in combination with trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg maintenance, administered 3-weekly) for 3 cycles;
followed by paclitaxel (175 mg/m²) and trastuzumab (6 mg/kg, administered 3-weekly) for 4 cycles;
followed by CMF on day 1 and 8 every 4 weeks for 3 cycles, in combination with 4 cycles of trastuzumab (6 mg/kg administered 3-weekly);
followed by up to 7 additional cycles of trastuzumab (6 mg/kg, administered 3-weekly) alone to complete 1 year after starting trastuzumab.
The primary endpoint for the trial, event-free survival (EFS), was defined as the time from randomization to disease recurrence or progression (local, regional, distant or contralateral), or death of any cause. The efficacy results from NOAH (full analysis population, defined as all patients who were randomized in the trial following the intent-to-treat principle, with the exception of 3 patients whose data could not be evaluated) are summarized in Table 11. The median duration of follow-up in the trastuzumab arm was 3.8 years.

The addition of trastuzumab to neoadjuvant chemotherapy, followed by adjuvant trastuzumab for a total duration of 52 weeks, resulted in a 35% reduction in the risk of disease recurrence/progression. The hazard ratio translates into an absolute benefit, in terms of 3-year event-free survival rate estimates of 13 percentage points (65% vs. 52%) in favour of the trastuzumab arm.
To date, results are not available comparing the efficacy of trastuzumab administered with chemotherapy in the adjuvant setting with that obtained in the neoadjuvant/adjuvant setting.
Metastatic breast cancer. There are no data available to establish the efficacy of trastuzumab for the treatment of metastatic disease in patients who have previously received the medicine for the treatment of early disease.
The safety and efficacy of trastuzumab has been studied in randomized, controlled clinical trials in combination with chemotherapy (Studies H0648g, M77001 and TaNDEM) and in an open-label monotherapy clinical trial (Study H0649g) for the treatment of metastatic breast cancer. All trials studied patients with metastatic breast cancer whose tumours overexpress HER2. Patients were eligible if they had 2+ or 3+ levels of overexpression based on a 0 - 3+ scale by immunohistochemical (IHC) assessment of tumour tissue or whose tumours have HER2 gene amplification as determined by fluorescence in situ hybridization (FISH) test (see Section 4.2 Dose and Method of Administration).

Trastuzumab in combination with chemotherapy.

Study H0648g was an open-label, randomized controlled, multinational trial of chemotherapy-alone and in combination with trastuzumab. Patients with previously untreated metastatic breast cancer were treated with either an anthracycline (doxorubicin 60 mg/m² or epirubicin 75 mg/m²) plus cyclophosphamide (600 mg/m²) with or without trastuzumab or paclitaxel (175 mg/m² infused over 3 hours) with or without trastuzumab. Patients on trastuzumab treatment received 4 mg/kg intravenous loading dose on Day 0, followed by weekly infusions of 2 mg/kg from Day 7, which they could continue to receive until evidence of disease progression. Patients who had previously received anthracycline based adjuvant therapy were treated with paclitaxel whereas those who were anthracycline naïve were treated with an anthracycline + cyclophosphamide.
The prospectively defined, primary intent-to-treat analysis indicated that the combination of trastuzumab and chemotherapy significantly prolonged time to disease progression (progression-free survival) compared with chemotherapy-alone as first-line treatment of women with metastatic breast cancer who had tumours that overexpressed HER2. The addition of trastuzumab to chemotherapy extended the median time to disease progression by 2.8 months representing a 61% increase (p=0.0001).
Both anthracycline-treated and paclitaxel-treated patients benefited from trastuzumab treatment, although the effect appeared to be greater in the paclitaxel stratum. The efficacy of trastuzumab treatment was further supported by the secondary endpoints of response rate, duration of response and one-year survival (see Table 12).
One-year survival rates (the prospectively defined survival endpoint) were significantly better for the trastuzumab + chemotherapy versus chemotherapy-alone (79% vs. 68%; p=0.008). With a median follow-up of approximately two years, overall survival is improved for patients initially treated with trastuzumab + chemotherapy compared with those receiving chemotherapy-alone (25.4 vs. 20.3 months; p=0.025) with a relative risk of death of 0.769 (95% CI: 0.607 - 0.973; p=0.028).

The relative overall survival advantage with the addition of trastuzumab was observed in both subgroups: AC [26.8 months (H + AC) vs. 22.8 months (AC-alone); p=0.052] and paclitaxel [22.1 months (H + P) vs. 18.4 months (P-alone); p=0.273] (also see Figures 1 and 2). The analysis of overall survival was, however, greatly confounded by subsequent trastuzumab treatment of each of control arms' patients, following disease progression, in the open-label extension study, H0659g (59% of patients in the AC-alone group, and 75% of patients in the paclitaxel-alone group subsequently received trastuzumab). Hence, the survival advantage seen above, for trastuzumab + chemotherapy treatment versus chemotherapy-alone (which includes patients who subsequently received trastuzumab) may underestimate the benefit to patients.
Importantly, the efficacy described above was obtained without a significant negative impact on the quality of life. Global quality of life decreased equally in both the chemotherapy-alone group and the trastuzumab + chemotherapy group and was most likely related to the effects of cytotoxic chemotherapy. However, at weeks 20 and 32, the global quality of life score had returned to baseline or better than baseline in the group receiving trastuzumab + chemotherapy, while it remained low in the chemotherapy-alone arm (see Figure 3).

Study M77001 was a multinational, multi-centre, randomized, controlled trial investigating the safety and efficacy of trastuzumab in combination with docetaxel, as first-line treatment in HER2 positive metastatic breast cancer patients. One hundred and eighty six patients received docetaxel (100 mg/m² infused over 1 hour on Day 2) with or without trastuzumab (4 mg/kg loading dose, followed by 2 mg/kg weekly). Sixty percent of patients had received prior anthracycline based adjuvant chemotherapy. Trastuzumab with docetaxel was shown to be efficacious in patients whether or not they had received prior adjuvant anthracyclines and regardless of their oestrogen and/or progesterone receptor status.
The combination of trastuzumab + docetaxel significantly increased response rate (61% vs. 34%) and prolonged the median time to disease progression by 4.9 months compared with patients treated with docetaxel-alone (see Table 12). Median survival was also significantly increased in patients receiving the combination therapy compared with those receiving docetaxel-alone (30.5 months vs. 22.1 months) (see Figure 4).

Trastuzumab in combination with anastrozole.

The TAnDEM trial was a multi-centre, randomized, open-label, phase III trial comparing trastuzumab + anastrozole with anastrozole-alone for the first-line treatment of metastatic breast cancer in HER2 overexpressing, hormone-receptor (i.e. oestrogen-receptor (ER) and/or progesterone-receptor (PR)) positive post-menopausal patients. Two hundred and seven patients were randomized to receive oral anastrozole (1 mg/day) with or without trastuzumab (4 mg/kg loading dose, followed by 2 mg/kg weekly). Patients who had received trastuzumab for early disease were excluded from this trial.
Median progression free survival (PFS) was doubled in the trastuzumab + anastrozole arm compared to the anastrozole-alone arm (4.8 months vs. 2.4 months; p = 0.0016). For the other parameters the improvements seen for trastuzumab + anastrozole were; overall response (16.5% vs. 6.7%); clinical benefit rate (42.7% vs. 27.9%); time to progression (4.8 months vs. 2.4 months). For time to response and duration of response no difference could be recorded between the arms. There was no significant difference in overall survival, however more than half of the patients in the anastrozole-alone arm crossed over to a trastuzumab-containing regimen after progression of disease.

Trastuzumab monotherapy.

Study H0649g was a multinational, multi-centre, single arm trial of trastuzumab as monotherapy in 222 women with HER2 overexpressing metastatic breast cancer. All patients had relapsed following treatment with the best available agents (e.g. anthracyclines and taxanes) and were heavily pre-treated. Two-thirds of the patients had prior adjuvant chemotherapy and all patients had tumour progression following at least one prior regimen of cytotoxic chemotherapy for metastatic disease. Ninety-four percent of the patients had prior anthracycline therapy, approximately 60% had prior paclitaxel therapy and 26% had prior bone marrow or stem cell transplants. Together with HER2 overexpression, which is associated with poorer clinical outcomes, aggressive disease was also suggested by nodal status at diagnosis and by the disease-free interval. Twenty-seven percent of patients had 10 or more positive nodes at the time of diagnosis. Thirty-eight percent of patients had a disease-free interval of less than one year prior to enrolment.
Patients received an intravenous loading dose of 4 mg/kg trastuzumab on Day 0, followed by weekly intravenous infusions of 2 mg/kg until there was evidence of disease progression. Patients who developed progressive disease could stop treatment, continue on the 2 mg/kg weekly dose or receive an increased intravenous dose of 4 mg/kg, as the investigator deemed appropriate. The primary efficacy parameter was tumour response rate.
Trastuzumab as second- or third-line therapy induced objective, durable tumour responses in women with metastatic breast cancer who had tumours that overexpressed HER2. There were 8 complete responses and 26 partial responses yielding an overall response rate of 15%. The durability of the responses was particularly notable. The median duration of the responses was 9.1 months at the cut-off date for analysis (see Table 13).

The clinical significance of the objective tumour responses in this group of patients was supported by the quality-of-life and survival data. Responders had clinically meaningful improvements in physical function, role function, social function, global quality of life and fatigue scale scores during trastuzumab treatment. Most responders were still alive at data cut-off (28/34; 82%). The Kaplan-Meier estimate of median survival for all treated patients at the data cut-off date was 12.8 months.
Evidence of efficacy for trastuzumab monotherapy is based upon response rates. No data are available to demonstrate improvement in survival or quality of life.
Advanced gastric cancer. Study BO18255 (ToGA) was a randomized, open-label, multicentre phase III trial investigating trastuzumab in combination with a fluoropyrimidine and cisplatin (FP) versus chemotherapy alone as first-line therapy in patients with HER2 positive, inoperable, locally advanced or recurrent and/or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction.
Patients were eligible if they had 3+ levels of HER2 overexpression based on a 0 - 3+ scale by IHC assessment of tumour tissue and/or those whose tumours had HER2 gene amplification as determined by a FISH test (see Section 4.2 Dose and Method of Administration).
After satisfying the screening eligibility criteria, including assessment of HER2 status, patients were randomly assigned (1:1) to receive either trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) + fluoropyrimidine/cisplatin (FP+H) or FP alone. The chemotherapy regimen was chosen between 5-FU/cisplatin and capecitabine/cisplatin at the investigator's discretion and could be determined on an individual patient basis.
The efficacy results from ToGA are summarized in Table 14. The primary endpoint was overall survival, defined as the time from the date of randomization to the date of death from any cause. At the time of analysis a total of 349 randomized patients had died: 182 patients (62.8%) in the control arm and 167 patients (56.8%) in the treatment arm. The majority of the deaths were due to events related to the underlying cancer.
Overall survival was significantly improved in the FP + H arm compared to the FP arm (p = 0.0046, log-rank test). The median survival time was 11.1 months with FP and 13.8 months with FP + H. The risk of death was decreased by 26% (HR = 0.74; 95% CI: 0.60 - 0.91) for patients in the FP + H arm compared to the FP arm.
Post-hoc subgroup analyses indicate that targeting tumours with higher levels of HER2 protein (IHC 2+/FISH+ and IHC 3+/regardless of FISH status) results in a greater treatment effect. The median overall survival for the high HER2 expressing group was 11.8 months versus 16 months, HR = 0.65 (95% CI: 0.51 - 0.83) and the median PFS was 5.5 months vs. 7.6 months, HR = 0.64 (95% CI: 0.51 - 0.79).

5.2 Pharmacokinetic Properties

The pharmacokinetics of trastuzumab have been studied in patients with breast cancer (metastatic and early) and advanced gastric cancer (AGC).
The pharmacokinetics of trastuzumab were evaluated in a population pharmacokinetic model analysis using pooled data from 1,582 from 18 Phase I, II and III trials receiving trastuzumab IV to treat a range of cancers, but mostly breast and gastric cancer. A two-compartment model with parallel linear and non-linear elimination from the central compartment described the trastuzumab concentration-time profile. Due to the non-linear elimination, total clearance increased with decreasing concentrations. Linear clearance was 0.127 L/day for breast cancer (metastatic and early) and 0.176 L/day for AGC. The nonlinear elimination parameter values were 8.81 mg/day for the maximum elimination rate (V_max) and 8.92 mg/L for the Michaelis-Menten constant (Km). The central compartment volume was 2.62 L for patients with breast cancer and 3.63 L for patients with AGC.
The population predicted PK exposures (with 5th - 95th Percentiles) and PK parameter values at clinically relevant concentrations (C_max and C_min) for breast cancer and AGC patients treated with the approved q1w and q3w dosing regimens are shown in Table 15 (Cycle 1) and Table 16 (steady-state).

Pharmacokinetics in special populations.

Dedicated pharmacokinetic studies in the elderly and those with renal or hepatic impairment have not been carried out. However, in a population PK analysis, age and renal impairment were not shown to affect trastuzumab disposition. The population PK analysis showed that the estimated creatinine clearance (Cockcroft and Gault) does not correlate with the pharmacokinetics of trastuzumab.

5.3 Preclinical Safety Data

Genotoxicity.

Trastuzumab did not induce gene mutations in bacteria, nor did it cause chromosomal damage in vitro (chromosome aberration assay in human lymphocytes) or in vivo (mouse micronucleus test).

Carcinogenicity.

No studies on the carcinogenic potential of trastuzumab have been conducted to date.

6 Pharmaceutical Particulars

6.1 List of Excipients

Histidine hydrochloride monohydrate, histidine, polysorbate 20, sucrose.

6.2 Incompatibilities

Dextrose (5%) solution should not be used since it causes aggregation of the protein.
Trazimera should not be mixed or diluted with other medicines.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

Reconstituted solution.

A vial of Trazimera reconstituted with sterile Water for Injections without preservative is physicochemically stable for 48 hours at 2°C - 8°C. However, from a microbiological point of view, the product should be used immediately. Any unused portion must be discarded. Product is for single use in one patient only. Do not freeze the reconstituted solution.

Diluted solution for infusion.

From a microbiological point of view, the Trazimera infusion solution should be diluted and used immediately. The product is not intended to be stored after dilution. Solutions of Trazimera for infusion are physically and chemically stable in polyvinylchloride, polyethylene, polypropylene or ethylene vinyl acetate bags or glass IV bottles containing 0.9% sodium chloride at 2 to 8°C for 24 hours. Diluted Trazimera has been shown to be stable for up to 24 hours at temperatures up to 30°C.

6.4 Special Precautions for Storage

Store at 2-8˚C. Refrigerate. Do not freeze.
Trazimera should be stored in the original package in order to protect from light.
Unopened vials of Trazimera may be stored up to 30°C for a single period of up to 3 months. Discard at the end of this 3-month period or by the expiry date on the vial, whichever occurs first. Record the "discard by" date in the date field provided on the carton.

6.5 Nature and Contents of Container

Trazimera powder for injection contains 60 mg or 150 mg trastuzumab and is available in 8 mL or 15 mL glass vial.
Each carton contains one vial.
Not all strengths may be marketed.

6.6 Special Precautions for Disposal

The release of medicines into the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Unused or expired medicine should be returned to a pharmacy for disposal.

6.7 Physicochemical Properties

CAS number.

CAS-180288-69-1.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

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