Drugs List

Therapeutic Indications

Uses

Locally advanced squamous cell head & neck cancer with radiation
Metastatic/recurrent squamous cell head & neck cancer w. platinum agents
Treatment of EGFR expressing, RAS wild-type metastatic colorectal cancer

For the treatment of patients with epidermal growth factor receptor (EGFR)-expressing, RAS wild type metastatic colorectal cancer:
In combination with chemotherapy (either irinotecan-based or oxaliplatin, fluorouracil and folinic acid (FOLFOX))
As a single agent in patients who have failed oxaliplatin and irinotecan based therapy and who are intolerant to irinotecan.

Determination of RAS (KRAS and NRAS) mutational status must be performed prior to the first cetuximab infusion using a validated test method by an experienced laboratory.

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

Administration

Cetuximab is administered as an intravenous infusion, with an infusion pump, gravity drip or a syringe pump.

A separate infusion line must be used for the administration of cetuximab, and the infusion line must be flushed with sterile sodium chloride 0.9% solution for injection at the end of the infusion.

For the initial dose, the manufacturer recommends an infusion period of 120 minutes. For the subsequent weekly doses, the recommended infusion period is 60 minutes. The maximum infusion rate must not exceed 10mg/minute.

Monitor patients during the infusion and for at least 2 hours thereafter; resuscitation equipment must be immediately available because of the risk of infusion related reactions.

Contraindications

Children under 18 years
Breastfeeding

Precautions and Warnings

Cardiopulmonary disorder
Patients over 75 years
Wearing of contact lenses
Cardiac disorder
Haematological disorder
Hepatic impairment
History of keratitis
Keratitis
Pregnancy
Pulmonary disease
Renal impairment
Severe dry eyes

Not suitable for treatment of mutant RAS metastatic colorectal cancer
Refer patients with symptoms of keratitis to an ophthalmology specialist
Advise ability to drive/operate machinery may be affected by side effects
Before initiating, ensure patient positive for wild type KRAS or NRAS
Patients must be premedicated with an antihistamine and corticosteroid
Supplemental electrolytes may be required
Consider prophylactic oral tetracycline/topical hydrocortisone
Consult local policy on the safe use of anti-cancer drugs
Reduce infusion rate if mild to moderate infusion reaction occurs
Resuscitation facilities must be immediately available
Treatment to be administered under the supervision of a specialist
Monitor serum electrolytes before and during treatment
Monitor closely patients who develop neutropenia
Monitor patient throughout infusion and for at least 2 hours afterwards
Advise patient of the risk of late onset adverse reactions
Advise patient to report any blurred vision or any other eye symptoms
Advise patients at risk of neutropenia to report any signs of infection
Discontinue / interrupt treatment if ulcerative keratitis develops
Discontinue treatment if interstitial lung disease develops
Dosage may require adjustment if skin reactions recur
Discontinue if severe hypersensitivity reactions occur
Interrupt treatment if allergic skin reactions occur
Female: Contraception required during and for 2 months after treatment
Advise patient to report signs / symptoms of infusion related reactions

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.

Any patient with keratitis or eye symptoms including inflammation, lacrimation, photosensitivity, blurred vision, eye pain or red eye should be referred to an ophthalmologist promptly. Discontinue or interrupt cetuximab if ulcerative keratitis occurs and assess the risk to the patient of continued treatment if keratitis is diagnosed.

Progressively decreasing serum magnesium levels occur frequently and may lead to severe hypomagnesaemia in some patients. Hypomagnesaemia is reversible following discontinuation of cetuximab. Hypokalaemia may develop 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.

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 (non-small cell lung cancer) association with age 65 years and above has been observed . When prescribing cetuximab, the cardiovascular status of the patients and concomitant administration of cardiotoxic compounds such as fluoropyrimidines should be taken into account.

Patients who receive cetuximab in combination with platinum-based chemotherapy are at an increased risk of the occurrence of severe neutropenia, which may lead to subsequent infectious complications such as febrile neutropenia, pneumonia or sepsis. Careful monitoring is recommended in such patients, in particular in those who experience skin lesions, mucositis or diarrhoea that may facilitate the occurrence of infections.

Cases of interstitial lung disease (ILD), including fatal cases, have been reported. If ILD is diagnosed, cetuximab must be discontinued and the patient be treated appropriately. Factors such as concomitant chemotherapy known to be associated with ILD and pre-existing pulmonary diseases were frequent in fatal cases.

Pregnancy and Lactation

Pregnancy

Use cetuximab with caution in pregnancy.

At the time of writing there is limited published experience concerning the use of cetuximab during pregnancy. It is not known whether cetuximab crosses the placenta, other IgG1 antibodies have been found to cross the placental barrier.
EGFR is involved in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the embryo. Cetuximab has a long half life and women should not conceive for 60 days after their last treatment. Limited observations in animals are indicative of placental transfer but have revealed no evidence of teratogenicity. However, dependent on the dose, an increased incidence of abortion was observed. Because of the potential harm, cetuximab should not be used in pregnancy.
However, Briggs concludes that as head, neck and colorectal cancers can be fatal, if a woman requires cetuximab and informed consent is obtained, treatment with cetuximab should not be withheld because of pregnancy. If an inadvertent pregnancy occurs, the woman should be advised of the possible risk for severe adverse effects in the embryo and foetus.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Cetuximab is contraindicated in breastfeeding.

At the time of writing there is little published experience concerning the use of cetuximab during breastfeeding, and it is not known whether cetuximab is excreted in human breast milk. A very high molecular weight (about 152,000) suggests that cetuximab will not be excreted into breast milk. However, human IgG is excreted into milk, and therefore cetuximab may also be excreted. The effects of this potential exposure on a nursing infant are unknown, but immunosuppression and other severe adverse effects are potential complications. Due to the potential for serious adverse reactions in the nursing infant, the manufacturer recommends that nursing mothers do not breastfeed during cetuximab therapy and for 60 days after their last dose. However, Hale suggests that the amount of IgG in mature milk is low and suggests withholding breast milk for an unspecified period of less than 60 days. Schaefer suggests withholding breast milk for 55 days after the last dose of cetuximab.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Acne-like rash
Anaphylactic reaction
Anaphylactoid reaction
Angina pectoris
Anorexia
Aseptic meningitis
Blepharitis
Blindness
Bronchospasm
Cardiac arrest
Cellulitis
Chills
Congestive cardiac failure
Conjunctivitis
Corneal perforation
Deep vein thrombosis (DVT)
Dehydration
Desquamation
Diarrhoea
Dizziness
Dry skin
Dysphagia
Dyspnoea
Elevation of liver enzymes
Epistaxis
Erysipelas
Fatigue
Febrile neutropenia
Fever
Hand-foot syndrome
Headache
Hypersensitivity reactions
Hypertension
Hypertrichosis
Hypocalcaemia
Hypomagnesaemia
Hypotension
Infusion-related symptoms
Interstitial lung disease
Keratitis
Leukopenia
Loss of consciousness (transient)
Lymphocytopenia
Mucositis
Myocardial infarction
Nail disorders
Nausea
Neutropenia
Pneumonia
Pruritus
Pulmonary embolism
Radiation recall dermatitis
Rash
Sepsis
Shock
Skin necrosis
Skin reactions
Staphylococcal scalded skin syndrome
Stevens-Johnson syndrome
Superinfections
Toxic epidermal necrolysis
Ulcerative keratitis
Urticaria
Vomiting
Weight loss

Presentation

Infusions containing cetuximab.

Drugs List

Therapeutic Indications

Uses

Locally advanced squamous cell head & neck cancer with radiation
Metastatic/recurrent squamous cell head & neck cancer w. platinum agents
Treatment of EGFR expressing, RAS wild-type metastatic colorectal cancer

For the treatment of patients with epidermal growth factor receptor (EGFR)-expressing, RAS wild type metastatic colorectal cancer:
In combination with chemotherapy (either irinotecan-based or oxaliplatin, fluorouracil and folinic acid (FOLFOX))
As a single agent in patients who have failed oxaliplatin and irinotecan based therapy and who are intolerant to irinotecan.

Determination of RAS (KRAS and NRAS) mutational status must be performed prior to the first cetuximab infusion using a validated test method by an experienced laboratory.

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

Dosage

Before the first infusion, patients must receive premedication with an antihistamine and a corticosteroid at least 1 hour prior to administration of cetuximab. This premedication is recommended prior to all subsequent infusions.

Whilst the doses stated below are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.

Cetuximab is administered once a week in all indications.

Adults

Elderly

Patients with Renal Impairment

Additional Dosage Information

Administration

Cetuximab is administered as an intravenous infusion, with an infusion pump, gravity drip or a syringe pump.

A separate infusion line must be used for the administration of cetuximab, and the infusion line must be flushed with sterile sodium chloride 0.9% solution for injection at the end of the infusion.

For the initial dose, the manufacturer recommends an infusion period of 120 minutes. For the subsequent weekly doses, the recommended infusion period is 60 minutes. The maximum infusion rate must not exceed 10mg/minute.

Monitor patients during the infusion and for at least 2 hours thereafter; resuscitation equipment must be immediately available because of the risk of infusion related reactions.

Contraindications

Children under 18 years
Breastfeeding

Precautions and Warnings

Cardiopulmonary disorder
Patients over 75 years
Wearing of contact lenses
Cardiac disorder
Haematological disorder
Hepatic impairment
History of keratitis
Keratitis
Pregnancy
Pulmonary disease
Renal impairment
Severe dry eyes

Not suitable for treatment of mutant RAS metastatic colorectal cancer
Refer patients with symptoms of keratitis to an ophthalmology specialist
Advise ability to drive/operate machinery may be affected by side effects
Before initiating, ensure patient positive for wild type KRAS or NRAS
Patients must be premedicated with an antihistamine and corticosteroid
Supplemental electrolytes may be required
Consider prophylactic oral tetracycline/topical hydrocortisone
Consult local policy on the safe use of anti-cancer drugs
Reduce infusion rate if mild to moderate infusion reaction occurs
Resuscitation facilities must be immediately available
Treatment to be administered under the supervision of a specialist
Monitor serum electrolytes before and during treatment
Monitor closely patients who develop neutropenia
Monitor patient throughout infusion and for at least 2 hours afterwards
Advise patient of the risk of late onset adverse reactions
Advise patient to report any blurred vision or any other eye symptoms
Advise patients at risk of neutropenia to report any signs of infection
Discontinue / interrupt treatment if ulcerative keratitis develops
Discontinue treatment if interstitial lung disease develops
Dosage may require adjustment if skin reactions recur
Discontinue if severe hypersensitivity reactions occur
Interrupt treatment if allergic skin reactions occur
Female: Contraception required during and for 2 months after treatment
Advise patient to report signs / symptoms of infusion related reactions

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.

Any patient with keratitis or eye symptoms including inflammation, lacrimation, photosensitivity, blurred vision, eye pain or red eye should be referred to an ophthalmologist promptly. Discontinue or interrupt cetuximab if ulcerative keratitis occurs and assess the risk to the patient of continued treatment if keratitis is diagnosed.

Progressively decreasing serum magnesium levels occur frequently and may lead to severe hypomagnesaemia in some patients. Hypomagnesaemia is reversible following discontinuation of cetuximab. Hypokalaemia may develop 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.

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 (non-small cell lung cancer) association with age 65 years and above has been observed . When prescribing cetuximab, the cardiovascular status of the patients and concomitant administration of cardiotoxic compounds such as fluoropyrimidines should be taken into account.

Patients who receive cetuximab in combination with platinum-based chemotherapy are at an increased risk of the occurrence of severe neutropenia, which may lead to subsequent infectious complications such as febrile neutropenia, pneumonia or sepsis. Careful monitoring is recommended in such patients, in particular in those who experience skin lesions, mucositis or diarrhoea that may facilitate the occurrence of infections.

Cases of interstitial lung disease (ILD), including fatal cases, have been reported. If ILD is diagnosed, cetuximab must be discontinued and the patient be treated appropriately. Factors such as concomitant chemotherapy known to be associated with ILD and pre-existing pulmonary diseases were frequent in fatal cases.

Pregnancy and Lactation

Pregnancy

Use cetuximab with caution in pregnancy.

At the time of writing there is limited published experience concerning the use of cetuximab during pregnancy. It is not known whether cetuximab crosses the placenta, other IgG1 antibodies have been found to cross the placental barrier.
EGFR is involved in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the embryo. Cetuximab has a long half life and women should not conceive for 60 days after their last treatment. Limited observations in animals are indicative of placental transfer but have revealed no evidence of teratogenicity. However, dependent on the dose, an increased incidence of abortion was observed. Because of the potential harm, cetuximab should not be used in pregnancy.
However, Briggs concludes that as head, neck and colorectal cancers can be fatal, if a woman requires cetuximab and informed consent is obtained, treatment with cetuximab should not be withheld because of pregnancy. If an inadvertent pregnancy occurs, the woman should be advised of the possible risk for severe adverse effects in the embryo and foetus.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Cetuximab is contraindicated in breastfeeding.

At the time of writing there is little published experience concerning the use of cetuximab during breastfeeding, and it is not known whether cetuximab is excreted in human breast milk. A very high molecular weight (about 152,000) suggests that cetuximab will not be excreted into breast milk. However, human IgG is excreted into milk, and therefore cetuximab may also be excreted. The effects of this potential exposure on a nursing infant are unknown, but immunosuppression and other severe adverse effects are potential complications. Due to the potential for serious adverse reactions in the nursing infant, the manufacturer recommends that nursing mothers do not breastfeed during cetuximab therapy and for 60 days after their last dose. However, Hale suggests that the amount of IgG in mature milk is low and suggests withholding breast milk for an unspecified period of less than 60 days. Schaefer suggests withholding breast milk for 55 days after the last dose of cetuximab.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Acne-like rash
Anaphylactic reaction
Anaphylactoid reaction
Angina pectoris
Anorexia
Aseptic meningitis
Blepharitis
Blindness
Bronchospasm
Cardiac arrest
Cellulitis
Chills
Congestive cardiac failure
Conjunctivitis
Corneal perforation
Deep vein thrombosis (DVT)
Dehydration
Desquamation
Diarrhoea
Dizziness
Dry skin
Dysphagia
Dyspnoea
Elevation of liver enzymes
Epistaxis
Erysipelas
Fatigue
Febrile neutropenia
Fever
Hand-foot syndrome
Headache
Hypersensitivity reactions
Hypertension
Hypertrichosis
Hypocalcaemia
Hypomagnesaemia
Hypotension
Infusion-related symptoms
Interstitial lung disease
Keratitis
Leukopenia
Loss of consciousness (transient)
Lymphocytopenia
Mucositis
Myocardial infarction
Nail disorders
Nausea
Neutropenia
Pneumonia
Pruritus
Pulmonary embolism
Radiation recall dermatitis
Rash
Sepsis
Shock
Skin necrosis
Skin reactions
Staphylococcal scalded skin syndrome
Stevens-Johnson syndrome
Superinfections
Toxic epidermal necrolysis
Ulcerative keratitis
Urticaria
Vomiting
Weight loss

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: March 2014

Reference Sources

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Joint Formulary Committee. British National Formulary. 66th ed. London: BMJ Group and Pharmaceutical Press; 2013.

Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press https://www.medicinescomplete.com [Accessed on March 17, 2014].

Medications and Mothers' Milk, 14th Edition (2010) Hale, T. Hale Publishing, Amarillo, Texas.

The Renal Drug Handbook. 3rd edition. (2009) ed. Ashley, C and Currie, Radcliffe Publishing Ltd, Abingdon.

Summary of Product Characteristics: Erbitux 5mg/ml solution for infusion. Merck Serono. Revised October 2018.

MHRA Drug Safety Update February 2014
Available at: https://www.mhra.gov.uk
Last accessed: March 17, 2014