Aflibercept

Aflibercept is a recombinant fusion protein made of the VEGF-binding parts of the extracellular domains of human VEGF receptors 1 and 2, joined to the Fc portion of human IgG1 and produced in Chinese hamster ovary (CHO) K1 cells. Two different kinds of product share this active substance. Eylea and its biosimilars act locally in the eye after injection into the vitreous, whereas Zaltrap acts throughout the body after intravenous infusion and limits the new blood vessels that feed tumours.

Mechanism of Action

• Decoy receptor: aflibercept binds VEGF-A and placental growth factor (PlGF) with higher affinity than their natural receptors, VEGFR-1 and VEGFR-2, so these ligands cannot bind and activate their receptors. The Zaltrap SmPC adds VEGF-B to the ligands it binds.
• Binding strength: dissociation constants are 0.5 pM for VEGF-A165, 0.36 pM for VEGF-A121, 1.92 pM for VEGF-B and 39 pM for PlGF-2. The complex formed is stable and has no detectable biological activity.
• In the eye: excess VEGF-A activity causes abnormal new vessel growth and leakage. In wet AMD, leakage from choroidal neovascularisation thickens the retina and causes oedema or bleeding, and visual acuity falls. After Eylea was started, central retinal thickness decreased soon afterwards and the mean size of the neovascular lesion was reduced.
• In tumours: by blocking receptor activation and endothelial cell proliferation, aflibercept inhibits the growth of new vessels that supply tumours with oxygen and nutrients. PlGF is also linked to abnormal new vessel growth and to the recruitment of inflammatory cells into tumours.

Pharmacokinetics

• Eylea 40 mg/mL (2 mg into the vitreous): aflibercept is slowly absorbed from the eye and appears in the blood mainly as an inactive, stable complex with VEGF; only free aflibercept can bind VEGF. The mean peak of free aflibercept in plasma was about 0.02 µg/mL (range 0–0.054) 1–3 days after a 2 mg injection in wet AMD, and it was undetectable after two weeks in almost all patients. In retinal vein occlusion, diabetic macular oedema and myopic choroidal neovascularisation the mean peaks were 0.03–0.05 µg/mL. There is no accumulation with injections every 4 weeks. These levels are 50 to 500 times below those needed to halve systemic VEGF activity in animals, so systemic effects such as blood pressure changes are unlikely.
• Eylea 114.3 mg/mL (8 mg): the mean peak of free aflibercept was 0.25 mg/L (standard deviation 0.21), reached after a median of 1 day in wet AMD and diabetic macular oedema combined. Accumulation after three monthly doses was minimal and none followed. The median time to the last measurable level was 3 weeks.
• Elimination of Eylea: aflibercept is a protein, so no metabolism studies were done. Free and bound aflibercept are cleared by binding to VEGF and by proteolytic breakdown. Renal impairment did not change plasma levels after eye injection (40 mg/mL, in 40% of patients in one study) or systemic exposure (8 mg); limited data in mild hepatic impairment showed no influence on exposure (8 mg).
• Preterm infants (retinopathy of prematurity): after 0.4 mg per eye, levels of free and bound aflibercept were higher than in adults treated with 2 mg but lower than after intravenous 1 mg/kg in adults. Free aflibercept fell to about 0.13 µg/mL at week 4 and to near or below the limit of quantification within about 8 weeks, with no relationship between blood levels and effects such as blood pressure change.
• Zaltrap (4 mg/kg intravenously every 2 weeks): free aflibercept is close to steady state by the second cycle, with essentially no accumulation (ratio 1.2). The volume of distribution of free aflibercept at steady state is about 8 L. Free aflibercept is cleared mainly by binding to VEGF, faster and non-linearly below 2 mg/kg; above 2 mg/kg clearance is about 1.0 L/day with a terminal half-life of about 6 days. Renal elimination is expected to be minimal.
• Zaltrap special populations: clearance was 15.5% higher and volume of distribution 20.6% higher in men, which weight-based dosing offsets; exposure was 29% higher at 100 kg or more. Age and race had no effect, and mild or moderate hepatic or renal impairment did not change clearance; data in severe impairment are very limited or absent.

Eylea and Zaltrap are different products with separate indications. All uses are in adults except retinopathy of prematurity.

Eylea 40 mg/mL (2 mg dose)

• Neovascular (wet) age-related macular degeneration (AMD).
• Visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO).
• Visual impairment due to diabetic macular oedema (DME).
• Visual impairment due to myopic choroidal neovascularisation (myopic CNV).
• Retinopathy of prematurity (ROP) in preterm infants, with zone I disease (stage 1+, 2+, 3 or 3+), zone II disease (stage 2+ or 3+) or aggressive posterior ROP (AP-ROP). This applies to the 40 mg/mL pre-filled syringe used with the PICLEO paediatric dosing device.

Eylea 114.3 mg/mL (8 mg dose)

• Neovascular (wet) AMD (nAMD).
• Visual impairment due to diabetic macular oedema (DME).
• Visual impairment due to macular oedema secondary to retinal vein occlusion (branch, central and hemiretinal RVO).

Zaltrap (intravenous)

• Metastatic colorectal cancer (MCRC) that is resistant to or has progressed after an oxaliplatin-containing regimen, in adults, in combination with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) chemotherapy.

Biosimilars of Eylea also contain aflibercept; the indications and presentations of each biosimilar are listed in its own SmPC.

• Eylea 40 mg/mL: hypersensitivity to aflibercept or to any excipient; active or suspected ocular or periocular infection; active severe intraocular inflammation.
• Eylea 114.3 mg/mL: hypersensitivity to aflibercept or to any excipient; ocular or periocular infection; active severe intraocular inflammation.
• Zaltrap: hypersensitivity to aflibercept or to any excipient; ophthalmic or intravitreal use, because of its hyperosmotic properties. The contraindications of the FOLFIRI components (irinotecan, 5-fluorouracil and folinic acid) also apply; see their SmPCs.

Eye injections of Eylea mostly cause local eye reactions. Zaltrap, given by infusion with FOLFIRI, causes the bleeding, blood pressure, kidney, blood-count and bowel effects typical of VEGF blockade in addition to the side effects of the chemotherapy. The frequencies below are product-specific and should not be mixed.

Eylea 40 mg/mL and Biosimilars

The safety population was 3,102 patients in eight phase III studies (2,501 on 2 mg). The most frequent reactions (5% or more) were conjunctival haemorrhage (25%), retinal haemorrhage (11%), reduced visual acuity (11%), eye pain (10%), cataract (8%), raised intraocular pressure (8%), vitreous detachment (7%) and vitreous floaters (7%). Serious eye reactions related to the injection procedure occurred in fewer than 1 in 1,900 injections and included blindness, endophthalmitis, retinal detachment, traumatic cataract, cataract, vitreous haemorrhage, vitreous detachment and raised intraocular pressure.

Very common (≥1/10): visual acuity reduced, retinal haemorrhage, conjunctival haemorrhage, eye pain.

Common (≥1/100 to <1/10): retinal pigment epithelial tear (wet AMD studies), detachment of the retinal pigment epithelium, retinal degeneration, vitreous haemorrhage, cataract (including cortical, nuclear and subcapsular), corneal erosion, corneal abrasion, raised intraocular pressure, blurred vision, vitreous floaters, vitreous detachment, injection site pain, foreign body sensation in the eye, increased lacrimation, eyelid oedema, injection site haemorrhage, punctate keratitis, conjunctival hyperaemia, ocular hyperaemia.

Uncommon (≥1/1,000 to <1/100): hypersensitivity (rash, itching, urticaria, and isolated severe anaphylactic or anaphylactoid reactions after marketing), endophthalmitis, retinal detachment, retinal tear, iritis, uveitis, iridocyclitis, lenticular opacities, corneal epithelium defect, injection site irritation, abnormal sensation in the eye, eyelid irritation, anterior chamber flare, corneal oedema.

Rare (≥1/10,000 to <1/1,000): blindness, traumatic cataract, vitritis, hypopyon.

Not known: scleritis (post-marketing).

Conjunctival haemorrhage was more frequent in patients taking antithrombotic medicines. Arterial thromboembolic events were rare, with no notable difference from comparator groups. In the retinopathy of prematurity study (75 infants given 0.4 mg), reactions reported in more than one infant were retinal detachment, retinal haemorrhage, conjunctival haemorrhage, injection site haemorrhage, raised intraocular pressure and eyelid oedema; the reactions known in adults are considered applicable, and long-term safety in preterm infants is not established.

Eylea 114.3 mg/mL (8 mg)

The safety population was 1,808 patients treated with 8 mg for up to 96 weeks in four studies; the profile was similar to that of the 40 mg/mL arm (857 patients) and across wet AMD, diabetic macular oedema and retinal vein occlusion. The most frequent reactions were cataract (7.1%), reduced visual acuity (4.3%), conjunctival haemorrhage (4.0%), raised intraocular pressure (3.8%), vitreous detachment (3.5%), vitreous floaters (3.2%) and retinal haemorrhage (2.8%). Serious reactions were cataract (7.1%), raised intraocular pressure (3.8%), retinal haemorrhage (2.8%), vitreous haemorrhage (1.1%), subcapsular cataract (0.6%), retinal tear (0.5%), nuclear cataract (0.4%) and retinal detachment (0.4%).

Common (≥1/100 to <1/10): hypersensitivity (rash, itching, urticaria), cataract, raised intraocular pressure, vitreous floaters, vitreous detachment, vitreous haemorrhage, retinal haemorrhage, reduced visual acuity, eye pain, conjunctival haemorrhage, punctate keratitis, corneal abrasion.

Uncommon (≥1/1,000 to <1/100): retinal detachment, retinal tear, retinal pigment epithelial tear, detachment of the retinal pigment epithelium, uveitis, iritis, iridocyclitis, vitritis, cortical, nuclear and subcapsular cataract, corneal erosion, blurred vision, injection site pain, foreign body sensation in the eye, increased lacrimation, injection site haemorrhage, conjunctival hyperaemia, lenticular opacities, eyelid oedema, ocular hyperaemia, injection site irritation, retinal degeneration, corneal oedema.

Rare (≥1/10,000 to <1/1,000): blindness, endophthalmitis, eyelid irritation.

Not known: scleritis (post-marketing).

The reactions known with the 40 mg/mL product are also expected with 8 mg, including abnormal sensation in the eye, corneal epithelium defect, traumatic cataract, hypopyon and severe anaphylactic or anaphylactoid reactions.

Zaltrap

The safety of Zaltrap with FOLFIRI was assessed in 1,216 patients with previously treated metastatic colorectal cancer (611 on Zaltrap 4 mg/kg every two weeks, 605 on placebo/FOLFIRI), with a median of 9 cycles. The most common reactions (20% or more, and at least 2% more than with placebo/FOLFIRI) were leucopenia, diarrhoea, neutropenia, proteinuria, raised AST, stomatitis, fatigue, thrombocytopenia, raised ALT, hypertension, weight loss, decreased appetite, epistaxis, abdominal pain, dysphonia, raised serum creatinine and headache. The most common grade 3–4 reactions (5% or more) were neutropenia, diarrhoea, hypertension, leucopenia, stomatitis, fatigue, proteinuria and asthenia. Frequencies below are for reactions of all grades.

Very common (≥1/10): infection; leucopenia, neutropenia, thrombocytopenia; decreased appetite, weight loss; headache; hypertension, haemorrhage; dyspnoea, epistaxis, dysphonia; diarrhoea, stomatitis, abdominal pain, upper abdominal pain; raised AST and ALT; palmar-plantar erythrodysaesthesia syndrome; proteinuria, raised serum creatinine; asthenic conditions.

Common (≥1/100 to <1/10): neutropenic infection or sepsis, urinary tract infection, nasopharyngitis; febrile neutropenia; hypersensitivity; dehydration; arterial thromboembolism, venous thromboembolism; oropharyngeal pain, rhinorrhoea; rectal haemorrhage, fistula, aphthous stomatitis, haemorrhoids, proctalgia, toothache; skin hyperpigmentation.

Uncommon (≥1/1,000 to <1/100): cardiac failure; posterior reversible encephalopathy syndrome (PRES); gastrointestinal perforation; compromised wound healing; osteonecrosis of the jaw; nephrotic syndrome; thrombotic microangiopathy.

Rare (≥1/10,000 to <1/1,000): reduced ejection fraction.

Not known: aneurysms and artery dissections.

Bleeding of any grade occurred in 37.8% of patients on Zaltrap/FOLFIRI against 19.0% on placebo/FOLFIRI; minor epistaxis was the commonest form (27.7%), and grade 3–4 haemorrhage was reported in 2.9% against 1.7%. Gastrointestinal perforation (any grade) was reported in 0.8% of Zaltrap-treated patients against 0.3% on placebo across three phase III studies, and fatal cases occurred. Reactions leading to permanent discontinuation in 1% of patients or more were vascular disorders (3.8%, including hypertension 2.3%), infections (3.4%), diarrhoea (2.3%), fatigue (2.1%), asthenia (1.6%), proteinuria (1.5%), stomatitis (1.1%), neutropenia (1.1%), pulmonary embolism (1.1%) and dehydration (1%).

• Eylea: no interaction studies have been performed. Verteporfin photodynamic therapy combined with Eylea has not been studied, so its safety profile is not established. There are no or limited data on the combined use of Eylea with other anti-VEGF medicines, whether given into the eye or systemically.
• Zaltrap: population pharmacokinetic analysis and comparison between studies showed no pharmacokinetic interaction between aflibercept and the FOLFIRI regimen. Interactions of irinotecan, 5-fluorouracil and folinic acid are described in their own SmPCs.
• Food: no food interactions are described for either product.

Eylea is for intravitreal injection only and must be given by a qualified physician experienced in intravitreal injections. Zaltrap is given only as an intravenous infusion, under the supervision of a physician experienced in antineoplastic medicinal products. The two are never interchangeable, and Zaltrap must never be injected into the eye.

Eylea 40 mg/mL: Adults (2 mg = 0.05 mL per injection)

• Wet AMD: one injection per month for three consecutive doses, then one injection every two months. Based on the physician’s judgement of visual and anatomic outcomes, the interval may stay at two months or be extended with a treat-and-extend regimen (increases of 2 or 4 weeks); it is shortened if outcomes deteriorate. No monitoring between injections is required, and monitoring visits may be more frequent than injection visits. Intervals longer than four months or shorter than 4 weeks have not been studied.
• Macular oedema secondary to retinal vein occlusion: after the first injection, monthly treatment until maximum visual acuity is reached and/or there are no signs of disease activity; three or more consecutive monthly injections may be needed. Treatment may then continue with a treat-and-extend regimen, although data on the length of the intervals are insufficient. The interval between two doses should not be shorter than one month, and Eylea is stopped if the patient is not benefiting.
• Diabetic macular oedema: one injection per month for five consecutive doses, then one injection every two months. The interval may be kept at two months or individualised, for example with treat-and-extend (usually 2-week increases); data for intervals longer than 4 months are limited, and intervals shorter than 4 weeks have not been studied. Eylea is stopped if the patient is not benefiting.
• Myopic choroidal neovascularisation: a single injection; further doses only if outcomes show that the disease persists, with recurrences treated as a new manifestation. The interval between two doses should not be shorter than one month.

Eylea 40 mg/mL: Retinopathy of Prematurity (Preterm Infants)

• A single intravitreal injection of 0.4 mg (0.01 mL) per eye, which may be given in both eyes on the same day. Up to two injections per eye may be given within 6 months of starting if there are signs of disease activity, at least 4 weeks apart.
• The 40 mg/mL pre-filled syringe must be used with the PICLEO paediatric dosing device. The needle is inserted 1.0 to 2.0 mm from the limbus, pointing towards the optic nerve.

Eylea 114.3 mg/mL (8 mg = 0.07 mL per injection)

• Wet AMD and DME: one injection per month for three consecutive doses. Intervals may then be extended up to every 4 months, and further up to 6 months (for example with treat-and-extend), according to visual and anatomic outcomes. Monthly 8 mg doses were not studied beyond three in the pivotal studies; limited data support more than three for some patients.
• Retinal vein occlusion: one injection per month for three consecutive doses; intervals are then extended according to outcomes.
• Switching from Eylea 40 mg/mL or another anti-VEGF medicine: with stable outcomes, the previous interval can be kept or extended after the first 8 mg injection; with suboptimal outcomes, 8 mg may start with monthly injections for up to three doses before intervals are adjusted.
• The 8 mg dose needs the 114.3 mg/mL product; it cannot be given using the 40 mg/mL product. The interval between two injections should not be shorter than one month, and treatment is stopped if the patient is not benefiting.

Zaltrap (Intravenous)

• Dose: 4 mg/kg body weight as an intravenous infusion over 1 hour, followed by the FOLFIRI regimen. This is one treatment cycle.
• FOLFIRI: irinotecan 180 mg/m² as an intravenous infusion over 90 minutes and folinic acid (dl racemic) 400 mg/m² as an intravenous infusion over 2 hours at the same time on day 1 using a Y-line, followed by 5-fluorouracil (5-FU) 400 mg/m² as an intravenous bolus, then 5-FU 2,400 mg/m² as a continuous intravenous infusion over 46 hours.
• Schedule: the cycle is repeated every 2 weeks until disease progression or unacceptable toxicity.

Dose Adjustments

• Eylea: treatment is withheld in the situations listed under Special Instructions, and the interval is shortened if outcomes deteriorate.
• Zaltrap, permanent discontinuation for severe haemorrhage, gastrointestinal perforation, fistula formation, hypertension that cannot be controlled with treatment, hypertensive crisis or hypertensive encephalopathy, cardiac failure and reduced ejection fraction, arterial thromboembolic events, grade 4 venous thromboembolic events (including pulmonary embolism), nephrotic syndrome or thrombotic microangiopathy, severe hypersensitivity reactions, compromised wound healing needing medical intervention, and PRES. Zaltrap is suspended for at least 4 weeks before elective surgery.
• Neutropenia or thrombocytopenia: Zaltrap/FOLFIRI is delayed until neutrophils are 1.5 × 10⁹/L or more and platelets 75 × 10⁹/L or more. After febrile neutropenia or neutropenic sepsis, the irinotecan dose is reduced by 15–20% in later cycles; if it recurs, the 5-FU bolus and infusion doses are also reduced by 20%; if it recurs after both reductions, reducing Zaltrap to 2 mg/kg can be considered. G-CSF may be considered.
• Hypersensitivity: for mild to moderate reactions (flushing, rash, urticaria, itching) the infusion is paused until the reaction resolves, with corticosteroids and/or antihistamines as needed and pre-treatment considered in later cycles. For severe reactions (bronchospasm, dyspnoea, angioedema, anaphylaxis) Zaltrap/FOLFIRI is stopped and appropriate treatment given.
• Hypertension and proteinuria: Zaltrap is suspended until hypertension is controlled; if significant or severe hypertension recurs despite optimal treatment, it is suspended until controlled and the dose reduced to 2 mg/kg. For proteinuria of 2 g/24 hours or more it is suspended and resumed when below 2 g/24 hours; if it recurs, it is suspended again and the dose reduced to 2 mg/kg.
• FOLFIRI components: for severe stomatitis or palmar-plantar erythrodysaesthesia syndrome the 5-FU bolus and infusion doses are reduced by 20%. For severe diarrhoea, irinotecan is reduced by 15–20% and, if it recurs, the 5-FU doses by a further 20%; if it persists despite both reductions, FOLFIRI is stopped. Anti-diarrhoeal medicines and rehydration are used as needed. For other toxicities, see the SmPCs of irinotecan, 5-FU and folinic acid.

Special Populations

• Eylea, hepatic and renal impairment: no specific studies; available data do not suggest a need for dose adjustment.
• Eylea, elderly: no special considerations; experience is limited in patients over 75 years with DME.
• Eylea, children: safety and efficacy below 18 years are not established for indications other than retinopathy of prematurity. There is no relevant paediatric use in wet AMD, retinal vein occlusion, DME or myopic CNV.
• Zaltrap, elderly: no dose adjustment (28.2% of patients in the pivotal study were 65 to under 75 years, and 5.4% were 75 or over).
• Zaltrap, hepatic impairment: no formal studies; clinical data suggest no change is needed in mild or moderate impairment, and there are no data in severe impairment.
• Zaltrap, renal impairment: no formal studies; no change in the starting dose in mild or moderate impairment; data in severe impairment are very limited, so these patients are treated with caution.
• Zaltrap, children: no relevant use in the paediatric population for metastatic colorectal cancer.

Method of Administration

• Eylea: intravitreal injections are given under aseptic conditions, with adequate anaesthesia and a broad-spectrum topical microbicide (for example povidone iodine on the periocular skin, eyelid and ocular surface); surgical hand disinfection, sterile gloves, a sterile drape and a sterile eyelid speculum are recommended. The needle is inserted 3.5–4.0 mm behind the limbus into the vitreous cavity, avoiding the horizontal meridian and aiming towards the centre of the globe, and a different scleral site is used for each later injection. The volume is 0.05 mL (2 mg) or 0.07 mL (8 mg).
• Syringe and vial handling: the 40 mg/mL pre-filled syringe and vial hold more than the dose, so the excess volume must be expelled before injecting. Each vial or pre-filled syringe is used for one eye only; extracting several doses from one container raises the risk of contamination and infection.
• After injection: intraocular pressure is checked immediately (perfusion of the optic nerve head or tonometry), with sterile paracentesis equipment available if required. Patients are told to report eye pain, redness, light sensitivity or blurred vision without delay.
• Zaltrap: infusion only, over 1 hour, prepared by a healthcare professional. Because the concentrate is hyperosmolar (1,000 mOsmol/kg), undiluted Zaltrap must never be given as an intravenous push or bolus. The concentrate is diluted in 0.9% sodium chloride or 5% glucose to 0.6–8 mg/mL in PVC (with DEHP) or polyolefin bags and given through an infusion set with a 0.2 micron polyethersulfone filter; polyvinylidene fluoride or nylon filters must not be used. Each vial is single-use.

Eylea: Injection-Related Reactions

Intravitreal injections, including those with Eylea, have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract. Aseptic technique must always be used, and patients should be monitored during the week after the injection so that infection can be treated early. Adult patients must be told to report symptoms at once. For preterm infants, healthcare professionals look for signs of endophthalmitis (redness or irritation of the eye, discharge, lid swelling, light sensitivity) and parents and caregivers are told to report them without delay.

Eylea: Raised Eye Pressure

Intraocular pressure can rise within 60 minutes of an injection. Both the pressure and the perfusion of the optic nerve head are monitored and managed. Special care is needed in poorly controlled glaucoma: Eylea is not injected while intraocular pressure is 30 mmHg or higher. In preterm infants the PICLEO device must be used to avoid a volume larger than the dose, which could raise eye pressure.

Eylea: Immune Response and Systemic Effects

As a therapeutic protein, aflibercept can provoke an immune response. Patients should report pain, light sensitivity or redness, which may reflect hypersensitivity. Non-ocular bleeding and arterial thromboembolic events have been reported after intravitreal injection of VEGF inhibitors, and a link with VEGF inhibition is theoretically possible. Data are limited in patients who had a stroke, transient ischaemic attack or myocardial infarction in the previous 6 months, and these patients are treated with caution.

Eylea: When Treatment Is Withheld

Treatment is withheld in the event of rhegmatogenous retinal detachment or stage 3 or 4 macular holes; a retinal break (until it has been adequately repaired); a fall in best-corrected visual acuity of 30 letters or more compared with the last assessment; a subretinal haemorrhage involving the centre of the fovea or making up 50% or more of the lesion; and intraocular surgery performed or planned within the previous or next 28 days. For the 40 mg/mL product, treatment after a visual acuity fall or a fovea-involving haemorrhage is not resumed before the next scheduled treatment.

Eylea: Other Cautions

• Both eyes: treating both eyes at the same time has not been systematically studied and could raise systemic exposure and the risk of systemic adverse events.
• Retinal pigment epithelial tear: risk factors in wet AMD include a large or high pigment epithelial retinal detachment; caution when starting treatment in these patients.
• Limited experience: type 1 diabetes with DME, HbA1c above 12%, proliferative diabetic retinopathy, active systemic infection, concurrent eye conditions such as retinal detachment or macular hole, and diabetic patients with uncontrolled hypertension. For myopic CNV there is no experience in non-Asian patients, in patients previously treated for myopic CNV, or with extrafoveal lesions. In retinal vein occlusion, treatment is not recommended when there are clinical signs of irreversible ischaemic loss of visual function.
• Preterm infants: the warnings for adults also apply to retinopathy of prematurity; long-term safety is not established.

Zaltrap: Main Warnings

• Haemorrhage: severe and sometimes fatal bleeding has been reported. Patients are monitored for gastrointestinal and other bleeding, and Zaltrap is not given to patients with severe haemorrhage. Blood counts with platelets are checked at baseline, before each cycle and as needed.
• Gastrointestinal perforation and fistula: perforation (including fatal cases) and fistulae at gastrointestinal and other sites have occurred. Zaltrap is stopped if either develops.
• Hypertension: pre-existing hypertension must be adequately controlled before starting, and treatment should not begin if it cannot be controlled. Blood pressure is checked every two weeks, including before each administration. Zaltrap is stopped permanently if hypertension cannot be managed, or in hypertensive crisis or hypertensive encephalopathy. Patients with NYHA class III or IV heart failure should not be treated, and caution applies in clinically significant cardiovascular disease.
• Aneurysms and artery dissections: VEGF pathway inhibitors may promote these; the risk is weighed before starting in patients with hypertension or a history of aneurysm.
• Cardiac failure: cardiac failure and reduced ejection fraction have been reported. Left ventricular function should be assessed at baseline and periodically, and Zaltrap stopped if either occurs.
• Thromboembolic events: arterial events (transient ischaemic attack, stroke, angina pectoris, intracardiac thrombus, myocardial infarction, arterial embolism, ischaemic colitis) lead to discontinuation. Venous thromboembolism, including deep vein thrombosis and pulmonary embolism, also occurs: life-threatening (grade 4) events lead to discontinuation, while grade 3 deep vein thrombosis is anticoagulated and Zaltrap continued unless it recurs despite anticoagulation.
• Proteinuria: severe proteinuria, nephrotic syndrome and thrombotic microangiopathy have been reported. Urine is checked by dipstick or urinary protein/creatinine ratio before each administration, and a 24-hour urine collection is done if the dipstick shows 2+ or more or the ratio is raised. Zaltrap is suspended at 2 g/24 hours or more and stopped for nephrotic syndrome or thrombotic microangiopathy.
• Neutropenia and infection: neutropenic complications (febrile neutropenia, neutropenic infection) are more frequent with Zaltrap/FOLFIRI. Blood counts with differential are checked before each cycle, and G-CSF may be considered in patients at higher risk.
• Diarrhoea and dehydration: severe diarrhoea is more frequent; FOLFIRI doses are adjusted, and anti-diarrhoeal medicines and rehydration are given as needed.
• Hypersensitivity: severe reactions were reported in the pivotal study. Caution is needed when treating patients with a previous reaction, as reactions recurred in some patients despite prophylaxis with corticosteroids.
• Wound healing and surgery: aflibercept can impair wound healing. It is suspended at least 4 weeks before elective surgery, not started for at least 4 weeks after major surgery and until the wound is fully healed, and stopped if wound healing needs medical intervention. After minor procedures such as port placement, biopsy or tooth extraction it can be started or restarted once the wound has healed.
• Osteonecrosis of the jaw: reported in cancer patients, several of whom had received intravenous bisphosphonates. Caution applies when the two are used together or in sequence. A dental examination and preventive dentistry should be considered before starting, and invasive dental procedures avoided where possible in patients on or previously on intravenous bisphosphonates.
• PRES: can present with altered mental status, seizure, nausea, vomiting, headache or visual disturbance; MRI confirms it, and Zaltrap is stopped.
• Older patients and general condition: patients aged 65 or over had more diarrhoea, dizziness, asthenia, weight loss and dehydration and need careful monitoring. Patients with ECOG performance status 2 or higher, or significant co-morbidities, may be at greater risk of a poor outcome and should be watched for early deterioration. Data in severe renal impairment are very limited.
• Never into the eye: Zaltrap is hyperosmotic and not formulated for the eye. It must not be given as an intravitreal injection.
• Traceability: for both Eylea and Zaltrap, the product name and batch number should be recorded.

Pregnancy, Breastfeeding and Fertility

• Eylea 40 mg/mL: women of childbearing potential must use effective contraception during treatment and for at least 3 months after the last intravitreal injection. There are no data in pregnant women, and animal studies showed embryo-foetal toxicity; although systemic exposure after eye injection is very low, Eylea should not be used in pregnancy unless the benefit outweighs the risk to the foetus. Aflibercept may pass into breast milk at low levels, and as a precaution breast-feeding is not recommended. Animal studies at high systemic exposure showed impaired male and female fertility; such effects are not expected after eye injection.
• Eylea 114.3 mg/mL: the same cautions apply, with effective contraception for at least 4 months after the last injection.
• Zaltrap: effective contraception during treatment and for 3 months after the last dose. Because angiogenesis is critical to foetal development, aflibercept may harm a pregnancy and is used only if the potential benefit justifies the risk. It is unknown whether it passes into breast milk, so breast-feeding or therapy must be stopped, weighing the benefit of each. Male and female fertility are likely to be compromised during treatment, based on monkey studies in which the effects were fully reversible within 8–18 weeks after the last injection.

Excipients and Driving

• Excipients: Eylea contains polysorbate 20 (0.3 mg/mL), which may cause allergic reactions, and less than 1 mmol of sodium per dose. Zaltrap contains up to 22 mg of sodium per vial, 1.1% of the WHO recommended maximum daily intake for an adult.
• Driving after Eylea: temporary visual disturbances after the injection or eye examination can affect driving and the use of machines. Patients should not drive or use machines until their vision has recovered sufficiently.
• Driving on Zaltrap: no or negligible influence, but patients with symptoms that affect vision, concentration or reaction should not drive or use machines.

• Eylea 40 mg/mL: store in a refrigerator (2–8 °C). Do not freeze. Keep in the original package to protect from light. The unopened blister (pre-filled syringe) or unopened vial may be kept outside the refrigerator below 25 °C for up to 24 hours before use. After opening the blister or vial, proceed under aseptic conditions.
• Eylea 114.3 mg/mL: store in a refrigerator (2–8 °C). Do not freeze. Keep the vial in its outer carton, or the pre-filled syringe in its blister and outer carton, to protect from light. Before use, the unopened vial or blister may be kept outside the refrigerator below 25 °C for up to 24 hours.
• Zaltrap: store in a refrigerator (2–8 °C) in the original package to protect from light. For storage after dilution, see Shelf Life.

All three presentations are cold-chain products and should be transported and held at 2–8 °C until shortly before use.

• Eylea 40 mg/mL (pre-filled syringe and vial): 2 years.
• Eylea 114.3 mg/mL: 3 years.
• Zaltrap, unopened vial: 3 years.
• Zaltrap, after dilution in the infusion bag: chemical and physical in-use stability has been shown for 24 hours at 2–8 °C and for 8 hours at 25 °C. From a microbiological point of view the solution should be used immediately; otherwise storage times are the responsibility of the user and would normally not exceed 24 hours at 2–8 °C, unless dilution took place under controlled and validated aseptic conditions.

Prescription only (Rx). Eylea and Zaltrap are both subject to restricted medical prescription (Annex II B). Eylea and its biosimilars are given as intravitreal injections by a qualified physician experienced in administering them, so they are supplied to the hospital or clinic that administers them, with cold-chain delivery at 2–8 °C. Zaltrap is given as an intravenous infusion prepared by a healthcare professional under the supervision of a physician experienced in antineoplastic medicinal products, so it is likewise supplied to the hospital or clinic that administers it, with cold-chain delivery.