Consumer medicine information

Herceptin SC

Trastuzumab

BRAND INFORMATION

Brand name

Herceptin SC

Active ingredient

Trastuzumab

Schedule

SUMMARY CMI

HERCEPTIN SC^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Herceptin SC?

Herceptin SC contains the active ingredient trastuzumab. Herceptin SC is used to treat breast cancer whose tumour has tested positive to HER2. For more information, see Section 1. Why am I using Herceptin SC? in the full CMI.

2. What should I know before I use Herceptin SC?

Do not use if you have ever had an allergic reaction to trastuzumab or any of the ingredients listed at the end of the CMI.

Tell your doctor if 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 Herceptin SC.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Herceptin SC? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Herceptin SC and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How is Herceptin SC given?

Herceptin SC will be given to you in a hospital or clinic by a doctor or nurse. Herceptin SC is given as a subcutaneous injection (under the skin) over 2 to 5 minutes every three weeks. More instructions can be found in Section 4. How do I use Herceptin SC? in the full CMI.

5. What should I know while receiving Herceptin SC?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using Herceptin SC. Keep all your appointments with your doctor so that you do not miss a dose and your progress is monitored. Tell your doctor or nurse immediately if you have any signs and symptoms of an allergic or anaphylactic reaction Tell your doctor or nurse immediately if you have any signs and symptoms of heart problems.
Things you should not do	Do not stop your Herceptin SC treatment without talking to your doctor first. Do not take any other medicines, whether they require a prescription or not, without first telling your doctor or consulting with a pharmacist.
Pregnancy and Breastfeeding	Avoid becoming pregnant by using effective contraception while you are being treated with Herceptin SC and for 7 months after stopping treatment. It is recommended that you discontinue breastfeeding while you are being treated with Herceptin SC and not restart breastfeeding until 7 months after completing Herceptin SC treatment.

For more information, see Section 5. What should I know while receiving Herceptin SC? in the full CMI.

6. Are there any side effects?

Tell your doctor or nurse immediately or go to the nearest hospital Emergency Department if you experience any side effects. Some serious side effects that may occur during or after the treatment includes swelling of your face, lips, tongue or throat with difficulty breathing, swelling of other parts of your body such as hands or feet, shortness of breath, wheezing or trouble breathing, abnormal or irregular heartbeat, rash, itching, hives on the skin, nausea, vomiting, diarrhoea, stomach pain, back pain, chest, shoulder or neck pain, fever or chills, headache, fatigue, tiredness, severe coughing. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

HERCEPTIN SC^® subcutaneous injection

Active ingredient(s): trastuzumab (rch)

Consumer Medicine Information (CMI)

This leaflet provides important information about using Herceptin SC. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Herceptin SC.

Where to find information in this leaflet:

1. Why am I using Herceptin SC?
2. What should I know before I use Herceptin SC?
3. What if I am taking other medicines?
4. How is Herceptin SC given?
5. What should I know while receiving Herceptin SC?
6. Are there any side effects?
7. Product details

1. Why am I using Herceptin SC?

Herceptin SC contains the active ingredient trastuzumab. Herceptin SC belongs to a group of medicines known as anti-neoplastic (or anti-cancer) agents. There are many different classes of anti-neoplastic agents. Herceptin SC belongs to a class of anti-neoplastic agents 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.

Herceptin SC 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 Herceptin SC binds to HER2 receptors it stops the growth and spread of the cancer cells.

Herceptin SC is used to treat the following stages of breast cancer;

early breast cancer after surgery
locally advanced breast cancer
metastatic (spreading) breast cancer

Herceptin SC is only used for patients whose tumour has tested positive to HER2.

Herceptin SC may be used alone or in combination 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 further information about the other medicines you are receiving with Herceptin SC, please ask your doctor, nurse or pharmacist for the CMI leaflet.

Ask your doctor if you have any questions why Herceptin SC has been prescribed for you.

2. What should I know before I use Herceptin SC?

Warnings

Do not use Herceptin SC if:

you are allergic to trastuzumab, or any of the ingredients listed at the end of this leaflet or any protein of Chinese hamster origin
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 buildup, abnormal or irregular heartbeat.

Check with your doctor if:

you have a history of heart problems such as; 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.
Your doctor will monitor your heart function closely before and during your treatment with Herceptin SC. Your heart function may also be monitored for years after ceasing Herceptin SC treatment.
you have previously been treated with chemotherapy medicines known as anthracyclines (e.g. doxorubicin); these medicines can damage the heart muscle and increase the risk of heart problems with Herceptin SC
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 Herceptin SC treatment (known as administration related reactions). Your doctor or nurse will monitor you for side effects during treatment. See Section 6. Are there any side effects? for symptoms to look out for.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy

Check with your doctor if you are pregnant or intend to become pregnant.

Herceptin SC may be harmful to an unborn baby. If there is a need for Herceptin SC 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 Herceptin SC and for 7 months after stopping treatment.

Tell your doctor right away if you become pregnant during treatment with Herceptin.

Breastfeeding

Check with your doctor if you are breastfeeding or intend to breastfeed.

It is not known if Herceptin SC passes into breast milk.

It is recommended that you discontinue breast-feeding while you are being treated with Herceptin SC and not restart breast-feeding until 7 months after completing Herceptin SC treatment.

Use in children

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

3. What if I am taking other medicines?

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

Herceptin SC treatment in combination with certain medicines used in the treatment of cancer, such as 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 Herceptin SC.

It may take up to seven months for Herceptin SC to be removed from your body.

Tell your doctor or pharmacist that you have had Herceptin SC if you start any new medication in the seven months after stopping treatment.

4. How is Herceptin SC given?

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

The recommended dose is 600 mg (in a solution of 5 mL). Herceptin SC is given as a subcutaneous injection (under the skin) over 2 to 5 minutes every three weeks.
The injection site should be alternated between the left and right thigh. New injections should be given at least 2.5 cm away from an old site. The injection should not be given into areas where the skin is red, bruised, tender or hard.
If other medicines for subcutaneous use are used during the treatment course with Herceptin SC, a different injection site should be used.

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

Herceptin SC should not be mixed or diluted with other products.

Your doctor will decide how long you should receive Herceptin SC; this will depend on your response to Herceptin SC and the state of your disease.

If you miss a dose or your appointment to get Herceptin SC

As Herceptin SC 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 Herceptin SC, make another appointment as soon as possible. Your doctor will decide when your next dose of Herceptin SC will be.

If you are given too much Herceptin SC (overdose)

As Herceptin SC 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 Herceptin SC, tell your doctor immediately.

5. What should I know while receiving Herceptin SC?

Things you should do

Tell all doctors, dentists and pharmacists who are treating you that you are receiving Herceptin SC.

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.

Your doctor may perform regular tests, including checking your heart function whilst you are being treated with Herceptin SC.

Be sure to keep all of your appointments with your doctor so that your progress can be checked.

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

Things you should not do

Do not stop your Herceptin SC treatment without talking to your doctor first.

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

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Herceptin SC affects you.

If you experience symptoms during your treatment with Herceptin SC you should not drive or operate machinery.

Looking after your medicine

Herceptin SC will be stored in the pharmacy or on the hospital ward in a refrigerator at a temperature between 2°C and 8°C. Herceptin SC should not be frozen.

The vial must be stored in the outer carton to protect it from light.

6. Are there any side effects?

Tell your doctor as soon as possible if you do not feel well while you are receiving Herceptin SC.

Herceptin SC helps most people with HER2 positive breast cancer but it may have some 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 treatment if you get some of the side effects.

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

Because Herceptin SC may be used with other medicines that treat breast cancer, it may be difficult for your doctor to tell whether the side effects are due to Herceptin SC 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 CMI leaflets for these medicines

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Serious side effects

Serious side effects	What to do
At the time of your injection 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	Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects. These may be serious side effects. You may require urgent medical attention.
After your injection: swelling of your face, lips, tongue or throat with difficulty breathing severe swelling of the hands, feet or legs severe shortness of breath, wheezing or trouble breathing severe chest pain spreading out to the arms, neck, shoulder and/or back abnormal or irregular beating of the heart rash, itching or hives on the skin fever or chills severe coughing	Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects. These are serious side effects. You may require urgent medical attention.

Less serious side effects

Less serious side effects

What to do

After your injection:

pain or reaction at the site of your injection
getting tired more easily after light physical activity, such as walking
shortness of breath, especially when lying down or being woken from your sleep
runny or blocked nose, or nosebleeds
insomnia (difficulty sleeping)
confusion
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)
decrease in or loss of appetite
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)

Speak to your doctor or nurse as soon as possible if you have any of these side effects.

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

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.

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

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

Herceptin SC fixed dose formulation is not for intravenous use and should be given as a subcutaneous injection only.

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

What Herceptin SC contains

Active ingredient
(main ingredient)

Each vial of Herceptin SC contains 600 mg of the active ingredient trastuzumab

The trastuzumab protein is made using Chinese hamster ovary cells

Other ingredients
(inactive ingredients)

histidine hydrochloride monohydrate, histidine, methionine, polysorbate 20, trehalose dihydrate, vorhyaluronidase alfa, water for injections

Do not take this medicine if you are allergic to any of these ingredients.

What Herceptin SC looks like

Herceptin SC for injection is a colourless to yellowish, clear to opalescent solution.

Herceptin SC is supplied as a single vial pack and is available in one strength, 600 mg in 5 mL solution for subcutaneous injection. (Aust R 220402)

Who distributes Herceptin SC

Roche Products Pty Limited
ABN 70 000 132 865
Level 8, 30-34 Hickson Road
Sydney NSW 2000
AUSTRALIA
Medical enquiries: 1800 233 950

This leaflet was prepared in September 2023.

Published by MIMS October 2023

BRAND INFORMATION

Brand name

Herceptin SC

Active ingredient

Trastuzumab

Schedule

1 Name of Medicine

Trastuzumab.

2 Qualitative and Quantitative Composition

Herceptin SC vial contains 600 mg/5 mL of trastuzumab.
For the full list of excipients, see Section 6.1.

3 Pharmaceutical Form

Solution for injection.
Clear to opalescent solution, colourless to yellowish.

4 Clinical Particulars

4.1 Therapeutic Indications

Early breast cancer.

Herceptin SC 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.

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

Metastatic breast cancer.

Herceptin SC 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 postmenopausal patients with hormone-receptor positive metastatic breast cancer.

4.2 Dose and Method of Administration

General.

In order to prevent medication errors, it is important to check the vial labels to ensure the medicine being prepared and administered is Herceptin SC (trastuzumab) and not Kadcyla (trastuzumab emtansine).
It is important to check the labels to ensure the correct formulation (intravenous or subcutaneous) is being administered to the patient as was prescribed. Switching treatment between Herceptin IV and Herceptin SC and vice versa, using a three-weekly (q3w) dosing regimen, was investigated in study MO22982 (PrefHER) (see Section 4.8 Adverse Effects (Undesirable Effects)).
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.
HER2 testing is mandatory prior to initiation of Herceptin SC therapy.

Detection of HER2 protein overexpression or HER2 gene amplification.

Herceptin should only be used in patients whose tumours have HER2 protein overexpression or HER2 gene amplification. Herceptin treatment is only appropriate if there is strong HER2 overexpression, as described by a 3+ score by immunohistochemistry (IHC) or a positive in situ hybridisation (ISH) result. For patients with an intensity score of 2+ on IHC, confirmation of HER2 positive status by ISH is mandatory.
To ensure accurate and reproducible results, testing must be performed in a specialised laboratory, which can ensure validation of the testing procedures.
HER2 protein overexpression should be detected using an IHC-based assessment of fixed tumour blocks. HER2 gene amplification should be detected using ISH of fixed tumour blocks. Examples of ISH include fluorescence in situ hybridisation (FISH), chromogenic in situ hybridisation (CISH) and silver in situ hybridisation (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.

Dosage.

No loading dose is required.
The recommended fixed dose of Herceptin SC is 600 mg, irrespective of the patient's body weight, administered every three weeks.
Duration of treatment. Patients with early or locally advanced breast cancer should be treated for 1 year or until disease recurrence or unmanageable toxicity, whichever occurs first. The optimal dosage regimen and its associated treatment duration have not been defined. However, extending adjuvant treatment beyond one year is not recommended (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Patients with metastatic breast cancer should be treated until progression of disease or unmanageable toxicity.
Missed doses. If the patient misses a dose, it is recommended the next 600 mg dose is administered as soon as possible. The interval between subsequent Herceptin SC injections should not be less than 3 weeks.
Dose modification. No reductions in the dose of Herceptin were made during clinical trials. Patients may continue Herceptin 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.
Special populations.

Use in elderly.

In clinical trials, patients ≥ 65 years of age 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).

Method of administration.

Herceptin SC solution is not to be used for intravenous administration and must be administered via a subcutaneous injection only.
The dose should be administered over 2 - 5 minutes.
The injection site should be alternated between the left and right thigh. New injections should be given at least 2.5 cm from the previous site in healthy skin and never into areas where the skin is red, bruised, tender, or hard. During the treatment course with Herceptin SC, other medications for SC administration should preferably be injected at different sites.
Patients should be observed for fever and chills or other administration associated symptoms (see Section 4.8 Adverse Effects (Undesirable Effects)). Interruption of the injection and/or medication may help to control such symptoms.

Preparation for SC injection.

Herceptin SC solution for injection is for single-use, in one patient only.
The 600 mg/5 mL ready-to-use solution does not need to be diluted. The solution should be inspected visually to ensure there is no particulate matter or discolouration prior to administration.
Herceptin SC does not contain any antimicrobial-preservative; from a microbiological point of view, the medicine should be used immediately. If not being used immediately, preparation should take place in controlled and validated aseptic conditions, and storage of the prepared product should not exceed 24 hours at 2°C to 8°C and 6 hours in total at ambient temperature (do not store above 30°C); also see Section 6.4 Special Precautions for Storage.
After transfer of the solution to the syringe, it is recommended to replace the transfer needle by a syringe closing cap to avoid drying of the solution in the needle and not compromise the quality of the medicinal product. The hypodermic injection needle must be attached to the syringe immediately prior to administration followed by volume adjustment to 5 mL.

4.3 Contraindications

Herceptin 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, Herceptin 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

In the phase III trial BO22227 (HANNAH), which compared the administration of Herceptin IV with Herceptin SC, subjects in the SC arm experienced a higher incidence of serious adverse events and discontinuation of treatment.
The potential impact of such effects should be considered for each patient when deciding to use Herceptin SC (see Section 4.8 Adverse Effects (Undesirable Effects)).

General.

Herceptin therapy should only be initiated under the supervision of a physician experienced in the treatment of cancer patients. Herceptin 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 Herceptin is used concurrently with cytotoxic chemotherapy, the specific guidelines used to reduce or hold the dose of chemotherapy should be followed. Patients may continue Herceptin therapy during periods of reversible chemotherapy induced myelosuppression, renal toxicity or hepatic toxicity.

Cardiac dysfunction.

General considerations. Patients treated with Herceptin 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 Herceptin 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.
The median half-life of trastuzumab following SC administration is 26.5 days, which is similar to the half-life following IV administration (see Section 5.2 Pharmacokinetic Properties). Patients who receive anthracycline after stopping Herceptin may also be at increased risk of cardiac dysfunction. If possible, physicians should avoid anthracycline based therapy for up to 27 weeks after stopping Herceptin. If anthracyclines are used, the patient's cardiac function should be monitored carefully.
Candidates for treatment with Herceptin, especially those with prior anthracycline and cyclophosphamide (AC) exposure, should undergo baseline cardiac assessment including history and physical examination, ECG and echocardiogram, 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 Herceptin.
The concomitant usage of Herceptin SC with other agents which can affect left ventricular function has not been formally studied.
If left ventricular ejection fraction (LVEF) drops 10 percentage points from baseline and to below 50%, Herceptin 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 Herceptin 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 unless the benefits for the individual patient are deemed to outweigh the risks.
The safety of continuation or resumption of Herceptin in patients who experience cardiac dysfunction has not been prospectively studied. If symptomatic cardiac failure develops during Herceptin 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 Herceptin treatment continued on weekly therapy with Herceptin 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 Herceptin. In patients who receive anthracycline containing chemotherapy further monitoring is recommended, and should occur yearly up to 5 years from the last administration of Herceptin, or longer if a continuous decrease of LVEF is observed.
All patients should have a determination of LVEF prior to treatment. Use of Herceptin 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 Herceptin 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 Herceptin.

Adjuvant treatment.

Herceptin 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 Herceptin IV was administered after anthracycline containing chemotherapy compared to administration with a non-anthracycline regimen of docetaxel and carboplatin. The incidence was more marked when Herceptin IV 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, Herceptin treatment, and prior or concurrent use of antihypertensive medications. In patients receiving Herceptin after completion of adjuvant chemotherapy the risk of cardiac dysfunction was associated with a higher cumulative dose of anthracycline given prior to initiation of Herceptin and a high body mass index (> 25 kg/m²).

Neoadjuvant-adjuvant treatment.

Herceptin 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 Herceptin in the neoadjuvant setting, no additional cytotoxic chemotherapy should be given after surgery.
Metastatic breast cancer. Herceptin and anthracyclines should not be given concurrently in the metastatic breast cancer setting.

Hypersensitivity reactions including anaphylaxis.

Severe hypersensitivity reactions have been infrequently reported in patients treated with the Herceptin IV formulation. Signs and symptoms included 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. 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.

Administration related reactions (ARRs).

In BO22227 study, ARRs (known to occur with the administration of Herceptin SC (see Section 4.8 Adverse Effects (Undesirable Effects))) occurred more frequently in the Herceptin SC arm when compared to the Herceptin IV arm (47.8% vs 37.2%) and the majority of events (97% of events in each treatment arm) were grade 1 or 2. The overall rate is in line with the results from other studies where IRR rates of up to 54% have been observed. Grade 3 ARRs were 1.7% and 2.0% in the Herceptin SC and Herceptin IV arms, respectively. Serious ARR's including dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress and supraventricular tachyarrhythmia have been reported in trastuzumab trials (see Section 4.8 Adverse Effects (Undesirable Effects)).
Premedication may be used to reduce risk of occurrence of ARRs.
Patients should be observed for ARRs. 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 treatment.
Patients who are experiencing dyspnoea at rest due to complications of advanced malignancy or co-morbidities may be at increased risk of a fatal reaction. Therefore, these patients should not be treated with Herceptin (see Pulmonary reactions below).

Pulmonary reactions.

Severe pulmonary events leading to death have been reported with the use of Herceptin in the post-marketing setting. These events may occur as part of an ARR (see Administration related reactions (ARRs) above) 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 comorbidities may be at increased risk of pulmonary events. Therefore, these patients should not be treated with Herceptin.

Tumour lysis syndrome (TLS).

Tumour lysis syndrome (TLS) refers to the constellation of metabolic disturbances that may be seen after initiation of effective cancer treatment. It usually occurs in patients with high grade, bulky, rapidly proliferating, treatment-responsive tumours and in patients with acute haematological malignancies.
Cases of possible TLS have been reported in patients treated with Herceptin. Patients with significant tumour burden (e.g. bulky metastases) may be at a higher risk. Patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure which may represent possible TLS. Providers should consider additional monitoring and/or treatment as clinically indicated.

Paediatric use.

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

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 Herceptin in clinical trials. However, greater sensitivity to Herceptin in some older patients cannot be ruled out.

Effects on laboratory tests.

No data available.

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 hepatic impairment.

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

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal drug interaction studies have been performed with Herceptin in humans. Clinically significant interactions with concomitant medication used in clinical trials have not been observed. A comparison of serum levels of Herceptin IV given in combination with cisplatin, doxorubicin or epirubicin-plus-cyclophosphamide has not suggested the possibility of any interaction.
Administration of paclitaxel in combination with IV trastuzumab resulted in a slightly less than twofold decrease in trastuzumab clearance in a nonhuman 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 Herceptin regimen (n = 25) were not altered appreciably, relative to parameters determined during the initiation of paclitaxel, prior to introduction of Herceptin. Similarly, docetaxel pharmacokinetics determined during the first dose of Herceptin in the standard weekly regimen (n = 10) were not altered appreciably relative to those determined 2 weeks earlier for docetaxel alone.
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 22 times higher than that in humans receiving the recommended 600 mg dose every 3 weeks. However, the binding affinity of trastuzumab to epidermal growth factor receptor 2 protein in cynomolgus monkeys is unclear.
(Category D)
Herceptin 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 Herceptin, unless the anticipated benefit for the mother outweighs the unknown risk to the foetus.
In the postmarketing 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 Herceptin.
Women of childbearing potential should be advised to use effective contraception during treatment with Herceptin 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 Herceptin, or becomes pregnant within 7 months following the last dose of Herceptin, close monitoring by a multidisciplinary team is desirable.
Herceptin SC contains vorhyaluronidase alfa (see Section 6.1 List of Excipients). Developmental toxicity studies in mice demonstrated reductions in foetal weight and increases in the number of resorptions following SC injections of vorhyaluronidase alfa. The no effect dose is estimated to be 160 times the dose (normalised to body surface area), to be administered to patients receiving Herceptin subcutaneous formulation.
A study conducted in lactating cynomolgus monkeys dosed with IV 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 exposure to trastuzumab in utero and 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, breastfeeding should be avoided during Herceptin therapy and for 7 months after the last dose of Herceptin.

4.7 Effects on Ability to Drive and Use Machines

Herceptin has a minor influence on the ability to drive and use machines. Dizziness and somnolence may occur during treatment with Herceptin (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients experiencing administration-related symptoms should be advised not to drive or use machines until symptoms resolve completely.

4.8 Adverse Effects (Undesirable Effects)

Table 1 summarises the adverse drug reactions (ADRs) that have been reported in association with the use of Herceptin alone, or in combination with chemotherapy in the below pivotal clinical trials as well as in the post-marketing setting.
The corresponding frequency categories for each adverse drug reaction is based on 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.

Early breast cancer.

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

Locally advanced breast cancer.

MO16432 (NOAH): Herceptin IV arm (n = 115). Control arm (n = 116).
BO22227 (HANNAH): Herceptin IV arm (n = 298). Herceptin SC arm (n = 297).

Metastatic breast cancer (MBC).

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

Advanced gastric cancer (Herceptin SC is not approved for this indication).

BO18255 (ToGA): Herceptin IV 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.
Subcutaneous administration. In the neoadjuvant-adjuvant study BO22227, subjects in the SC arm experienced a higher incidence of serious adverse events (21.9% vs. 15.1%). The higher incidence was predominantly due to a higher incidence of serious infections in the SC arm.
The incidence of discontinuation of Herceptin due to adverse effects was higher in the Herceptin SC arm (2.7% (IV) vs. 5.7% (SC)). The overall incidence of discontinuation due to left ventricular dysfunction (LVD) was 2.0% (SC) vs. 1.0% (IV).
Herceptin SC administration was also associated with a higher incidence of administration related reactions (ARRs) (48% vs. 37%) such as rash, erythema and cough. Antibodies to trastuzumab also developed more commonly in the Herceptin SC arm (14.6% vs. 7.1%). The clinical relevance of these antibodies is unknown. However, the pharmacokinetics, efficacy, or safety of Herceptin SC did not appear to be adversely affected by these antibodies and no relationship could be identified.
The potential impact of such effects should be considered for each patient when deciding to use Herceptin SC (see Section 4.4 Special Warnings and Precautions for Use).

Switching treatment from Herceptin IV to Herceptin SC and vice versa.

Study MO22982 (PrefHER) investigated switching from Herceptin IV to Herceptin SC, and vice versa, in patients with HER2 positive EBC, with a primary objective to evaluate patient preference for either Herceptin IV infusion or Herceptin SC injection. This trial investigated using a 2 arm, crossover design with patients being randomised to one of two different q3w Herceptin treatment sequences (Herceptin IV (cycles 1-4) followed by Herceptin SC (cycles 5-8), or Herceptin SC (cycles 1-4) followed by Herceptin IV (cycles 5-8)). Patients participating in this trial could be enrolled at any time as long as there were at least 10 remaining cycles of Herceptin in their planned treatment regimen, therefore patients were either naive to Herceptin IV treatment (20.3%) or pre-exposed to Herceptin IV (79.7%) as part of ongoing adjuvant treatment for HER2 positive EBC. Overall, switches from Herceptin IV to Herceptin SC and vice versa were well tolerated. Pre-switch rates (cycles 1-4) for SAEs, grade 3 AEs and treatment discontinuations due to AEs were low (< 5%) and similar to postswitch rates (cycles 5-8). No grade 4 or grade 5 AEs were reported. The effect of multiple switches back and forth was not investigated.

Herceptin SC safety and tolerability in EBC patients.

In a study (study MO28048 SafeHer) investigating the safety and tolerability of Herceptin SC as adjuvant therapy in 1868 patients with HER2 positive EBC no new safety signals were identified. Results were consistent with the known safety profile for Herceptin IV and Herceptin SC. In addition, treatment of lower bodyweight patients with Herceptin SC fixed dose in adjuvant EBC was not associated with increased safety risk, AEs and SAEs, compared to the higher bodyweight.
Infusion/ administration related reactions (IRRs/ ARRs) and hypersensitivity. IRRs/ ARRs such as chills and/or fever, dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress were seen in trastuzumab clinical trials (see Section 4.4 Special Warnings and Precautions for Use).
In the neoadjuvant-adjuvant study BO22227, the rate of ARRs was 47.8% in the Herceptin SC arm, compared to 37.2% in the Herceptin IV arm. Severe grade 3 events IRR/ ARR events were 2.0% and 1.7% in the Herceptin IV and Herceptin SC arms, respectively. There were no grade 4 or 5 IRRs/ ARRs.
IRRs may be clinically difficult to distinguish from hypersensitivity reactions.
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 Herceptin. 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 Herceptin (see Section 4.4 Special Warnings and Precautions for Use).

Locally advanced breast cancer (neoadjuvant-adjuvant setting).

In study BO22227, when Herceptin was administered concurrently with neoadjuvant chemotherapy that contained four cycles of epirubicin (cumulative dose 300 mg/m²), at a median follow-up exceeding 70 months the incidence of cardiac failure/ congestive heart failure was 0.3% in the Herceptin IV arm and 0.7% in the Herceptin SC arm. In patients with lower bodyweights (< 59 kg, the lowest bodyweight quartile), the fixed dose used in the Herceptin SC arm was not associated with an increased risk of cardiac events or significant drop in LVEF.
In study MO16432 (NOAH), Herceptin IV was administered concurrently with neoadjuvant chemotherapy containing 3-4 cycles of a neoadjuvant anthracycline (cumulative doxorubicin dose 180 mg/m²) overall, the incidence of symptomatic cardiac dysfunction was 1.7% in the Herceptin IV arm.

Early breast cancer (adjuvant setting).

In 3 pivotal clinical trials of adjuvant Herceptin IV 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 Herceptin IV sequentially to a taxane (0.3-0.4%). The rate was highest in patients who were administered Herceptin IV concurrently with a taxane (2.0%). At 3 years, the cardiac event rate in patients receiving AC followed by P (doxorubicin plus cyclophosphamide followed by paclitaxel) + H (Herceptin IV) was estimated at 3.2%, compared with 0.8% in AC followed by 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 followed by D (doxorubicin plus cyclophosphamide, followed by docetaxel), AC followed by DH (doxorubicin plus cyclophosphamide, followed by docetaxel plus trastuzumab), and DCarbH (docetaxel, carboplatin and Herceptin IV) 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 followed by D, AC followed by DH, and DCarbH treatment arms, respectively. The overall risk of developing symptomatic cardiac events was low and similar for patients in AC followed by D and DCarbH arms; relative to both the AC followed by D and DCarbH arms there was an increased risk of developing a symptomatic cardiac event for patients in the AC followed by DH arm, being discernable 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 followed by D and DCarbH).
When Herceptin IV 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 Herceptin IV 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 Herceptin IV therapy (combined analysis of the two Herceptin IV 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 Herceptin IV treated patients. Reversibility of mild symptomatic and asymptomatic left ventricular dysfunction was demonstrated for 79.5% of Herceptin IV treated patients. Approximately 17% of cardiac dysfunction related events occurred after completion of Herceptin IV.
In the joint analysis of studies NSABP B-31 and NCCTG N9831, with a median follow-up of 8.1 years for the AC followed by PH group (doxorubicin plus cyclophosphamide, followed by paclitaxel plus trastuzumab); in patients with a symptomatic CHF event in the AC followed by PH arm, 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 Herceptin + paclitaxel subgroup, compared with 1-4% for the paclitaxel alone subgroup. For Herceptin monotherapy, the rate was 6-9%. The highest rate of cardiac dysfunction was seen in patients receiving concurrent Herceptin + 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 Herceptin 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.
Haematological toxicity.

Monotherapy (study H0649g).

Haematological toxicity is infrequent following the administration of Herceptin as monotherapy in the metastatic setting, WHO grade 3 leucopenia, 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 Herceptin and an anthracycline/ cyclophosphamide compared to an incidence of 62% in patients treated with the anthracycline/ cyclophosphamide combination without Herceptin.
There was an increase in WHO grade 3 or 4 haematological toxicity in patients treated with the combination of Herceptin and paclitaxel compared with patients receiving paclitaxel alone (34% vs. 21%). Haematological toxicity was also increased in patients receiving Herceptin 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 Herceptin + 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 Herceptin treated patients experienced a shift of 3 or 4 grades from baseline, compared with 0.6% in the observation arm.
Hepatic and renal toxicity.

Monotherapy (study H0649g).

WHO Grade 3 or 4 hepatic toxicity was observed in 12% of patients following administration of Herceptin 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 Herceptin and an anthracycline/ cyclophosphamide compared with an incidence of 8% in patients treated with the anthracycline/ cyclophosphamide combination without Herceptin. No WHO grade 3 or 4 renal toxicity was observed.
WHO grade 3 or 4 hepatic toxicity was less frequently observed among patients receiving Herceptin and paclitaxel than among patients receiving paclitaxel alone (7% vs. 15%). No WHO grade 3 or 4 renal toxicity was observed.
Diarrhoea.

Monotherapy (study H0649g).

Of patients treated with Herceptin 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 Herceptin in combination with chemotherapy compared with patients receiving chemotherapy alone or Herceptin alone.

Early setting (HERA study).

In the HERA trial, 8% of Herceptin treated patients experienced diarrhoea during the first year of treatment.
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 Herceptin IV + chemotherapy compared with patients receiving chemotherapy alone or Herceptin IV alone. In study BO22227, subjects in the SC arm experienced a higher incidence of serious infections with or without neutropenia (4.4% versus 8.1%).
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. In a neoadjuvant-adjuvant breast cancer trial (BO22227) at a median follow-up exceeding 70 months 15.9% (47/295) of patients treated with Herceptin SC developed antibodies against trastuzumab.
Neutralising anti-trastuzumab antibodies were detected in post-baseline samples in 3 of 47 Herceptin patients. The clinical relevance of these antibodies is not known. The presence of anti-trastuzumab antibodies had no impact on 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 trastuzumab IV or SC.

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 www.tga.gov.au/reporting-problems.

4.9 Overdose

Single doses of up to 960 mg have been administered with no reported untoward effect.
Treatment of overdose should consist of general supportive measures.
For information on the management of overdose, contact the Poisons Information Centre (in Australia call 13 11 26, in New Zealand call 0800 767 766).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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

Mechanism of action.

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 humanised antibody (trastuzumab) is likely also to have antiproliferative activity in vivo against human breast tumours expressing high levels of HER2.

Clinical trials.

Early breast cancer.

Early breast cancer is defined as nonmetastatic, primary, invasive carcinoma of the breast.

Herceptin IV in combination with adjuvant chemotherapy.

The use of adjuvant Herceptin IV in the setting of early breast cancer (after surgery and in association with chemotherapy and, if applicable, radiotherapy) has been studied in four multicentre randomised 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 summarised in Table 2 and efficacy results are presented in Tables 2-7.

The HERA trial was designed to compare 1 and 2 years of 3 weekly Herceptin IV 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 Herceptin IV treatment vs. 1 year Herceptin IV treatment was performed. Patients assigned to receive Herceptin IV 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 summarised in Table 3.

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 Herceptin IV vs. 5.5% with observation).
In the final analysis (8 year median follow-up) extending Herceptin IV 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 summarised in Table 4.

The preplanned 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 followed by PH group). At 8 years, the survival rate was estimated to be 86.9% in the AC followed by PH arm and 79.4% in the AC followed by 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 summarised in Table 5.

The efficacy results from the BCIRG 006 are summarised in Tables 6 and 7.

Based on studies to date, the optimal duration of adjuvant trastuzumab therapy is 1 year, and may be clarified in further randomised trials. However, extending adjuvant treatment beyond 1 year is not recommended (see Section 4.2 Dose and Method of Administration).

Switching treatment from Herceptin IV to Herceptin SC and vice versa.

Study MO22982 (PrefHER) investigated switching from Herceptin IV to Herceptin SC, and vice versa, in patients with HER2 positive EBC, with a primary objective to evaluate patient preference for either Herceptin IV infusion or Herceptin SC injection. This trial investigated using a 2 arm, crossover design with patients being randomised to one of two different q3w Herceptin treatment sequences (Herceptin IV (cycles 1-4) followed by Herceptin SC (cycles 5-8), or Herceptin SC (cycles 1-4) followed by Herceptin IV (cycles 5-8)). Patients participating in this trial could be enrolled at any time as long as there were at least 10 remaining cycles of Herceptin in their planned treatment regimen, therefore patients were either naive to Herceptin IV treatment (20.3%) or pre-exposed to Herceptin IV (79.7%) as part of ongoing adjuvant treatment for HER2 positive EBC. Overall, switches from Herceptin IV to Herceptin SC and vice versa were well tolerated. Preswitch rates (cycles 1-4) for SAEs, grade 3 AEs and treatment discontinuations due to AEs were low (< 5%) and similar to postswitch rates (cycles 5-8). No grade 4 or grade 5 AEs were reported. The effect of multiple switches back and forth was not investigated (see Section 4.8 Adverse Effects (Undesirable Effects)).

Herceptin SC safety and tolerability in EBC patients.

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.
Herceptin in combination with neoadjuvant-adjuvant chemotherapy. In the neoadjuvant-adjuvant setting Herceptin has been evaluated in 2 phase III studies.

Study BO22227 (HANNAH).

Study BO22227 (HANNAH) was conducted to demonstrate noninferiority of Herceptin SC vs. Herceptin IV. Steady-state (predose cycle 8) serum trastuzumab C_trough values and pCR were coprimary endpoints. Secondary endpoints included event free survival and overall survival for which the study was not powered to measure differences between treatment arms. Patients with HER2 positive operable or locally advanced breast cancer (LABC) including inflammatory breast cancer received 8 cycles of either Herceptin SC or Herceptin IV concurrently with chemotherapy (four cycles of docetaxel 75 mg/m² followed by four cycles of a FEC combination regimen comprising fluorouracil 500 mg/m², epirubicin 75 mg/m², and cyclophosphamide 500 mg/m²), followed by surgery, and continued therapy with Herceptin SC or Herceptin IV, as originally randomised, for an additional 10 cycles for a total of 1 year of treatment. In HANNAH, in the majority of cases, it was retrospectively determined that the pathologist assessing the primary specimens and nodes was masked to treatment allocation and no supplemental independent review was performed.
The coprimary endpoint, pCR as defined by the absence of invasive neoplastic cells in the breast, resulted in rates of 40.7% (95% CI: 34.7, 46.9) in the Herceptin IV arm and 45.4% (95% CI: 39.2%, 51.7%) in the Herceptin SC arm, a difference of 4.7% in favour of the Herceptin SC arm. The lower boundary of the 1-sided 97.5% CI for the difference in pCR rates was -4.0, whereas the predefined noninferiority margin was -12.5%, confirming the noninferiority of Herceptin SC compared to the Herceptin IV based on this endpoint. The PK coprimary endpoint was C_trough, at predose cycle 8 selected to ensure that the minimum serum concentration after the Herceptin SC fixed dosing should be at least as high as that after Herceptin IV weight based dosing (i.e. comparable receptor saturation). For the results of the PK coprimary endpoint, see Section 5.2 Pharmacokinetic Properties.
Analyses with longer-term follow-up of a median duration exceeding 40 months supported the noninferior efficacy of Herceptin SC compared to Herceptin IV with comparable results of both EFS and OS (3 year EFS rates of 73% in the Herceptin IV arm and 76% in the Herceptin SC arm, and 3 year OS rates of 90% in the Herceptin IV arm and 92% in the Herceptin SC arm). The final analysis at a median follow-up exceeding 70 months showed similar EFS and OS between patients who received Herceptin IV and those who received Herceptin SC. The 6-year EFS was 65% in both arms (ITT population: HR=0.98 [95% CI: 0.74; 1.29]) and the OS rate 84% in both arms (ITT population: HR=0.94 [95% CI: 0.61; 1.45]).

Study MO16432 (NOAH).

Study MO16432 (NOAH) is a multicentre randomised trial, designed to investigate the concurrent administration of Herceptin IV with neoadjuvant chemotherapy, including both an anthracycline and a taxane, followed by adjuvant Herceptin IV, 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 randomised to receive either neoadjuvant chemotherapy concurrently with neoadjuvant-adjuvant Herceptin IV (n = 116), or neoadjuvant chemotherapy alone (n = 118). Herceptin IV was administered concurrently with 10 cycles of neoadjuvant chemotherapy as follows:
doxorubicin (60 mg/m²) and paclitaxel (150 mg/m²) in combination with Herceptin IV (8 mg/kg loading dose, followed by 6 mg/kg maintenance, administered 3 weekly) for 3 cycles;
followed by paclitaxel (175 mg/m²) and Herceptin IV (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 Herceptin IV (6 mg/kg administered 3 weekly);
followed by up to 7 additional cycles of Herceptin IV (6 mg/kg, administered 3 weekly) alone to complete 1 year after starting Herceptin.
The primary endpoint for the trial, event free survival (EFS), was defined as the time from randomisation 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 randomised in the trial following the intent to treat principle, with the exception of 3 patients whose data could not be evaluated) are summarised in Table 8. The median duration of follow-up in the Herceptin IV arm was 3.8 years.

The addition of Herceptin IV to neoadjuvant chemotherapy, followed by adjuvant Herceptin IV 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 Herceptin arm.

Metastatic breast cancer.

There are no data available to establish the efficacy of Herceptin for the treatment of metastatic disease in patients who have previously received the medicine for the treatment of localised disease.
The safety and efficacy of Herceptin IV has been studied in randomised, 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 hybridisation (FISH) test (see Section 4.2 Dose and Method of Administration).
Herceptin IV in combination with chemotherapy. Study H0648g was an open label, randomised controlled, multinational trial of chemotherapy alone and in combination with Herceptin. 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 Herceptin or paclitaxel (175 mg/m² infused over 3 hours) with or without Herceptin. Patients on Herceptin IV treatment received 4 mg/kg 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 naive were treated with an anthracycline + cyclophosphamide.
The prospectively defined, primary intent to treat analysis indicated that the combination of Herceptin 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 Herceptin 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 Herceptin treatment, although the effect appeared to be greater in the paclitaxel stratum. The efficacy of Herceptin treatment was further supported by the secondary endpoints of response rate, duration of response and one year survival (see Table 9).
One year survival rates (the prospectively defined survival endpoint) were significantly better for the Herceptin + 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 Herceptin + 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 Herceptin 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] (see also Figures 1 and 2). The analysis of overall survival was, however, greatly confounded by subsequent Herceptin 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 Herceptin). Hence, the survival advantage seen above, for Herceptin + chemotherapy treatment versus chemotherapy alone (which includes patients who subsequently received Herceptin) 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 Herceptin + 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 Herceptin + chemotherapy, while it remained low in the chemotherapy alone arm (see Figure 3).

Study M77001 was a multinational, multicentre, randomised, controlled trial investigating the safety and efficacy of Herceptin 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 Herceptin IV (4 mg/kg loading dose, followed by 2 mg/kg weekly). Sixty percent of patients had received prior anthracycline based adjuvant chemotherapy. Herceptin IV 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 Herceptin IV + 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 9). 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).

Herceptin IV in combination with anastrozole. The TAnDEM trial was a multicentre, randomised, open label, phase III trial comparing Herceptin + 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 postmenopausal patients. Two hundred and seven patients were randomised to receive oral anastrozole (1 mg/day) with or without Herceptin IV (4 mg/kg loading dose, followed by 2 mg/kg weekly). Patients who had received Herceptin for localised disease were excluded from this trial.
Median progression free survival (PFS) was doubled in the Herceptin + 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 Herceptin + 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 Herceptin containing regimen after progression of disease.
Herceptin IV monotherapy. Study H0649g was a multinational, multicentre, single arm trial of Herceptin 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 pretreated. 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 Herceptin IV on day 0, followed by weekly IV infusions of 2 mg/kg until there was evidence of disease progression. Patients who developed progressive disease could stop treatment, continue on the Herceptin IV 2 mg/kg weekly dose or receive an increased IV dose of 4 mg/kg, as the investigator deemed appropriate. The primary efficacy parameter was tumour response rate.
Herceptin 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 10).

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 Herceptin 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 Herceptin monotherapy is based upon response rates. No data are available to demonstrate improvement in survival or quality of life.

5.2 Pharmacokinetic Properties

Subcutaneous (SC) formulation.

The pharmacokinetics of trastuzumab in Herceptin IV and SC formulations were compared in the phase III trial BO22227 (HANNAH) (SC formulation: fixed dose of 600 mg administered 3 weekly; IV formulation: 8 mg/kg loading dose, 6 mg/kg maintenance dose every 3 weeks). The pharmacokinetic results for the coprimary endpoint, C_trough predose cycle 8, showed noninferiority of steady-state C_trough values for the Herceptin SC arm (fixed dosing) compared to the Herceptin IV arm (bodyweight adjusted dosing).
The mean observed steady-state trough serum trastuzumab concentration during the neoadjuvant treatment phase, at the predose cycle 8 time point, was higher in the Herceptin SC arm than the IV arm, with mean observed values of 78.7 microgram/mL (standard deviation (SD): 43.9 microgram/mL) as compared to 57.8 microgram/mL (SD: 30.3 microgram/mL). During the adjuvant phase of treatment, at the predose cycle 13 time point, the mean observed trastuzumab concentration values, were 90.4 microgram/mL (SD: 41.9 microgram/mL) and 62.1 microgram/mL (SD: 37.1 microgram/mL), respectively for the Herceptin SC and Herceptin IV arms. While approximate steady-state concentrations with the Herceptin IV or Herceptin SC formulations were reached at predose cycle 8, observed concentrations with the Herceptin SC formulation tended to increase slightly up to predose cycle 13. The mean observed serum trastuzumab concentration at predose cycle 18 was: 90.7 microgram/mL, similar to that at predose cycle 13, suggesting no further increase after cycle 13.
The median T_max following Herceptin SC cycle 7 administration was approximately 3 days, with high variability (range 1-14 days). The mean C_max was expectedly lower in the Herceptin SC arm (149 microgram/mL) than in the Herceptin IV arm (end of infusion value: 221 microgram/mL).
The mean observed AUC_{0-21 days} following the cycle 7 dose was approximately 10% higher with Herceptin SC as compared to the Herceptin IV formulation. With the Herceptin IV and Herceptin SC formulations, bodyweight had an influence on the predose cycle 8 serum trastuzumab concentration and AUC_{0-21 days} values. In patients with bodyweight (BW) below 51 kg (10^th percentile), the mean steady-state AUC of trastuzumab following the cycle 7 dose was about 80% higher after Herceptin SC than after Herceptin IV treatment. Whereas in the highest BW group, above 90 kg (90^th percentile) AUC was 20% lower after Herceptin SC than after Herceptin IV treatment. Across BW subsets, patients who received Herceptin SC had a predose trastuzumab concentration and AUC_{0-21 days} values that were comparable to, or higher than observed in patients who received Herceptin IV. Multiple logistic regression analyses showed no correlation of trastuzumab exposure values to efficacy (pCR) or safety results, and dose adjustment for bodyweight is not needed.
A population PK model with parallel linear and nonlinear elimination from the central compartment was constructed using pooled Herceptin SC and Herceptin IV PK data from the HANNAH (BO22227) study. The model described the observed PK profiles following Herceptin IV and Herceptin SC administration in the study's patient population: operable or locally advanced breast cancer (LABC). Bioavailability of the subcutaneous formulation was estimated to be 77.1%. Linear elimination clearance (linear CL) was 0.111 L/day and the central compartment volume (Vc) was 2.91 L.
The population predicted PK exposure parameter values (with 5^th-95^th percentiles) for Herceptin SC dosing regimen in EBC patients are shown in Table 11.

Intravenous (IV) formulation.

Information in this section reports data from the Herceptin product information for the intravenous formulation.
The pharmacokinetics of trastuzumab were evaluated in a population pharmacokinetic model analysis using pooled data from 1,582 patients from 18 phase I, II and III trials receiving Herceptin IV to treat a range of cancers, but mostly breast and gastric cancer. A two compartment model with parallel linear and nonlinear elimination from the central compartment described the trastuzumab concentration time profile. Due to the nonlinear elimination, total clearance increased with decreasing concentrations. Linear clearance was 0.127 L/day for breast cancer (metastatic and early). 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.
The population predicted PK exposures (with 5^th-95^th percentiles) and PK parameter values at clinically relevant concentrations (C_max and C_min) for breast cancer patients treated with the approved q1w and q3w dosing regimens are shown in Table 12 (cycle 1) and Table 13 (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 of the IV formulation 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 Herceptin have been conducted to date.

6 Pharmaceutical Particulars

6.1 List of Excipients

Vorhyaluronidase alfa (an enzyme used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously), histidine hydrochloride monohydrate, histidine, trehalose dihydrate, polysorbate 20, methionine, water for injections.

6.2 Incompatibilities

No incompatibilities between Herceptin and the following materials have been observed: propylene or polycarbonate syringe, stainless steel transfer, injection needles, polyethylene luer cones stoppers.

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.

6.4 Special Precautions for Storage

Store Herceptin SC vials at 2°C to 8°C. Refrigerate. Do not freeze. Store in the original package in order to protect from light. Do not use beyond the expiration date stamped on the vial.
From a microbiological point of view, Herceptin SC solution should be used immediately. Once transferred from the vial to the syringe, the product is physically and chemically stable at 2 to 8°C for 24 hours.
Once removed from the refrigerator, Herceptin SC solution in the vial or transferred to syringe should not be kept for more than 6 hours in total at ambient temperature (do not store above 30°C).

6.5 Nature and Contents of Container

Herceptin SC solution for injection is a ready-to-use solution (600 mg/5 mL) supplied as one single use vial.
Herceptin is also available as a sterile single-dose vial, white to pale yellow, preservative-free lyophilised powder for IV infusion containing 60 mg or 150 mg of trastuzumab (See separate Herceptin Powder for Intravenous (IV) Infusion Product Information).

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.
The following points should be strictly adhered to regarding the use and disposal of syringes and other medicinal sharps:
needles and syringes should never be reused;
place all used needles and syringes into a sharps container (puncture proof disposable container).

6.7 Physicochemical Properties

Chemical structure.

Herceptin (trastuzumab) is a recombinant DNA derived humanised 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 humanised 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.

CAS number.

180288-69-1.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

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