Consumer medicine information

Erbitux

Cetuximab

BRAND INFORMATION

Brand name

Erbitux

Active ingredient

Cetuximab

Schedule

SUMMARY CMI

ERBITUX^®

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 ERBITUX?

ERBITUX contains the active ingredient cetuximab. ERBITUX is used to treat metastatic colorectal cancer, locally advanced head and neck cancer, and recurrent/metastatic head and neck cancer.

For more information, see Section 1. Why am I using ERBITUX? in the full CMI.

2. What should I know before I use ERBITUX?

Do not use if your cancer cells have been found to contain a mutated form of the RAS gene, if your RAS status is not known, or if you have ever had an allergic reaction to ERBITUX or any of the ingredients listed at the end of the CMI.

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 ERBITUX? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ERBITUX 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 do I use ERBITUX?

Before receiving the first dose, you should be given anti-allergy medicines (an antihistamine and a corticosteroid) at least 1 hour prior to receiving ERBITUX.
The first dose is approximately 2 hours via infusion. The following doses are every week (1 hour infusion period) or every 2 weeks (2 hours infusion period).

More instructions can be found in Section 4. How do I use ERBITUX? in the full CMI.

5. What should I know while using ERBITUX?

Things you should do	Remind any doctor, nurse, dentist or pharmacist you visit that you are using ERBITUX. Maintain adequate contraception during treatment and for two months after your last dose. Limit your exposure to sunlight. Wear a hat, protective clothing and sunscreen when you go outside. Keep all appointments with your doctor so that your progress can be checked.
Driving or using machines	Treatment-related symptoms can affect your concentration and ability to react. Be careful until you know how ERBITUX affects you.

For more information, see Section 5. What should I know while using ERBITUX? in the full CMI.

6. Are there any side effects?

Common side effects include headache; conjunctivitis; diarrhoea; nausea; vomiting; skin reactions; low magnesium/calcium levels in the blood; dehydration; loss of appetite, leading to weight loss; infusion-related reactions; sore, red mouth (which may lead to nosebleeds); tiredness; increased infections in combination with chemotherapy; increased radiation-related effects in combination with radiotherapy; increased liver enzyme levels.

Serious side effects include inflammation of the lining of the brain; blood clots; lung inflammation; severe blistering or peeling of the skin; skin infections; heart failure/attack; low white cell count.

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

ERBITUX^®

Active ingredient(s): cetuximab (rmc)

Consumer Medicine Information (CMI)

This leaflet provides important information about using ERBITUX. 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 ERBITUX.

Where to find information in this leaflet:

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

1. Why am I using ERBITUX?

ERBITUX contains the active ingredient cetuximab. ERBITUX is a monoclonal antibody. Monoclonal antibodies are proteins that specifically recognise and attach to other unique proteins.

When a growth factor called an epidermal growth factor (EGF) attaches to an epidermal growth factor receptor (EGFR), it turns on signals within the cell causing it to grow and divide to form more cells. In many human tumours, there is an over-activation of these receptors, which leads to increased uncontrolled growth of cancer cells and development into a tumour. ERBITUX attaches to the EGFR more tightly than EGF and thereby interferes with the growth of cancer cells.

ERBITUX is used to treat:

Metastatic colorectal cancer (cancer of the colon or large intestine and rectum that has spread to other parts of the body). It may be used alone or in combination with certain types of medicines called chemotherapy.
Locally advanced head and neck cancer, in combination with radiation therapy.
Recurrent/metastatic head and neck cancer (cancer of the head and neck that has reoccurred or spread to other parts of the body) in combination with certain types of chemotherapy.

2. What should I know before I use ERBITUX?

If you have metastatic colorectal cancer, your doctor will order tests to see if ERBITUX is suitable for you. The test will check if your cancer cells contain either the normal (wild-type) or mutated forms of genes called RAS. ERBITUX is used to treat patients who express normal RAS genes.

Warnings

Do not use ERBITUX if:

You are allergic to cetuximab, or any of the ingredients listed at the end of this leaflet. If you have had an allergic reaction to ERBITUX, your doctor will decide whether or not you can receive it again. This will depend on the severity of your reaction.
Always check the ingredients to make sure you can use this medicine.
If your cancer cells have been found to contain a mutated form of the RAS gene or if your RAS status is not known (particularly, in combination with anticancer treatments containing oxaliplatin).

Check with your doctor if you have any other medical conditions, including:

abnormal blood test results
liver problems
kidney problems
heart problems. If you have heart problems, your doctor will discuss with you whether you can receive ERBITUX in combination with other anticancer medicines, especially if you are 65 years of age or older.
lung problems or difficulty in breathing
acute or worsening eye problems such as blurred vision, eye pain, red eyes and/or severe dry eye, or if you use contact lenses.
history of allergy to red meat, tick bites or to α-1-galactose

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 and breastfeeding

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

ERBITUX is not recommended for use during pregnancy. Make sure you maintain adequate contraception during treatment and for two months after your last dose.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

You should not breastfeed during treatment and for 2 months after your last dose.

If it is necessary for you to use ERBITUX, your doctor will discuss the risks and benefits of having it if you are pregnant or breastfeeding.

Use in children

The effectiveness of ERBITUX in children under the age of 18 years has 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 or health food shop.

Some medicines may interfere with ERBITUX and affect how it works.

If your doctor is giving you other medicines, such as chemotherapy, with ERBITUX, or is also treating you with radiation, he/she will discuss with you the benefits and risks involved. If you receive ERBITUX in combination with chemotherapy medicines, ask your doctor or pharmacist for the Consumer Medicine Information for these medicines.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect ERBITUX.

4. How do I use ERBITUX?

Before receiving the first dose, you should be given anti-allergy medicines (an antihistamine and a corticosteroid) at least 1 hour prior to receiving ERBITUX to minimise the chances of an allergic reaction. Pre-treatment with an antihistamine and a corticosteroid is also recommended for the following doses.

Your doctor may also prescribe oral antibiotics or a topical steroid cream for your skin before you are given ERBITUX. This may help prevent or minimise skin reactions.

How much to use

A doctor experienced in the use of medicines for cancer will supervise your treatment with ERBITUX. Trained nurses will administer ERBITUX to you.
ERBITUX may be administered either diluted or undiluted. Your doctor will determine the dilution for you.
Your doctor will calculate the correct dose of ERBITUX for you because it depends on your body surface area (a measurement based on your height and weight).
The first dose is given over a period of approximately 2 hours via infusion.
The following doses are infused over a period of approximately 1 hour for weekly infusions or 2 hours for every two week infusions.
Your doctor will decide how long you will receive ERBITUX based on your response to the medicine and the type of cancer you have.

When to use ERBITUX

ERBITUX is either given once a week or once every two weeks by intravenous infusion (slow injection into a vein).
If you are being treated with a chemotherapy medicine in combination with ERBITUX, the chemotherapy medicine can only be started 1 hour after the end of the ERBITUX infusion.

If you use too much ERBITUX

As ERBITUX is given to you under the supervision of your doctor, it is very unlikely that you will receive too much.

However, if you think that you have been given too much ERBITUX, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using ERBITUX?

Things you should do

Keep all appointments with your doctor so that your progress can be checked. Your doctor may also conduct blood tests before starting ERBITUX and from time to time during treatment. This is to make sure the medicine is working and to check for unwanted side effects.

If you miss an appointment, call your healthcare provider to reschedule.

Limit your exposure to sunlight by wearing a hat, protective clothing and SPF 30+ or higher sunscreen when you go outside. Sun exposure may make your skin reactions worse.

Call your doctor straight away if you:

become pregnant while you are treated with ERBITUX

Remind any doctor, nurse, dentist or pharmacist you visit that you are using ERBITUX.

Driving or using machines

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

Treatment-related symptoms can affect your concentration and ability to react.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

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

Tell your doctor or nurse as soon as possible if you do not feel well while you are having ERBITUX.

Less serious side effects

Less serious side effects

What to do

Infusion-related:

Fever, chills, shortness of breath, dizziness

To recognise early signs of these side effects, you will be monitored closely while you are receiving each infusion and for at least 1 hour afterwards.
Your doctor may consider reducing the infusion rate of ERBITUX in order to manage these symptoms.
Sometimes these side effects may occur up to several hours later.
If you experience them any time after receiving ERBITUX, contact your doctor or nurse.
Skin-related:

Acne-like rash
Itchy, dry, scaling skin
Excessive growth of hair on your body
Nail problems

These skin-related side effects can develop within the first three weeks of treatment. They usually disappear over time after the end of ERBITUX therapy.
Other:

headache
red, watery eye(s) which can be accompanied by pain and blurring of your vision, eye sore, severe dry eye(s) or crusty eyelids
abdominal pain or diarrhoea
weakness, fatigue, loss of appetite, weight loss, vomiting or nausea (feeling sick). These symptoms may be due to low levels of magnesium, calcium, other electrolytes or high levels of liver enzymes in your blood.
feeling dehydrated
sore, red or dry mouth, which may be accompanied by a nosebleed
signs of frequent infections such as fever, tiredness, chills, sore throat or mouth ulcers
chest pain or tightness
sudden-onset fever, severe headache, vomiting, stiff neck and sensitivity to light.

In combination with radiation therapy:

sore, red or dry mouth, which may be accompanied by a nosebleed
severe flaking or peeling of the skin
difficulty swallowing

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

Infusion-related:

Asthma-like symptoms such as severe breathing difficulties with wheezing, hoarseness, hives and difficulty speaking.
A rapidly developing lumpy rash, chest pain, leg pain, feeling dizzy or faint.

Skin-related:

Severe blistering or peeling of the skin (Stevens-Johnson syndrome)
Already affected areas of your skin getting worse, especially if you also experience general signs of infection such as fever and tiredness.

Tell your doctor if you notice any other extensive skin rash. Depending on how severe your skin reaction is and how often it occurs, your doctor may:

stop ERBITUX for up to 2 weeks before giving you the next dose,
administer a lower dose, or
stop treatment altogether.

Other:

sudden or worsened breathing difficulties, especially with cough or fever (lung inflammation)
inflammation of the lining of the brain (aseptic meningitis)
leg swelling or pain (signs of a blood clot)
blood clots in the lungs

In combination with chemotherapy:

signs of frequent infections such as fever, tiredness, chills, sore throat or mouth ulcers (reduced white blood cell count, which can lead to fever, pneumonia, and infection in the blood).
chest pain (symptom of heart attack or heart failure)
redness and swelling of the palms of the hands or the soles of the feet which may cause the skin to peel (hand-foot syndrome).

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.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

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.

What ERBITUX contains

Active ingredient (main ingredient)	Cetuximab (rmc)
Other ingredients (inactive ingredients)	Glycine, polysorbate 80, citric acid monohydrate, sodium chloride, water for injections, sodium hydroxide
Potential allergens	N/A

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

What ERBITUX looks like

ERBITUX is a clear to slightly opalescent, colourless to yellowish solution. It is supplied in 20 mL or 100 mL colourless glass vials with a rubber stopper and aluminium seal. Each pack contains 1 vial. (Aust R 132393, 132396).

Who distributes ERBITUX

Merck Healthcare Pty Ltd
Suite 1, Level 1
Building B
11 Talavera Road
Macquarie Park NSW 2113
Medical Information: 1800 633 463

Healthcare Logistics
58 Richard Pearse Drive
Airport Oaks
Auckland
Medical Information: 0800 426 252

This leaflet was prepared in November 2023.

Erbitux^® is a trademark of ImClone LLC, used under license by Merck KGaA and its affiliates.

Published by MIMS December 2023

BRAND INFORMATION

Brand name

Erbitux

Active ingredient

Cetuximab

Schedule

1 Name of Medicine

Cetuximab (rmc).

2 Qualitative and Quantitative Composition

Each 20 mL vial contains 100 mg cetuximab.
Each 100 mL vial contains 500 mg cetuximab.
Each mL solution contains 5 mg cetuximab.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Erbitux is a sterile, preservative-free, clear to slightly opalescent, colourless to yellowish solution that is intended for intravenous infusion.

4 Clinical Particulars

4.1 Therapeutic Indications

Erbitux is indicated for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing, RAS wild-type metastatic colorectal cancer:
in combination with infusional 5-fluorouracil/folinic acid plus irinotecan;
in combination with irinotecan in patients who are refractory to first-line chemotherapy;
in first-line in combination with FOLFOX;
as a single agent in patients who have failed or are intolerant to oxaliplatin based therapy and irinotecan based therapy.
(See Clinical trials.)
Erbitux is indicated for the treatment of patients with squamous cell cancer of the head and neck:
in combination with radiation therapy for locally advanced disease;
in combination with platinum-based chemotherapy for recurrent and/or metastatic disease.

4.2 Dose and Method of Administration

Erbitux must be administered under the supervision of a physician experienced in the use of antineoplastic agents. Close monitoring is required during the infusion and for at least 1 hour after the end of the infusion. Availability of resuscitation equipment must be ensured. If during the first infusion, an infusion-related reaction occurs within the first 15 minutes, the infusion should be stopped.
Prior to the first infusion, patients must receive a premedication with an antihistamine and a corticosteroid at least 1 hour prior to administration of cetuximab. Similar premedication is recommended prior to all subsequent infusions.
Chemotherapy must not be administered earlier than 1 hour after the end of the cetuximab infusion.

Colorectal cancer.

Detection of RAS mutational status (K-RAS and N-RAS exons 2, 3 and 4) must be performed prior to the first cetuximab infusion. It is important that a validated test method is used by an experienced laboratory (see Clinical trials; see Section 4.4 Special Warnings and Precautions for Use).
In patients with metastatic colorectal cancer, cetuximab is used as monotherapy or in combination with chemotherapy, either once a week or every two weeks.
It is recommended that cetuximab treatment be continued until progression of the underlying disease.

Weekly dose regimen.

Erbitux is administered once a week. The initial dose is 400 mg cetuximab per m² body surface area (BSA); the recommended infusion period is 120 minutes. All subsequent weekly doses are 250 mg/m² each; the recommended infusion period is 60 minutes.

Every two weeks dose regimen.

For initial and subsequent doses, Erbitux is administered once every two weeks: each dose is 500 mg cetuximab per m² BSA. The recommended infusion period is 120 minutes.

Squamous cell cancer of the head and neck.

In combination with radiation therapy. In patients with locally advanced squamous cell cancer of the head and neck, cetuximab is used concomitantly with radiation therapy.
Erbitux is administered once a week. The initial dose is 400 mg cetuximab per m² BSA; the recommended infusion period is 120 minutes. All subsequent weekly doses are 250 mg/m² each; the recommended infusion period is 60 minutes.
It is recommended to start cetuximab therapy one week before radiation therapy and to continue cetuximab therapy until the end of the radiation therapy period (see Clinical trials).
In combination with platinum-based chemotherapy. In patients with recurrent and/or metastatic squamous cell cancer of the head and neck, cetuximab is used in combination with platinum based chemotherapy followed by cetuximab as maintenance therapy until disease progression. Erbitux is administered either once a week or every two weeks.

Weekly dose regimen.

Erbitux is administered once a week. The initial dose is 400 mg cetuximab per m² BSA; the recommended infusion period is 120 minutes. All subsequent weekly doses are 250 mg/m² each; the recommended infusion period is 60 minutes.

Every two weeks dose regimen.

For initial and subsequent doses, Erbitux is administered once every two weeks: each dose is 500 mg cetuximab per m² BSA. The recommended infusion period is 120 minutes.

Administration.

Erbitux is administered intravenously with an infusion pump, gravity drip or a syringe pump (see Instructions for use/handling).
The initial dose, should be given slowly to minimise the risk of infusion-related reactions (see Section 4.4 Special Warnings and Precautions for Use). The recommended infusion period is 120 minutes. For subsequent administration, the infusion rate must not exceed 10 mg/min. If the initial infusion is well tolerated, the recommended infusion period for weekly dose regimen of 250 mg/m² is 60 minutes and recommended infusion period for the every two weeks dose regimen of 500 mg/m² is 120 minutes.

Special recommendations.

The following measures are to be taken if a patient experiences infusion related or skin reactions.

Infusion-related reactions.

Mild or moderate (symptoms include fever, chills, dizziness or dyspnoea): infusion rate should be decreased. It is recommended that the infusion rate remain at the lower value for all subsequent infusions (see Section 4.4 Special Warnings and Precautions for Use, Infusion-related, including anaphylactic, reactions).
Severe (symptoms include rapid onset of airway obstruction, urticaria, increase or decrease of blood pressure, loss of consciousness or shock; in rare cases, angina pectoris, myocardial infarction or cardiac arrest have also been observed): immediate and permanent discontinuation of cetuximab therapy. Emergency treatment may be necessary (see Section 4.4 Special Warnings and Precautions for Use, Infusion-related, including anaphylactic, reactions).

Skin reactions.

First occurrence of severe skin reaction (≥ grade 3; US National Cancer Institute, common terminology criteria for adverse events, CTCAE): cetuximab should be ceased for up to 2 consecutive weeks. If the reaction has resolved to grade 2 when the next infusion is due, treatment may be resumed without any change in dose level.
If a second severe skin reaction occurs, cease cetuximab for up to 2 consecutive weeks. If the skin reaction has resolved to grade 2 when the next infusion is due, treatment may be resumed with a dose reduction of 20% (200 mg/m² BSA in the weekly dosing regimen or 400 mg/m² BSA in the every two weeks dosing regimen).
If a third severe skin reaction occurs at the lower dose, cease cetuximab for up to 2 consecutive weeks. If the skin reaction has resolved to grade 2 when the next infusion is due, treatment may be resumed with a dose reduction of 40% (150 mg/m² BSA in the weekly dosing regimen or 300 mg/m² BSA in the every two weeks dosing regimen). Dose reductions should continue for the duration of treatment.
If a fourth severe skin reaction occurs or the skin reaction fails to resolve to grade 2 during interruption of treatment, permanent discontinuation of cetuximab is required.

Combination treatment.

For the dosage or recommended dose modifications of concomitantly used chemotherapeutic agents, refer to the product information for these products. They must not be administered earlier than 1 hour after the end of the cetuximab infusion.

4.3 Contraindications

Erbitux is contraindicated in patients with known severe (grade 3 or 4) hypersensitivity reactions to cetuximab.
The combination of Erbitux with oxaliplatin containing chemotherapy is contraindicated for patients with mutant RAS metastatic colorectal cancer (mCRC) or for whom RAS mCRC status is unknown.
Before initiation of combination treatment, contraindications for concomitantly used chemotherapeutic agents (refer to their product information documents) or radiation therapy must be considered.

4.4 Special Warnings and Precautions for Use

Infusion-related, including anaphylactic, reactions.

Prior to the first infusion, patients must receive premedication with an antihistamine and a corticosteroid at least 1 hour prior to administration of cetuximab. Similar premedication is recommended for all subsequent infusions. Cetuximab infusion must be carried out in an area where resuscitation equipment and agents are available.
Severe infusion related reactions, including anaphylactic reactions, may commonly occur, in some cases with fatal outcome (see Section 4.8 Adverse Effects (Undesirable Effects)). Occurrence of a severe infusion-related reaction requires immediate and permanent discontinuation of cetuximab therapy and may necessitate emergency treatment. Some of these reactions may be anaphylactic or anaphylactoid in nature or represent a cytokine release syndrome (CRS). Symptoms may occur during the initial infusion and for several hours afterwards, or with subsequent infusions. It is recommended to warn patients of the possibility of such a late onset and instruct them to contact their physician if symptoms of an infusion-related reaction occur. Symptoms may include bronchospasm, urticaria, increase or decrease in blood pressure, loss of consciousness, or shock. In rare cases, angina pectoris, myocardial infarction or cardiac arrest have been observed.
Anaphylactic reactions may occur as early as within a few minutes of the first infusion, e.g. due to preformed IgE antibodies cross-reacting with cetuximab. These reactions are commonly associated with bronchospasm and urticaria. They can occur despite the use of premedication.
The risk for anaphylactic reactions is much increased in patients with a history of allergy to red meat or tick bites or positive results of tests for IgE antibodies against cetuximab (α-1-3-galactose). In these patients cetuximab should be administered only after a careful assessment of benefit/risk, including alternative treatments, and only under close supervision of well trained personnel with resuscitation equipment ready.
The first dose should be administered slowly whilst all vital signs are closely monitored for at least two hours. If during the first infusion, an infusion-related reaction occurs within the first 15 minutes, the infusion should be stopped. A careful benefit/risk assessment should be undertaken including consideration whether the patient may have preformed IgE antibodies before a subsequent infusion is given.
If an infusion-related reaction develops later during the infusion or at a subsequent infusion, further management will depend on its severity:
a) Grade 1: continue slow infusion under close supervision;
b) Grade 2: continue slow infusion and immediately administer treatment for symptoms;
c) Grade 3 and 4: stop infusion immediately, treat symptoms vigorously and contraindicate further use of cetuximab.
A cytokine release syndrome (CRS) typically occurs within one hour after infusion and is less commonly associated with bronchospasm and urticaria. CRS is normally most severe in relation to the first infusion.
Mild or moderate infusion-related reactions are very common, comprising symptoms such as fever, chills, dizziness, or dyspnoea that occur in a close temporal relationship mainly to the first cetuximab infusion. If the patient experiences a mild or moderate infusion related reaction, the infusion rate may be decreased. It is recommended to maintain this lower infusion rate in all subsequent infusions.
Close monitoring of patients, particularly during the first administration, is required. Special attention is recommended for patients with reduced performance status and pre-existing cardio-pulmonary disease.

Respiratory disorders.

If patients develop dyspnoea during the course of cetuximab treatment, it is recommended to investigate them for signs of progressive pulmonary disorders as appropriate. In the event of acute onset or worsening dyspnoea, cetuximab therapy should be interrupted.
Cases of interstitial lung disease (ILD), including fatal cases, have been reported, with the majority of cases arising from a Japanese postmarketing surveillance study in metastatic colorectal cancer. Confounding or contributing factors, such as concomitant chemotherapy known to be associated with ILD, and pre-existing pulmonary diseases were frequent in fatal cases. Such patients should be closely monitored. In the event of symptoms (such as dyspnoea, cough, fever) or radiographic findings suggestive of ILD, prompt diagnostic investigation should occur. Geriatric patients and patients with a history of interstitial lung disease may be at an increased risk of developing this event. If interstitial lung disease is diagnosed, cetuximab must be discontinued and the patient treated appropriately.

Skin reactions.

Skin reactions are very common and treatment interruption or discontinuation may be required. According to clinical practice guidelines, prophylactic use of oral tetracyclines (e.g. doxycycline) for 6-8 weeks and topical application of 1% hydrocortisone cream with moisturiser should be considered. Use of sunscreen should also be considered.
Medium to high-potency topical corticosteroids or oral tetracyclines have been used for the treatment of skin reactions.
If a patient experiences a severe skin reaction (≥ grade 3; US National Cancer Institute - common terminology criteria for adverse events, CTCAE), cetuximab therapy must be interrupted. Treatment may be resumed if the reaction has resolved to grade 2 (see Section 4.8 Adverse Effects (Undesirable Effects); Section 4.2 Dose and Method of Administration for further information on handling skin reactions).

Electrolyte disturbances.

Progressively decreasing serum magnesium levels occur frequently and may lead to severe hypomagnesaemia. Hypomagnesaemia is reversible following discontinuation of cetuximab. In addition, hypokalaemia may develop sometimes as a consequence of diarrhoea. Hypocalcaemia may also occur; in particular, in combination with platinum based chemotherapy, the frequency of severe hypocalcaemia may be increased.
Measurement of serum electrolyte levels is recommended prior to and periodically during cetuximab treatment. Electrolyte replacement is recommended, as appropriate.

Cardiovascular disorders.

An increased frequency of severe and sometimes fatal cardiovascular events and treatment emergent deaths has been observed in the treatment of non-small cell lung cancer, squamous cell carcinoma of the head and neck and colorectal carcinoma. In some studies association with age ≥ 65 years has been observed. When prescribing cetuximab, the cardiovascular and performance status of the patients and concomitant administration of cardiotoxic compounds such as fluoropyrimidines should be taken into account.

Eye disorders.

Cases of keratitis and ulcerative keratitis have been reported with the use of cetuximab. It is recommended that patients with signs and symptoms suggestive of keratitis consult an ophthalmologist.
If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. If a diagnosis of ulcerative keratitis is confirmed, treatment with cetuximab must be interrupted or discontinued.
Special attention is recommended for patients with a history of keratitis, ulcerative keratitis or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration.

Colorectal cancer patients with RAS mutated tumours.

Cetuximab should not be used in the treatment of colorectal cancer patients whose tumours have RAS mutations or for whom RAS tumour status is unknown. Results from clinical studies show a negative benefit-risk balance in tumours with RAS mutations, in particular in combination with continuous infusional 5-flurouracil/folinic acid plus oxaliplatin (see Clinical trials; see Section 4.3 Contraindications).

Combination with capecitabine and irinotecan.

The benefit-risk balance of cetuximab in combination with XELIRI (capecitabine plus irinotecan) has not been established. This combination is therefore not recommended in the treatment of patients with metastatic colorectal cancer.

Colorectal cancer patients with resectable liver metastases.

There is insufficient evidence to determine the benefit/risk balance of administering cetuximab as peri-operative therapy to mCRC patients presenting with resectable liver metastases. Accordingly, cetuximab is not recommended for use in this patient population.

Wound healing.

To date, no data on the effect of cetuximab on wound healing are available. However, in preclinical wound healing models, EGFR selective tyrosine kinase inhibitors were shown to retard wound healing.

Hepatic and renal impairment.

Only patients with adequate hepatic and renal function have been investigated to date (serum creatinine ≤ 1.5-fold, transaminases ≤ 5-fold and bilirubin ≤ 1.5-fold the upper limit of normal).

Haematological.

Cetuximab has not been studied in patients presenting with an abnormal haematological profile as defined by one or more of the following: haemoglobin < 90 g/L; leukocyte count < 3 x 10⁹/L; absolute neutrophil count < 1.5 x 10⁹/L; platelet count < 100 x 10⁹/L.

Use in the elderly.

No dose adjustment is required in the elderly but experience is limited in patients 75 years of age and above. However, elderly patients, especially those with a history of cardiac disease, are at greater risk of adverse effects than younger patients and patients without a history of cardiac disease (see Section 4.8 Adverse Effects (Undesirable Effects)).

Paediatric use.

The effectiveness of cetuximab in paediatric patients below the age of 18 years has not been established. No new safety signals were identified in paediatric patients as reported from a phase I study (see Section 5.2 Pharmacokinetic Properties).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Physicians are advised to consider the toxicities of the individual components of therapy and to monitor patients receiving cetuximab in combination with other therapies closely.
When cetuximab is used in combination with chemo- or radiotherapy, patients may experience an increased incidence of specific adverse reactions (see Section 4.8 Adverse Effects (Undesirable Effects)).
In combination with fluoropyrimidines, the frequency of cardiac ischaemia including myocardial infarction and congestive heart failure as well as the frequency of hand-foot syndrome (palmar-plantar erythrodysaesthesia) were increased compared to that with fluoropyrimidines.
When used in combination with platinum based chemotherapy, the frequency of severe leukopenia or severe neutropenia is increased compared to use of platinum based chemotherapy alone, and this may lead to a higher rate of infectious complications such as febrile neutropenia, pneumonia and sepsis. Patients with skin lesions, mucositis or diarrhoea that may facilitate the development of infections are at particular risk.
In combination with capecitabine and oxaliplatin (XELOX) the frequency of severe diarrhoea may be increased.
In combination with local radiation therapy of the head and neck area, additional undesirable effects were those typical of radiation therapy (such as mucositis, radiation dermatitis, dysphagia or leukopenia, mainly presenting as lymphocytopenia). In a randomised controlled clinical study with 424 patients, reporting rates of severe acute radiation dermatitis and mucositis as well as of late radiation therapy related events were slightly higher in patients receiving radiation therapy in combination with cetuximab than in those receiving radiation therapy alone.
In squamous cell cancer of the head and neck, use of cetuximab in combination with chemoradiotherapy has not been adequately investigated. Therefore, benefits and risks of this combination are not known.
There is limited experience in the use of cetuximab in combination with radiation therapy in colorectal cancer.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data on the effect of cetuximab on human fertility. Fertility has not been specifically examined in animal studies. However, female cynomolgus monkeys given IV maintenance doses of 7.5-75 mg/kg/week (approx. 1-17 times the recommended maintenance dose in humans based on serum AUC values) showed impairment of menstrual cycling.
(Category D)
The epidermal growth factor receptor (EGFR) is involved in foetal development. Observations in animals are indicative of a placental transfer of cetuximab, and other IgG₁ antibodies have been found to cross the placental barrier. An embryo-foetal toxicity study in cynomolgus monkeys revealed no evidence of teratogenicity at exposures (AUC) up to 16 times that anticipated clinically. However, a dose-dependent, increased incidence of abortion was observed, with a NOAEL of 7.5 mg/kg/week (exposure (AUC) similar to clinical exposure). No data regarding use in pregnant women are available. It is recommended that Erbitux should not be administered during pregnancy. Adequate contraception should be maintained in women of child-bearing potential during treatment with Erbitux and for 2 months after the last dose.
Studies in animals or sufficient data from lactating women are not available. It is recommended that women do not breast-feed during treatment with Erbitux and for 2 months after the last dose.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. If patients experience treatment related symptoms affecting their ability to concentrate and react, it is recommended that they do not drive or use machines until the effect subsides.

4.8 Adverse Effects (Undesirable Effects)

The following definitions apply to the frequency terminology used hereafter. Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).
A hash symbol (^#) indicates that additional information on the respective undesirable effect is provided below.

Nervous system disorders.

Common: headache.
Frequency not known: aseptic meningitis.

Eye disorders.

Common: conjunctivitis.
Uncommon: blepharitis, keratitis.

Respiratory, thoracic and mediastinal disorders.

Uncommon: pulmonary embolism.
Rare: interstitial lung disease, which may be fatal (see Section 4.4 Special Warnings and Precautions for Use).

Gastrointestinal disorders.

Common: diarrhoea, nausea, vomiting.

Skin and subcutaneous tissue disorders.

Very common: skin reactions^#.
Common: hand-foot syndrome in combination with fluoropyrimidines (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Very rare: Stevens-Johnson syndrome/toxic epidermal necrolysis.
Frequency not known: superinfection of skin lesions^#.

Metabolism and nutrition disorders.

Very common: hypomagnesaemia (see Section 4.4 Special Warnings and Precautions for Use).
Common: dehydration, in particular, secondary to diarrhoea or mucositis; hypocalcaemia (see Section 4.4 Special Warnings and Precautions for Use); anorexia which may lead to weight decrease; hypokalaemia (in combination with irinotecan or platinum/fluorouracil combinations).

Vascular disorders.

Uncommon: deep vein thrombosis.

General disorders and administration site conditions.

Very common: mild or moderate infusion-related reactions^# (see Section 4.4 Special Warnings and Precautions for Use, Infusion-related, including anaphylactic, reactions); mucositis, in some cases severe. Mucositis may lead to epistaxis.
Common: severe infusion related reactions^#, in some cases with fatal outcome (see Section 4.4 Special Warnings and Precautions for Use, Infusion-related, including anaphylactic, reactions); fatigue; increased infections in combination with platinum based regimens and increased radiation-related effects in combination with radiotherapy (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Hepatobiliary disorders.

Very common: increase in liver enzyme levels (AST, ALT, AP).

Cardiac disorders.

Uncommon: ischaemia including myocardial infarction and congestive heart failure in combination with fluoropyrimidines, including capecitabine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Haematological disorders.

Frequency not known¹: increased severe neutropenia and leucopenia in combination with platinum based chemotherapy which may lead to a higher rate of infectious complications such as febrile neutropenia, pneumonia and sepsis (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
¹ Not to be estimated from the available data set in patients with recurrent and/or metastatic squamous cell cancer of the head and neck because patient numbers were too small to provide a meaningful frequency estimation.

Additional information.

Overall, no clinically relevant difference between genders was observed.

Skin reactions.

Skin reactions may develop in more than 80% of patients and mainly present as acne like rash and/or, less frequently, as pruritus, dry skin, desquamation, hypertrichosis, or nail disorders (e.g. paronychia). Approximately 15% of the skin reactions are severe, including single cases of skin necrosis. The majority of skin reactions develop within the first three weeks of therapy. They generally resolve, without sequelae, over time following cessation of treatment if the recommended adjustments in dose regimen are followed (see Section 4.2 Dose and Method of Administration).
Skin lesions induced by cetuximab may predispose patients to superinfections (e.g. with S. aureus), which may lead to subsequent complications, e.g. cellulitis, erysipelas, or, potentially with fatal outcome, staphylococcal scalded skin syndrome, necrotising fasciitis or sepsis.

Combination treatment.

When cetuximab is used in combination with chemotherapeutic agents or radiation therapy, also refer to the agents' respective product information and see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

Reporting suspected adverse effects.

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

There is limited experience to date with weekly administration of doses higher than 250 mg/m² BSA or every two weeks administrations of doses higher than 500 mg/m² BSA. In clinical studies with doses up to 700 mg/m² given every two weeks the safety profile was consistent with that described, see Section 4.8 Adverse Effects (Undesirable Effects).
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC Code: L01FE01.
In both in vitro and in vivo assays, cetuximab inhibits the proliferation and induces apoptosis of human tumour cells that express EGFR, but it has no anti-tumour effects in human tumour xenografts that do not express EGFR. In vitro cetuximab inhibits the production of angiogenic factors by tumour cells and blocks endothelial cell migration. In vivo cetuximab inhibits expression of angiogenic factors by tumour cells and causes a reduction in tumour neovascularisation and metastasis.
Cetuximab is a mediator of antibody-dependent cellular cytotoxicity in vitro, eliciting increased cytotoxicity of EGFR-expressing tumour cells in the presence of immune effector cells. Therefore, in addition to its inhibitory function on receptor signalling, patients with EGFR-expressing tumours may also benefit from this immune stimulatory effect of cetuximab.

Mechanism of action.

Cetuximab binds to the EGFR with an affinity that is approximately 5 to 10-fold higher than that of endogenous ligands. Cetuximab blocks binding of endogenous EGFR ligands resulting in inhibition of the function of the receptor. It induces the internalisation of the EGFR, which could lead to down-regulation of EGFR.
Cetuximab does not bind to other receptors belonging to the HER family (Erb B2, Erb B3, Erb B4).
The EGFR is constitutively expressed in many normal epithelial tissues, including the skin and hair follicles. Over-expression of EGFR is also detected in many human cancers, including those of the colon and rectum. The contribution of the EGFR signalling pathways in the development of malignancy of certain tumours has been extensively documented in in vitro and in vivo studies. EGFR signalling pathways are involved in the control of cell survival, cell cycle progression, angiogenesis, cell migration and cellular invasion/metastasis. Expression of EGFR and its cognate ligands in tumours has been correlated with poor prognosis, decreased survival, and/or increased metastases.
RAS is one of the most frequently activated families of oncogenes in human cancers. Mutations of RAS genes at certain hot spots on exons 2, 3 and 4 result in constitutive activation of RAS proteins independently of EGFR signalling.
The protein products of the proto-oncogene K-RAS (Kirsten rat sarcoma 2 viral oncogene homologue) and N-RAS (neuroblastoma RAS viral [v-rs] oncogene homologue) are central downstream signal transducers of EGFR. In tumours, activation of RAS by EGFR contributes to EGFR-mediated increased proliferation, survival and the production of proangiogenic factors.

Immunogenicity.

The development of human anti-chimaeric antibodies (HACA) is a class specific effect of monoclonal chimaeric antibodies. Measurable HACA titres developed in 3.4% of the patients studied. No conclusive data on the neutralising effect of HACAs on cetuximab is available to date. The appearance of HACA did not correlate with the occurrence of hypersensitivity reactions or any other undesirable effects of cetuximab.

Clinical trials.

Colorectal cancer.

A diagnostic assay (EGFR pharmDx) was used for immunohistochemical detection of EGFR expression in tumour material. Approximately 75% of the patients with metastatic colorectal cancer screened for clinical studies had an EGFR expressing tumour and were therefore considered eligible for cetuximab treatment.
In metastatic colorectal cancer, the incidence of RAS mutations is in the range of 40-55%. Study data demonstrate that patients with RAS wild type metastatic colorectal cancer have a significantly higher chance of benefiting from treatment with cetuximab or a combination of cetuximab and chemotherapy.
Cetuximab as a single agent or in combination with chemotherapy was investigated in 5 randomised controlled clinical studies and several supportive studies. The 5 randomised studies investigated a total of 3734 patients with metastatic colorectal cancer, in whom EGFR expression was detectable and who had an ECOG performance status of ≤ 2. The majority of patients included had an ECOG performance status of ≤ 1. In all studies, cetuximab was administered as described, see Section 4.2 Dose and Method of Administration.
RAS status was recognised as a predictive factor for treatment with cetuximab in studies EMR 62 202-013 and EMR 62-202 047.
Cetuximab in combination with chemotherapy.

EMR 62 202-013 (CRYSTAL).

This randomised, open label, phase III study in patients with metastatic colorectal cancer who had not received prior treatment for metastatic disease compared the combination of cetuximab and irinotecan plus infusional fluorouracil/folinic acid (5-FU/FA) (599 patients) to the same chemotherapy alone (599 patients).
The chemotherapy regimen was the FOLFIRI regimen. The median age of subjects was 61 years (range 19-84), with most being male (61%). The primary endpoint was progression free survival. Addition of cetuximab to FOLFIRI in the overall population marginally increased progression free and overall survival.
RAS status was assessed retrospectively in 69% of randomised subjects. The RAS mutant population consisted of subjects with mutations on exons 2, 3 or 4 of the K-RAS or N-RAS genes. Addition of cetuximab to FOLFIRI significantly increased progression free and overall survival in RAS wild type but not RAS mutant subjects (see Table 1).

Patients with K-RAS wild type tumours and an ECOG performance status of > 2 or who were 65 years of age or older, had no benefit in overall survival time, when cetuximab was added to FOLFIRI.

EMR 62 202-047 (OPUS).

This randomised, open label study in patients with metastatic colorectal cancer who had not received prior treatment for metastatic disease compared the combination of cetuximab and oxaliplatin plus continuous infusional fluorouracil/folinic acid (FOLFOX4) (169 patients) to the same chemotherapy alone (168 patients). The chemotherapy regimen was the FOLFOX4 regimen. The median age of subjects was 61 years (range 24-82), with most being male (54%).
The primary endpoint was objective response rate. Addition of cetuximab to FOLFOX4 in the overall population did not significantly increase objective response rate, overall survival or progression free survival.
RAS status was assessed retrospectively in 75% of randomised subjects. The RAS mutant population consisted of patients with mutations on exons 2, 3 or 4 of the K-RAS or N-RAS genes. Addition of cetuximab to FOLFOX4 significantly increased objective response rate in RAS wild type but not RAS mutant subjects. Addition of cetuximab to FOLFOX4 showed a trend to increased progression free and overall survival in RAS wild type subjects but had an adverse effect in RAS mutant subjects (see Table 2).

COIN.

This open label, randomised, investigator sponsored study compared the addition of cetuximab to first line chemotherapy (oxaliplatin plus oral or infusional fluoropyrimidine) to the same chemotherapy alone, in patients with advanced colorectal cancer who had not received prior treatment for metastatic disease. Prolonged survival with the addition of cetuximab could not be demonstrated in this study.
Comparison of outcomes in the subgroup of patients with K-RAS wild type tumours given cetuximab plus a FOLFOX-like regimen (modified de Gramont plus oxaliplatin, OxMdG), vs. a group given that chemotherapy alone, was possible. There was no evidence of any survival benefit in the patients given cetuximab. Median overall survival (OS) was 16.3 months in the cetuximab plus chemotherapy group (n = 117), vs. 18.2 months in the chemotherapy alone group (n = 127), with a hazard ratio of 0.93 (95% CI: 0.72, 1.19), slightly in favour of the cetuximab plus OxMdG combination. OS results may be biased due to imbalances in second line treatments. Significantly fewer patients treated with cetuximab received second line therapy. For progression free survival, a trend towards greater efficacy in the group receiving cetuximab plus OxMdG was suggested based on the hazard ratio of 0.77 (95% CI: 0.59, 1.01), although median progression free survival was broadly similar across groups: 9.2 months in the cetuximab plus OxMdG group vs. 9.0 months for this chemotherapy alone. However, unlike in the OPUS study, these results did not reach statistical significance. Best overall response rates were not statistically significantly different (68% for cetuximab; 59% for OxMdG; odds ratio, 1.44 [95% CI: 0.85, 2.43]).

CA225006 (EPIC).

This randomised, open label study in patients with metastatic colorectal cancer who had received initial combination treatment with oxaliplatin plus fluoropyrimidine for metastatic disease compared the combination of cetuximab and irinotecan (648 patients) with irinotecan alone (650 patients).
A significant difference in overall survival time could not be shown in this study. Following disease progression, treatment with EGFR targeting agents was initiated in 50% of patients in the irinotecan alone arm, which most likely impacted survival results. Objective response rate and progression free survival time were significantly improved with cetuximab. However, as no independent review of imaging data was conducted, these results have to be interpreted with caution. The impact of K-RAS status was evaluated retrospectively in 23% of subjects. Unlike in the other trials, cetuximab did not have a significant impact on either progression free survival or overall survival in wild type K-RAS disease. However, the results should be treated with caution due to the small number of subjects.

EMR 62 202-007 (BOND).

This randomised study in patients with metastatic colorectal cancer after failure of irinotecan based treatment for metastatic disease as the last treatment before study entry compared the combination of cetuximab and irinotecan (218 patients) with cetuximab monotherapy (111 patients).
Addition of irinotecan to cetuximab increased median progression free survival from 1.5 months to 4.1 months: hazard ratio 0.54, 95% CI (0.42, 0.71) and significantly increased the objective response rate. The improvement in overall survival time did not reach statistical significance; however, in the follow-up treatment, nearly 50% of patients in the cetuximab only arm received a combination of cetuximab and irinotecan after progression of disease, which may have influenced overall survival time.
Cetuximab as a single agent.

CA225025 (NCIC CTG CO.17).

This randomised, open label study in patients with metastatic colorectal cancer who had received prior oxaliplatin, irinotecan and fluoropyrimidine based treatment for metastatic disease compared the addition of cetuximab as a single agent to best supportive care (BSC) (287 patients) with BSC alone (285 patients). The median age of subjects was 63 years (range 29-88), with most being male (64%).
Addition of cetuximab to BSC (best supportive care) increased overall survival time significantly by 1.5 months from 4.6 to 6.1 months: hazard ratio 0.77, 95% CI (0.64, 0.92) while median progression free survival increased from 1.8 months to 1.9 months: hazard ratio 0.676, 95% CI (0.57, 0.80), in the overall population. The impact of K-RAS status was evaluated subsequently in 69% of patients. The benefits of cetuximab were enhanced in the K-RAS wild type population (see Table 3).

Squamous cell cancer of the head and neck.

Immunohistochemical detection of EGFR expression was not performed at study entry since more than 90% of patients with squamous cell cancer of the head and neck have tumours that express EGFR.
Cetuximab in combination with radiation therapy for locally advanced disease.

EMR 62 202-006.

This randomised study compared the combination of cetuximab and radiation therapy (211 patients) with radiation therapy alone (213 patients) in patients with locally advanced squamous cell carcinoma of the head and neck. Cetuximab was started one week before radiation therapy and administered at the doses described, see Section 4.2 Dose and Method of Administration until the end of the radiation therapy period.
The efficacy data generated in this study are summarised in Table 4.

Subgroup analyses indicated that patients with a good prognosis as indicated by tumour stage (stage II/III vs stage IV), baseline Karnofsky performance status (KPS: 90-100% vs 50-80%) and age (< 65 years vs ≥ 65 years) had a more pronounced benefit when cetuximab was added to radiation therapy. No clinical benefit could be demonstrated in patients with KPS ≤ 80 and aged 65 years or older.
The use of cetuximab in combination with chemo-radiotherapy has so far not been adequately investigated. Thus, a benefit risk ratio has not been established.
Cetuximab in combination with platinum based chemotherapy in recurrent and/or metastatic disease.

EMR 62 202 002 (EXTREME).

This randomised, open label study in patients with recurrent and/or metastatic squamous cell cancer of the head and neck who had not received prior chemotherapy for recurrent and/or metastatic disease compared the combination of cetuximab and cisplatin or carboplatin plus infusional fluorouracil (222 patients) to the same chemotherapy alone (220 patients). Patients may have received prior chemotherapy for locally advanced disease. The median age of subjects was 56 years (interquartile range 51-62), with most being male (90%). Treatment in the cetuximab arm consisted of up to 6 cycles of platinum based chemotherapy in combination with cetuximab followed by cetuximab as maintenance therapy until disease progression.
Addition of cetuximab to platinum based chemotherapy significantly increased progression free and overall survival by a median 2.3 and 2.7 months, respectively (see Table 5).

Patients with a good prognosis as indicated by tumour stage, baseline Karnofsky performance status (KPS) and age (< 65 years vs ≥ 65 years) had a more pronounced benefit when cetuximab was added to platinum based chemotherapy. In contrast to progression free survival time, no benefit in overall survival time could be demonstrated in patients with KPS ≤ 80 who were 65 years of age or older.

5.2 Pharmacokinetic Properties

Cetuximab pharmacokinetics were studied in clinical studies where cetuximab was administered as monotherapy or in combination with concomitant chemotherapy or radiotherapy. Intravenous infusions of cetuximab exhibited nonlinear pharmacokinetics at weekly doses ranging from 5 to 500 mg/m² body surface area. Cetuximab clearance decreased with increasing doses to 200 mg/m², then appeared to plateau.
When cetuximab was administered at an initial dose of 400 mg/m² body surface area, the mean volume of distribution was approximately equivalent to the vascular space (2.9 L/m² with a range of 1.5 to 6.2 L/m²). The mean C_max (± SD) was 185 ± 55 microgram/mL. The mean clearance was 0.022 L/h per m² body surface area. Cetuximab has a long elimination half-life with values ranging from 70 to 100 hours at the target dose.
Cetuximab serum concentrations reached stable levels after 3 weeks of cetuximab monotherapy. Mean peak cetuximab concentrations were 155.8 microgram/mL in week 3 and 151.6 microgram/mL in week 8, whereas the corresponding mean trough concentrations were 41.3 and 55.4 microgram/mL, respectively. In a study of cetuximab administered in combination with irinotecan, the mean cetuximab trough levels were 50.0 microgram/mL in week 12 and 49.4 microgram/mL in week 36.
Several pathways have been described that may contribute to the metabolism of antibodies. All of these pathways involve the biodegradation of the antibody to smaller molecules, i.e. small peptides or amino acids.
An integrated analysis across all clinical studies showed that the pharmacokinetic characteristics of cetuximab are not influenced by race, age, gender, renal or hepatic status. However, only patients with adequate renal and hepatic function have been investigated to date (serum creatinine ≤ 1.5-fold, transaminases ≤ 5-fold and bilirubin ≤ 1.5-fold the upper limit of normal).

Paediatric population.

In a phase I study in paediatric patients (1-18 years) with refractory solid tumours, cetuximab was administered in combination with irinotecan. The pharmacokinetic results were comparable to those in adults.

5.3 Preclinical Safety Data

Genotoxicity.

Cetuximab was not genotoxic in an in vitro microbial assay or an in vivo rat micronucleus assay.

Carcinogenicity.

No long-term animal studies have been performed to establish the carcinogenic potential of cetuximab.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride, glycine, polysorbate 80, citric acid monohydrate, sodium hydroxide and water for injections.

6.2 Incompatibilities

Erbitux must not be mixed with other intravenously administered medicines, except sterile sodium chloride 9 mg/mL (0.9%) solution. A separate infusion line must be used.

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

Vials: Store in a refrigerator (2°C to 8°C). Do not freeze.
Chemical and physical in-use stability of Erbitux has been demonstrated for 48 hours at 25°C if the solution is prepared as described, see Instructions for use/handling.
In-use storage times and conditions are the responsibility of the user. To reduce microbiological hazard, use as soon as practicable after preparation. If not used immediately and storage is necessary, hold at 2°C to 8°C for not more than 24 hours.

6.5 Nature and Contents of Container

Erbitux is a sterile, preservative-free solution for intravenous infusion containing 5 mg/mL of cetuximab. It is supplied in clear, colourless glass vials with a flurotec-coated bromobutyl rubber stopper and aluminium/polypropylene seal containing 20 mL or 100 mL. Each pack contains 1 single use vial.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

Instructions for use/handling.

Erbitux may be administered via a gravity drip, an infusion pump or a syringe pump method. A separate infusion line must be used for the infusion, and the line must be flushed with sterile sodium chloride 9 mg/mL (0.9%) solution for injection at the end of infusion.
Product is for single use in one patient only. Discard any residue.
Erbitux is compatible with:
Polyethylene (PE), ethyl vinyl acetate (EVA) or polyvinyl chloride (PVC) bags;
PE, polyurethane (PUR), EVA, polyolefine thermoplastic (TP) or PVC infusion sets;
Polypropylene (PP) syringes for syringe pump.
Since Erbitux does not contain any antimicrobial preservative or bacteriostatic agent, care must be taken to ensure aseptic handling when preparing the infusion.
Erbitux must be prepared as follows:

For administration with infusion pump or gravity drip (diluted with sterile sodium chloride 9 mg/mL (0.9%) solution).

Take an infusion bag of adequate size of sterile sodium chloride 9 mg/mL (0.9%) solution. Calculate the required volume of Erbitux. Remove an adequate volume of the sodium chloride solution from the infusion bag, using an appropriate sterile syringe with a suitable needle. Take an appropriate sterile syringe and attach a suitable needle. Draw up the required volume of Erbitux from a vial. Transfer the Erbitux into the prepared infusion bag. Repeat this procedure until the calculated volume has been reached. Connect the infusion line and prime it with the diluted Erbitux before starting the infusion. Use a gravity drip or an infusion pump for administration. Set and control the rate as explained, see Section 4.2 Dose and Method of Administration.

For administration with infusion pump (undiluted).

Calculate the required volume of Erbitux. Take an appropriate sterile syringe (minimum 50 mL) and attach a suitable needle. Draw up the required volume of Erbitux from a vial. Transfer the Erbitux into a sterile evacuated container or bag. Repeat this procedure until the calculated volume has been reached. Connect the infusion line and prime it with Erbitux before starting the infusion. Use an infusion pump for administration. Set and control the rate as explained, see Section 4.2 Dose and Method of Administration.

For administration with a syringe pump.

Calculate the required volume of Erbitux. Take an appropriate sterile syringe and attach a suitable needle. Draw up the required volume of Erbitux from a vial. Remove the needle and put the syringe into the syringe pump. Connect the infusion line to the syringe, set and control the rate as explained, see Section 4.2 Dose and Method of Administration and start the infusion after priming the line with Erbitux or sterile sodium chloride 9 mg/mL (0.9%) solution. If necessary, repeat this procedure until the calculated volume has been infused.

6.7 Physicochemical Properties

The pH of the solution is in the range of 5.3-5.7 and the osmolality is between 280 and 350 mOsm/kg.
The molecular weight is approximately 152 kDa.

Chemical structure.

Cetuximab is a chimaeric monoclonal antibody of the immunoglobulin G₁ (IgG₁) subclass, produced in mammalian cell culture by mouse myeloma cells (Sp2/0). It is obtained by attaching the variable regions of the murine monoclonal antibody M225 against epidermal growth factor receptor (EGFR) to constant regions of the human IgG₁.

CAS number.

205923-56-4.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

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