Drugs List

Therapeutic Indications

Uses

Treatment of advanced colorectal cancer combined with other cytotoxics

To be used in combination with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) chemotherapy in adults with metastatic colorectal cancer (mCRC) that is resistant to or has progressed after an oxaliplatin-containing regimen.

Administration

Following dilution, to be administered as a slow intravenous infusion over 1 hour.

Contraindications

Children under 18 years
Severe haemorrhage
Breastfeeding
New York Heart Association class III failure
New York Heart Association class IV failure
Pregnancy
Uncontrolled hypertension

Precautions and Warnings

Performance status of ECOG greater than or equal to 2
Tobacco smoking
Within 4 weeks of surgery
Behcet's disease
Cerebrovascular disorder
Diabetes mellitus
Giant cell arteritis
History of aneurysm
History of severe cardiac disorder
Hyperlipidaemia
Hypertension
Ischaemic heart disease
Marfan syndrome
Occlusive peripheral arterial disease
Severe hepatic impairment
Severe renal impairment
Takayasu arteritis
Vascular Ehlers-Danlos syndrome

Anti-diarrhoeals may be required during treatment
Consider a dental exam & appropriate preventive dentistry before treatment
Consider premedication with antihistamine and/or corticosteroid
Ensure hypertension is controlled prior to treatment
Prophylactic G-CSF should be considered
Treatment to be initiated and supervised by a specialist
Concentrate must be diluted and used as an infusion
Consult local policy on the safe use of anti-cancer drugs
Do not start therapy for 28 days post surgery, or until wound has healed
For intravenous use only
Interrupt treatment if infusion reaction occurs & monitor until resolution
Staff: Not to be handled by pregnant staff
Measurement of LV ejection fraction recommended before and during treatment
Perform full blood count before each treatment cycle
Monitor blood pressure every 2 weeks
Monitor for bleeding during treatment
Monitor for protein in urine
Monitor for symptoms of gastrointestinal perforation or fistula
Monitor patients for signs and symptoms of cardiac failure
Advise patient to report headaches, seizures, confusion, visual disturbance
Elderly patients may be more susceptible to local and systemic effects
Discontinue 4 weeks prior to major elective surgery
Discontinue at first signs of thrombotic microangiopathy
Discontinue at the first signs of cardiac failure
Discontinue if arterial thromboembolism develops
Discontinue if fistulae develop during treatment
Discontinue if grade 4 thromboembolic event occurs
Discontinue if hypertensive encephalopathy occurs
Discontinue if nephrotic syndrome occurs
Discontinue if persistent hypertension unresponsive to therapy occurs
Discontinue if posterior reversible encephalopathy syndrome (PRES) develops
Discontinue if severe haemorrhage occurs
Discontinue if severe hypersensitivity reactions occur
Discontinue permanently if hypertensive crisis occurs
Discontinue treatment if gastrointestinal perforation occurs
Suspend therapy if platelet count falls below 75,000 per cubic mm
Suspend treatment if hypertension cannot be controlled
Suspend treatment if neutrophil count is less than 1,500/cubic mm
Suspend treatment if proteinuria greater than or equal to 2g/ 24 hours
Discontinue if wound healing requires medical intervention
May cause impaired fertility
Male & female: Contraception required during & for 6 months after treatment
Advise patient on giving up smoking
Advise patient to report any dental mobility, pain or swelling

Posterior Reversible Encephalopathy Syndrome (PRES)
Posterior reversible encephalopathy syndrome (PRES) has been reported in some patients treated with aflibercept. If patients present with symptoms indicating PRES such as headache, altered mental state, seizures and visual disturbances, an MRI should be performed. If PRES is diagnosed aflibercept treatment should be discontinued and adequate blood pressure and seizure control administration is advisable.The safety of reinstating treatment in patients previously experiencing PRES is unknown.

Patients with grade 3 deep vein thrombosis (DVT) should be treated with appropriate anticoagulation and continue treatment with aflibercept. However, if grade 3 DVT recurs despite anticoagulation treatment, aflibercept should be discontinued. Patients with thromboembolic events grade 3 or lower need to be closely monitored.

Risk factors for aneurysm and artery dissection
Use of systemic VEGF inhibitors may promote the formation of aneurysms or artery dissections, mainly in relation to aortic aneurysm rupture and aortic dissection. It is therefore important to consider the risk of aneurysm and artery dissection in patients with risk factors such as hypertension, history of aneurysm, smoking, diabetes, coronary, cerebrovascular or peripheral arterial disease, and hyperlipidaemia. Other risk factors include Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, and the use of fluoroquinolones. In patients receiving VEGF inhibitors, any modifiable risk factors such as smoking and hypertension should be reduced as far as possible.

Pregnancy and Lactation

Pregnancy

Aflibercept is contraindicated in pregnancy.

Animal studies have shown reproductive toxicity. Angiogenesis which is critical to foetal development, is inhibited by aflibercept and this may result in adverse effects on the 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 effect of concurrent therapies must also be considered.

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

Aflibercept is contraindicated in breastfeeding.

It is unknown whether aflibercept is excreted in human milk, therefore a risk to breastfed infants cannot be excluded.

The effect of concurrent therapies must also be considered.

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

Abdominal pain
Aphthous stomatitis
Asthenia
Cardiac failure
Decreased appetite
Decreased ejection fraction
Dehydration
Diarrhoea
Dysphonia
Dyspnoea
Epistaxis
Febrile neutropenia
Fistulae
Gastro-intestinal perforation
Haemorrhage
Haemorrhoids
Headache
Hyperpigmentation of skin
Hypersensitivity reactions
Hypertension
Increase in serum ALT/AST
Infection
Leucopenia
Nasopharyngitis
Nephrotic syndrome
Neutropenia
Oropharyngeal pain
Osteonecrosis (primarily of the jaw)
Palmar-Plantar Erythrodysaesthesia syndrome
Posterior reversible encephalopathy syndrome (PRES)
Proctalgia
Proteinuria
Rectal haemorrhage
Rhinorrhoea
Sepsis
Serum creatinine increased
Stomatitis
Thrombocytopenia
Thromboembolic disorders
Thrombotic microangiopathy
Tooth ache
Upper abdominal pain
Urinary tract infections
Weight loss
Wound healing retarded

Presentation

Infusions containing aflibercept

These products have been produced by recombinant technology using Chinese Hamster Ovary (CHO) cell lines.

Drugs List

Therapeutic Indications

Uses

Treatment of advanced colorectal cancer combined with other cytotoxics

To be used in combination with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) chemotherapy in adults with metastatic colorectal cancer (mCRC) that is resistant to or has progressed after an oxaliplatin-containing regimen.

Dosage

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

Adults

Additional Dosage Information

Administration

Following dilution, to be administered as a slow intravenous infusion over 1 hour.

Contraindications

Children under 18 years
Severe haemorrhage
Breastfeeding
New York Heart Association class III failure
New York Heart Association class IV failure
Pregnancy
Uncontrolled hypertension

Precautions and Warnings

Performance status of ECOG greater than or equal to 2
Tobacco smoking
Within 4 weeks of surgery
Behcet's disease
Cerebrovascular disorder
Diabetes mellitus
Giant cell arteritis
History of aneurysm
History of severe cardiac disorder
Hyperlipidaemia
Hypertension
Ischaemic heart disease
Marfan syndrome
Occlusive peripheral arterial disease
Severe hepatic impairment
Severe renal impairment
Takayasu arteritis
Vascular Ehlers-Danlos syndrome

Anti-diarrhoeals may be required during treatment
Consider a dental exam & appropriate preventive dentistry before treatment
Consider premedication with antihistamine and/or corticosteroid
Ensure hypertension is controlled prior to treatment
Prophylactic G-CSF should be considered
Treatment to be initiated and supervised by a specialist
Concentrate must be diluted and used as an infusion
Consult local policy on the safe use of anti-cancer drugs
Do not start therapy for 28 days post surgery, or until wound has healed
For intravenous use only
Interrupt treatment if infusion reaction occurs & monitor until resolution
Staff: Not to be handled by pregnant staff
Measurement of LV ejection fraction recommended before and during treatment
Perform full blood count before each treatment cycle
Monitor blood pressure every 2 weeks
Monitor for bleeding during treatment
Monitor for protein in urine
Monitor for symptoms of gastrointestinal perforation or fistula
Monitor patients for signs and symptoms of cardiac failure
Advise patient to report headaches, seizures, confusion, visual disturbance
Elderly patients may be more susceptible to local and systemic effects
Discontinue 4 weeks prior to major elective surgery
Discontinue at first signs of thrombotic microangiopathy
Discontinue at the first signs of cardiac failure
Discontinue if arterial thromboembolism develops
Discontinue if fistulae develop during treatment
Discontinue if grade 4 thromboembolic event occurs
Discontinue if hypertensive encephalopathy occurs
Discontinue if nephrotic syndrome occurs
Discontinue if persistent hypertension unresponsive to therapy occurs
Discontinue if posterior reversible encephalopathy syndrome (PRES) develops
Discontinue if severe haemorrhage occurs
Discontinue if severe hypersensitivity reactions occur
Discontinue permanently if hypertensive crisis occurs
Discontinue treatment if gastrointestinal perforation occurs
Suspend therapy if platelet count falls below 75,000 per cubic mm
Suspend treatment if hypertension cannot be controlled
Suspend treatment if neutrophil count is less than 1,500/cubic mm
Suspend treatment if proteinuria greater than or equal to 2g/ 24 hours
Discontinue if wound healing requires medical intervention
May cause impaired fertility
Male & female: Contraception required during & for 6 months after treatment
Advise patient on giving up smoking
Advise patient to report any dental mobility, pain or swelling

Posterior Reversible Encephalopathy Syndrome (PRES)
Posterior reversible encephalopathy syndrome (PRES) has been reported in some patients treated with aflibercept. If patients present with symptoms indicating PRES such as headache, altered mental state, seizures and visual disturbances, an MRI should be performed. If PRES is diagnosed aflibercept treatment should be discontinued and adequate blood pressure and seizure control administration is advisable.The safety of reinstating treatment in patients previously experiencing PRES is unknown.

Patients with grade 3 deep vein thrombosis (DVT) should be treated with appropriate anticoagulation and continue treatment with aflibercept. However, if grade 3 DVT recurs despite anticoagulation treatment, aflibercept should be discontinued. Patients with thromboembolic events grade 3 or lower need to be closely monitored.

Risk factors for aneurysm and artery dissection
Use of systemic VEGF inhibitors may promote the formation of aneurysms or artery dissections, mainly in relation to aortic aneurysm rupture and aortic dissection. It is therefore important to consider the risk of aneurysm and artery dissection in patients with risk factors such as hypertension, history of aneurysm, smoking, diabetes, coronary, cerebrovascular or peripheral arterial disease, and hyperlipidaemia. Other risk factors include Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, and the use of fluoroquinolones. In patients receiving VEGF inhibitors, any modifiable risk factors such as smoking and hypertension should be reduced as far as possible.

Pregnancy and Lactation

Pregnancy

Aflibercept is contraindicated in pregnancy.

Animal studies have shown reproductive toxicity. Angiogenesis which is critical to foetal development, is inhibited by aflibercept and this may result in adverse effects on the 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 effect of concurrent therapies must also be considered.

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

Aflibercept is contraindicated in breastfeeding.

It is unknown whether aflibercept is excreted in human milk, therefore a risk to breastfed infants cannot be excluded.

The effect of concurrent therapies must also be considered.

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

Abdominal pain
Aphthous stomatitis
Asthenia
Cardiac failure
Decreased appetite
Decreased ejection fraction
Dehydration
Diarrhoea
Dysphonia
Dyspnoea
Epistaxis
Febrile neutropenia
Fistulae
Gastro-intestinal perforation
Haemorrhage
Haemorrhoids
Headache
Hyperpigmentation of skin
Hypersensitivity reactions
Hypertension
Increase in serum ALT/AST
Infection
Leucopenia
Nasopharyngitis
Nephrotic syndrome
Neutropenia
Oropharyngeal pain
Osteonecrosis (primarily of the jaw)
Palmar-Plantar Erythrodysaesthesia syndrome
Posterior reversible encephalopathy syndrome (PRES)
Proctalgia
Proteinuria
Rectal haemorrhage
Rhinorrhoea
Sepsis
Serum creatinine increased
Stomatitis
Thrombocytopenia
Thromboembolic disorders
Thrombotic microangiopathy
Tooth ache
Upper abdominal pain
Urinary tract infections
Weight loss
Wound healing retarded

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 2016

Reference Sources

Gov.uk. Government departments. Medicines and Healthcare products Regulatory Agency. Drug Safety Updates. Aflibercept (Zaltrap): Minimising the risk of osteonecrosis of the jaw. Available at: https://www.gov.uk/ Last accessed: 22 April 2016

Joint Formulary Committee. British National Formulary(online) London: BMJ Group and Pharmaceutical Press. Accessed on 29 February 2016.

MHRA Drug Safety Update July 2020
Available at: https://www.gov.uk/drug-safety-update/systemically-administered-vegf-pathway-inhibitors-risk-of-aneurysm-and-artery-dissection
Last accessed: 10 November 2020

Summary of Product Characteristics: Zaltrap 25mg/ml concentrate for solution for infusion. Sanofi. Revised October 2016.