Wetlia

Wetlia, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen.

Wetlia is indicated for adults for the treatment of

- 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).

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

Recommended Dose And Schedule

Administer Wetlia 4 mg per kg as an intravenous (IV) infusion over 1 hour every two weeks. Administer Wetlia prior to any component of the FOLFIRI regimen on the day of treatment.

Continue Wetlia until disease progression or unacceptable toxicity.

Dose Modification/Treatment Delay Recommendations

Discontinue Wetlia for

• Severe hemorrhage
• Gastrointestinal perforation
• Compromised wound healing
• Fistula formation
• Hypertensive crisis or hypertensive encephalopathy
• Arterial thromboembolic events
• Nephrotic syndrome or thrombotic microangiopathy (TMA)
• Reversible posterior leukoencephalopathy syndrome (RPLS)

Temporarily Suspend Wetlia

• At least 4 weeks prior to elective surgery
• For recurrent or severe hypertension, until controlled. Upon resumption, permanently reduce the Wetlia dose to 2 mg per kg.
• For proteinuria of 2 grams per 24 hours. Resume when proteinuria is less than 2 grams per 24 hours. For recurrent proteinuria, suspend Wetlia until proteinuria is less than 2 grams per 24 hours and then permanently reduce the Wetlia dose to 2 mg per kg.

For toxicities related to irinotecan, 5-fluorouracil (5-FU), or leucovorin, refer to the current respective prescribing information.

Preparation For Administration

Inspect vials visually prior to use. Wetlia is a clear, colorless to pale yellow solution. Do not use vial if the solution is discolored or cloudy or if the solution contains particles.

Do not re-enter the vial after the initial puncture. Discard any unused portion left in the vial.

Withdraw the prescribed dose of Wetlia and dilute in 0.9% sodium chloride solution, USP or 5% dextrose solution for injection, USP to achieve a final concentration of 0.6-8 mg/mL.

Use polyvinyl chloride (PVC) infusion bags containing bis (2-ethylhexyl) phthalate (DEHP) or polyolefin infusion bags.

Store diluted Wetlia at 2°-8°C (36°-46°F) for up to 24 hours, or at controlled room temperature 20°-25°C (68°-77°F) for up to 8 hours. Discard any unused portion left in the infusion bag.

Administration

Administer the diluted Wetlia solution as an intravenous infusion over 1 hour through a 0.2 micron polyethersulfone filter. Do not use filters made of polyvinylidene fluoride (PVDF) or nylon.

Do not administer as an intravenous (IV) push or bolus.

Do not combine Wetlia with other drugs in the same infusion bag or intravenous line.

Administer Wetlia using an infusion set made of one of the following materials:

• PVC containing DEHP
• DEHP free PVC containing trioctyl-trimellitate (TOTM)
• polypropylene
• polyethylene lined PVC
• polyurethane

Wetlia is for intravitreal injection only.

Wetlia must only be administered by a qualified physician experienced in administering intravitreal injections.

Posology

wet AMD

The recommended dose for Wetlia is 2 mg aflibercept, equivalent to 50 microlitres.

Wetlia treatment is initiated with one injection per month for three consecutive doses, followed by one injection every two months. There is no requirement for monitoring between injections.

After the first 12 months of treatment with Wetlia, and based on visual and/or anatomic outcomes, the treatment interval may be extended, such as with a treat-and-extend dosing regimen, where the treatment intervals are gradually increased to maintain stable visual and/or anatomic outcomes; however there are insufficient data to conclude on the length of these intervals. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly.

The schedule for monitoring should therefore be determined by the treating physician and may be more frequent than the schedule of injections.

Macular oedema secondary to RVO (branch RVO or central RVO)

The recommended dose for Wetlia is 2 mg aflibercept equivalent to 50 microlitres.

After the initial injection, treatment is given monthly. The interval between two doses should not be shorter than one month.

If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, Wetlia should be discontinued.

Monthly treatment continues until maximum visual acuity is achieved and/or there are no signs of disease activity. Three or more consecutive, monthly injections may be needed.

Treatment may then be continued with a treat-and-extend regimen with gradually increased treatment intervals to maintain stable visual and/or anatomic outcomes, however there are insufficient data to conclude on the length of these intervals. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly.

The monitoring and treatment schedule should be determined by the treating physician based on the individual patient's response.

Monitoring for disease activity may include clinical examination, functional testing or imaging techniques (e.g. optical coherence tomography or fluorescein angiography).

Diabetic macular oedema

The recommended dose for Wetlia is 2 mg aflibercept equivalent to 50 microlitres.

Wetlia treatment is initiated with one injection per month for five consecutive doses, followed by one injection every two months. There is no requirement for monitoring between injections.

After the first 12 months of treatment with Wetlia, and based on visual and/or anatomic outcomes, the treatment interval may be extended, such as with a treat-and-extend dosing regimen, where the treatment intervals are gradually increased to maintain stable visual and/or anatomic outcomes; however there are insufficient data to conclude on the length of these intervals. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly.

The schedule for monitoring should therefore be determined by the treating physician and may be more frequent than the schedule of injections.

If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, Wetlia should be discontinued.

Myopic choroidal neovascularisation

The recommended dose for Wetlia is a single intravitreal injection of 2 mg aflibercept equivalent to 50 microlitres.

Additional doses may be administered if visual and/or anatomic outcomes indicate that the disease persists. Recurrences should be treated as a new manifestation of the disease.

The schedule for monitoring should be determined by the treating physician.

The interval between two doses should not be shorter than one month.

Special populations

Hepatic and/or renal impairment

No specific studies in patients with hepatic and/or renal impairment have been conducted with Wetlia.

Available data do not suggest a need for a dose adjustment with Wetlia in these patients.

Elderly population

No special considerations are needed. There is limited experience in patients older than 75 years with DME.

Paediatric population

The safety and efficacy of Wetlia have not been established in children and adolescents. There is no relevant use of Wetlia in the paediatric population for the indications of wet AMD, CRVO, BRVO, DME and myopic CNV.

Method of administration

Intravitreal injections must be carried out according to medical standards and applicable guidelines by a qualified physician experienced in administering intravitreal injections. In general, adequate anaesthesia and asepsis, including topical broad spectrum microbicide (e.g. povidone iodine applied to the periocular skin, eyelid and ocular surface), have to be ensured. Surgical hand disinfection, sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent) are recommended.

The injection needle should be inserted 3.5-4.0 mm posterior to the limbus into the vitreous cavity, avoiding the horizontal meridian and aiming towards the centre of the globe. The injection volume of 0.05 ml is then delivered; a different scleral site should be used for subsequent injections.

Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If required, sterile equipment for paracentesis should be available.

Following intravitreal injection patients should be instructed to report any symptoms suggestive of endophthalmitis (e.g. eye pain, redness of the eye, photophobia, blurring of vision) without delay.

Each vial should only be used for the treatment of a single eye.

The vial contains more than the recommended dose of 2 mg aflibercept. The extractable volume of the vial (100 microlitres) is not to be used in total. The excess volume should be expelled before injecting.

Injecting the entire volume of the vial could result in overdose. To expel the air bubble along with excess medicinal product, slowly depress the plunger to align the cylindrical base of the dome plunger with the black dosing line on the syringe (equivalent to 50 microlitres i.e. 2 mg aflibercept).

After injection any unused product must be discarded.

ZALTRAP should be administered under the supervision of a physician experienced in the use of antineoplastic medicinal products.

Posology

The recommended dose of ZALTRAP, administered as an intravenous infusion over 1 hour, is 4 mg/kg of body weight, followed by the FOLFIRI regimen. This is considered as one treatment cycle.

The FOLFIRI regimen to be used is irinotecan 180 mg/m² intravenous infusion over 90 minutes and folinic acid (dl racemic) 400 mg/m² 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 intravenous bolus, followed by 5-FU 2400 mg/m² continuous intravenous infusion over 46 hours.

The treatment cycle is repeated every 2 weeks.

ZALTRAP treatment should be continued until disease progression or unacceptable toxicity occurs.

Dose modification

ZALTRAP should be discontinued for :

- Severe haemorrhage

- Gastrointestinal (GI) perforation

- Fistula formation

- Hypertension that is not adequately controlled with anti-hypertensive therapy or occurrence of hypertensive crisis or hypertensive encephalopathy

- Cardiac failure and ejection fraction decreased

- Arterial thromboembolic events (ATE)

- Grade 4 venous thromboembolic events (including pulmonary embolism)

- Nephrotic syndrome or thrombotic microangiopathy (TMA)

- Severe hypersensitivity reactions (including bronchospasm, dyspnoea, angioedema, and anaphylaxis)

- Compromised wound healing requiring medical intervention

- Posterior reversible encephalopathy syndrome (PRES) (also known as reversible posterior leukoencephalopathy syndrome (RPLS))

ZALTRAP should be temporarily suspended for at least 4 weeks prior to elective surgery.

For additional toxicities related to irinotecan, 5-FU, or folinic acid, refer to the current respective summary of product characteristics.

Special populations

Older people

In the pivotal MCRC study, 28.2% of patients were aged >65 and <75 and 5.4% of patients were aged >75. No dose adjustments of ZALTRAP is required in the older people.

Hepatic impairment

There have been no formal studies with ZALTRAP in patients with hepatic impairment. Clinical data suggest that no change in aflibercept dose is required in patients with mild to moderate hepatic impairment. There are no data regarding the administration of aflibercept in patients with severe hepatic impairment.

Renal impairment

There have been no formal studies with ZALTRAP in patients with renal impairment. Clinical data suggest that no change in starting dose is required in patients with mild to moderate renal impairment. There are very limited data in patients with severe renal impairment; therefore, these patients should be treated with caution.

Paediatric population

There is no relevant use of ZALTRAP in the paediatric population for the indication of metastatic colorectal cancer.

Method of administration

ZALTRAP is to be administered only as an intravenous infusion over 1 hour. Due to hyperosmolality (1000 mOsmol/kg) of the ZALTRAP concentrate, undiluted ZALTRAP concentrate must not be administered as an intravenous push or bolus. ZALTRAP must not be administered as an intravitreal injection.

Each vial of concentrate for solution for infusion is for single use (single-dose) only.

Precautions to be taken before handling or administering the medicinal product

None

Active or suspected ocular or periocular infection.

Active severe intraocular inflammation.

Ophthalmic / intravitreal use due to hyperosmotic properties of ZALTRAP.

For contraindications related to FOLFIRI components (irinotecan, 5-FU, and folinic acid), refer to the current respective summary of product characteristics.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hemorrhage

Patients treated with Wetlia have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In patients with mCRC, bleeding/hemorrhage (all grades) were reported in 38% of patients treated with Wetlia/FOLFIRI compared to 19% of patients treated with placebo/FOLFIRI. Grade 3-4 hemorrhagic events, including gastrointestinal hemorrhage, hematuria, and post-procedural hemorrhage, were reported in 3% of patients receiving Wetlia/FOLFIRI compared with 1% of patients receiving placebo/FOLFIRI. Severe intracranial hemorrhage and pulmonary hemorrhage/hemoptysis including fatal events have also occurred in patients receiving Wetlia.

Monitor patients for signs and symptoms of bleeding. Do not initiate Wetlia in patients with severe hemorrhage. Discontinue Wetlia in patients who develop severe hemorrhage.

Gastrointestinal Perforation

Gastrointestinal (GI) perforation including fatal GI perforation can occur in patients receiving Wetlia. Across three Phase 3 placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of GI perforation (all grades) was 0.8% for patients treated with Wetlia and 0.3% for patients treated with placebo. Grade 3-4 GI perforation events occurred in 0.8% of patients treated with Wetlia and 0.2% of patients treated with placebo.

Monitor patients for signs and symptoms of GI perforation. Discontinue Wetlia therapy in patients who experience GI perforation.

Compromised Wound Healing

Wetlia impairs wound healing in animal models. Grade 3 compromised wound healing was reported in 2 patients (0.3%) treated with Wetlia/FOLFIRI regimen and in none of the patients treated with placebo/FOLFIRI regimen.

Suspend Wetlia for at least 4 weeks prior to elective surgery. Do not resume Wetlia for at least 4 weeks following major surgery and until the surgical wound is fully healed. For minor surgery such as central venous access port placement, biopsy, and tooth extraction, Wetlia may be initiated/resumed once the surgical wound is fully healed. Discontinue Wetlia in patients with compromised wound healing.

Fistula Formation

Fistula formation involving gastrointestinal and non-gastrointestinal sites occurs at a higher incidence in patients treated with Wetlia. In patients with mCRC, fistulas (anal, enterovesical, enterocutaneous, colovaginal, intestinal sites) were reported in 9 of 611 patients (1.5%) treated with Wetlia/FOLFIRI regimen and 3 of 605 patients (0.5%) treated with placebo/FOLFIRI regimen. Grade 3 GI fistula formation occurred in 2 patients treated with Wetlia (0.3%) and in 1 placebo-treated patient (0.2%).

Discontinue Wetlia therapy in patients who develop fistula.

Hypertension

Wetlia increases the risk of Grade 3-4 hypertension. There is no clinical trial experience administering Wetlia to patients with NYHA class III or IV heart failure. In patients with mCRC, Grade 3 hypertension (defined as requiring adjustment in existing anti-hypertensive therapy or treatment with more than one drug) was reported in 1.5% of patients treated with placebo/FOLFIRI and 19% of patients treated with Wetlia/FOLFIRI. Grade 4 hypertension (hypertensive crisis) was reported in 1 patient (0.2%) treated with Wetlia/FOLFIRI. Among those patients treated with Wetlia/FOLFIRI developing Grade 3-4 hypertension, 54% had onset during the first two cycles of treatment.

Monitor blood pressure every two weeks or more frequently as clinically indicated during treatment with Wetlia. Treat with appropriate anti-hypertensive therapy and continue monitoring blood pressure regularly. Temporarily suspend Wetlia in patients with uncontrolled hypertension until controlled, and permanently reduce Wetlia dose to 2 mg per kg for subsequent cycles. Discontinue Wetlia in patients with hypertensive crisis or hypertensive encephalopathy.

Arterial Thromboembolic Events

Arterial thromboembolic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received Wetlia. In patients with mCRC, ATE was reported in 2.6% of patients treated with Wetlia/FOLFIRI and 1.7% of patients treated with placebo/FOLFIRI. Grade 3-4 events occurred in 11 patients (1.8%) treated with Wetlia/FOLFIRI and 4 patients (0.7%) treated with placebo/FOLFIRI.

Discontinue Wetlia in patients who experience an ATE.

Proteinuria

Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with Wetlia. In patients with mCRC, proteinuria was reported in 62% patients treated with Wetlia/FOLFIRI compared to 41% patients treated with placebo/FOLFIRI. Grade 3-4 proteinuria occurred in 8% of patients treated with Wetlia/FOLFIRI compared to 1% of patients treated with placebo/FOLFIRI. Nephrotic syndrome occurred in 2 patients (0.5%) treated with Wetlia/FOLFIRI compared to none of the patients treated with placebo/FOLFIRI. TMA was reported in 3 of 2258 patients with cancer enrolled across completed studies.

Monitor proteinuria by urine dipstick analysis and/or urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria during Wetlia therapy. Patients with a dipstick of ≥ 2+ for protein or a UPCR greater than 1 should undergo a 24-hour urine collection.

Suspend Wetlia administration for proteinuria 2 grams per 24 hours or more, and resume when proteinuria is less than 2 grams per 24 hours. If recurrent, suspend until proteinuria is less than 2 grams per 24 hours and then permanently reduce the Wetlia dose to 2 mg per kg. Discontinue Wetlia in patients who develop nephrotic syndrome or TMA.

Neutropenia And Neutropenic Complications

A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving Wetlia. In patients with mCRC, Grade 3-4 neutropenia occurred in 37% of patients treated with Wetlia/FOLFIRI compared to 30% patients treated with placebo/FOLFIRI. Grade 3-4 febrile neutropenia occurred in 4% of patients treated with Wetlia/FOLFIRI compared to 2% of patients treated with placebo/FOLFIRI. Grade 3-4 neutropenic infection/sepsis occurred in 1.5% of patients treated with Wetlia/FOLFIRI and 1.2% of patients treated with placebo/FOLFIRI.

Monitor CBC with differential count at baseline and prior to initiation of each cycle of Wetlia. Delay Wetlia/FOLFIRI until neutrophil count is at or above 1.5 x 10⁹/L.

Diarrhea And Dehydration

The incidence of severe diarrhea is increased in patients treated with Wetlia/FOLFIRI. In patients with mCRC, Grade 3-4 diarrhea was reported in 19% of patients treated with Wetlia/FOLFIRI compared to 8% of patients treated with placebo/FOLFIRI. Grade 3-4 dehydration was reported in 4% of patients treated with Wetlia/FOLFIRI compared to 1% of patients treated with placebo/FOLFIRI. The incidence of diarrhea is increased in patients who are age 65 years or older as compared to patients younger than 65 years of age. Monitor elderly patients closely for diarrhea.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

RPLS (also known as posterior reversible encephalopathy syndrome) was reported in 0.5% of 3795 patients treated with Wetlia monotherapy or in combination with chemotherapy.

Confirm the diagnosis of RPLS with MRI and discontinue Wetlia in patients who develop RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae or death.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No studies have been conducted to evaluate carcinogenicity or mutagenicity of ziv-aflibercept.

Ziv-aflibercept impaired reproductive function and fertility in monkeys. In a 6-month repeat-dose toxicology study in sexually mature monkeys, ziv-aflibercept inhibited ovarian function and follicular development, as evidenced by: decreased ovary weight, decreased amount of luteal tissue, decreased number of maturing follicles, atrophy of uterine endometrium and myometrium, vaginal atrophy, abrogation of progesterone peaks and menstrual bleeding. Alterations in sperm morphology and decreased sperm motility were noted in male monkeys. These effects were observed at all doses tested including the lowest dose tested, 3 mg per kg. Reversibility was observed within 18 weeks after cessation of treatment. Systemic exposure (AUC) with a 3 mg per kg per dose in monkeys was approximately 60% of the AUC in patients at the recommended dose.

Use In Specific Populations

Pregnancy

Pregnancy Category C

Risk Summary

There are no adequate and well-controlled studies with Wetlia in pregnant women. Wetlia was embryotoxic and teratogenic in rabbits at exposure levels lower than human exposures at the recommended dose, with increased incidences of external, visceral, and skeletal fetal malformations. Wetlia should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data

Ziv-aflibercept produced embryo-fetal toxicity when administered every 3 days during organogenesis in pregnant rabbits at all intravenous doses tested, ≥ 3 mg per kg. Adverse embryo-fetal effects included increased incidences of postimplantation losses and external (including anasarca, umbilical hernia, diaphragmatic hernia and gastroschisis, cleft palate, ectrodactyly, and atresia), visceral (in the heart, great vessels, and arteries), and skeletal fetal malformations (including fused vertebrae, sternebrae, and ribs; supernumerary arches and ribs, and incomplete ossification). Administration of the 3 mg per kg dose to rabbits resulted in systemic exposure (AUC) that was approximately 30% of the AUC in patients at the recommended dose. The incidence and severity of fetal anomalies increased with increasing dose.

Nursing Mothers

It is not known whether Wetlia is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Wetlia, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness in pediatric patients have not been established. In a dose-escalation, safety, and tolerability study, 21 patients ages 2 to 21 years (median age 12.9) with solid tumors received Wetlia at doses ranging from 2 to 3 mg/kg, IV, every two weeks. The pharmacokinetics of free ziv-aflibercept were evaluated in 8 of these patients (ages 5 to 17 years). The maximum tolerated dose in the study was 2.5 mg/kg, below the dose known to be safe and effective in adults with mCRC.

Geriatric Use

Of the 611 patients with mCRC, patients treated with Wetlia/FOLFIRI, 205 (34%) were 65 years or older, and 33 (5%) were 75 years or older. Elderly patients ( ≥ 65 years of age) experienced higher incidences ( ≥ 5%) of diarrhea, dizziness, asthenia, weight decrease, and dehydration when compared to younger patients. Monitor elderly patients more closely for diarrhea and dehydration.

The effect of Wetlia on overall survival was similar in patients < 65 years old and ≥ 65 years old who received Wetlia/FOLFIRI.

No dose adjustment of Wetlia is recommended for patients greater than or equal to 65 years of age.

Hepatic Impairment

No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ziv-aflibercept.

Based on a population PK analysis with data from 1507 patients, ziv-aflibercept exposure in patients with mild and moderate hepatic impairment were similar to those in patients with normal hepatic function. There are no data available for patients with severe hepatic impairment.

Renal Impairment

No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ziv-aflibercept.

Based on a population PK analysis with data from 1507 patients, ziv-aflibercept exposure in patients with mild, moderate, and severe renal impairment were similar to those in patients with normal renal function.

Females And Males Of Reproductive Potential

Male and female reproductive function and fertility may be compromised during treatment with Wetlia, as suggested by findings in monkeys. These animal findings were reversible within 18 weeks after cessation of treatment. Females and males of reproductive potential should use highly effective contraception during and up to a minimum of 3 months after the last dose of treatment.

Intravitreal injection-related reactions

Intravitreal injections, including those with Wetlia, have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract. Proper aseptic injection techniques must always be used when administering Wetlia. In addition, patients should be monitored during the week following the injection to permit early treatment if an infection occurs. Patients should be instructed to report any symptoms suggestive of endophthalmitis or any of the above mentioned events without delay.

Increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including those with Wetlia. Special precaution is needed in patients with poorly controlled glaucoma (do not inject Wetlia while the intraocular pressure is > 30 mmHg). In all cases, both the intraocular pressure and the perfusion of the optic nerve head must therefore be monitored and managed appropriately.

Immunogenicity

As this is a therapeutic protein, there is a potential for immunogenicity with Wetlia. Patients should be instructed to report any signs or symptoms of intraocular inflammation, e.g. pain, photophobia, or redness, which may be a clinical sign attributable to hypersensitivity.

Systemic effects

Systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events have been reported following intravitreal injection of VEGF inhibitors and there is a theoretical risk that these may relate to VEGF inhibition. There are limited data on safety in the treatment of patients with CRVO, BRVO, DME or myopic CNV with a history of stroke or transient ischaemic attacks or myocardial infarction within the last 6 months. Caution should be exercised when treating such patients.

Other

As with other intravitreal anti-VEGF treatments for AMD, CRVO, BRVO, DME and myopic CNV the following also applies:

- The safety and efficacy of Wetlia therapy administered to both eyes concurrently have not been systematically studied. If bilateral treatment is performed at the same time this could lead to an increased systemic exposure, which could increase the risk of systemic adverse events.

- Concomitant use of other anti-VEGF (vascular endothelial growth factor)

- There is no data available on the concomitant use of Wetlia with other anti-VEGF medicinal products (systemic or ocular).

- Risk factors associated with the development of a retinal pigment epithelial tear after anti-VEGF therapy for wet AMD, include a large and/or high pigment epithelial retinal detachment. When initiating Wetlia therapy, caution should be used in patients with these risk factors for retinal pigment epithelial tears.

- Treatment should be withheld in patients with rhegmatogenous retinal detachment or stage 3 or 4 macular holes.

- In the event of a retinal break the dose should be withheld and treatment should not be resumed until the break is adequately repaired.

- The dose should be withheld and treatment should not be resumed earlier than the next scheduled treatment in the event of:

â–ª a decrease in best-corrected visual acuity (BCVA) of >30 letters compared with the last assessment of visual acuity;

â–ª a subretinal haemorrhage involving the centre of the fovea, or, if the size of the haemorrhage is >50%, of the total lesion area.

- The dose should be withheld within the previous or next 28 days in the event of a performed or planned intraocular surgery.

- Wetlia should not be used in pregnancy unless the potential benefit outweighs the potential risk to the foetus.

- Women of childbearing potential have to use effective contraception during treatment and for at least 3 months after the last intravitreal injection of aflibercept.

- There is limited experience with treatment of patients with ischaemic CRVO and BRVO. In patients presenting with clinical signs of irreversible ischaemic visual function loss, the treatment is not recommended.

Populations with limited data

There is only limited experience in the treatment of subjects with DME due to type I diabetes or in diabetic patients with an HbA1c over 12% or with proliferative diabetic retinopathy.

Wetlia has not been studied in patients with active systemic infections or in patients with concurrent eye conditions such as retinal detachment or macular hole. There is also no experience of treatment with Wetlia in diabetic patients with uncontrolled hypertension. This lack of information should be considered by the physician when treating such patients.

In myopic CNV there is no experience with Wetlia in the treatment of non-Asian patients, patients who have previously undergone treatment for myopic CNV, and patients with extrafoveal lesions.

Haemorrhage

An increased risk of haemorrhage, including severe and sometimes fatal haemorrhagic events has been reported in patients treated with aflibercept.

Patients should be monitored for signs and symptoms of GI bleeding and other severe bleeding. Aflibercept should not be administered to patients with severe haemorrhage.

Thrombocytopenia has been reported in patients treated with the ZALTRAP/FOLFIRI regimen. Monitoring of complete blood count (CBC) with platelets is recommended at baseline, prior to initiation of each cycle of aflibercept, and as clinically necessary. Administration of the ZALTRAP/FOLFIRI should be delayed until platelet count is >75 x 10⁹/L.

Gastrointestinal perforation

GI perforation including fatal GI perforation has been reported in patients treated with aflibercept.

Patients should be monitored for signs and symptoms of GI perforation. Aflibercept treatment should be discontinued in patients who experience GI perforation.

Fistula formation

Fistula formation involving GI and non-GI sites has occurred in patients treated with aflibercept.

Aflibercept treatment should be discontinued in patients who develop fistula.

Hypertension

An increased risk of grade 3-4 hypertension (including hypertension and one case of essential hypertension) has been observed in patients treated with the ZALTRAP/FOLFIRI regimen.

Pre-existing hypertension must be adequately controlled before starting aflibercept. If hypertension cannot be adequately controlled, treatment with aflibercept should not be initiated. It is recommended to monitor blood pressure every two weeks, including before each administration or as clinically indicated during treatment with aflibercept. In the event of hypertension on aflibercept treatment, blood pressure should be controlled with appropriate anti-hypertensive therapy and blood pressure should be monitored regularly. In case of recurrent medically significant or severe hypertension, despite optimal treatment, aflibercept should be suspended until the hypertension is controlled and the aflibercept dose should be reduced to 2 mg/kg for subsequent cycles. Aflibercept should be permanently discontinued if hypertension cannot be adequately managed with appropriate anti-hypertensive therapy or aflibercept dose reduction, or if hypertensive crisis or hypertensive encephalopathy occurs.

Hypertension may exacerbate underlying cardiovascular disease. Caution should be exercised when treating patients with history of clinically significant cardiovascular disease such as coronary artery disease, or congestive heart failure with ZALTRAP. Patients with NYHA class III or IV congestive heart failure should not be treated with ZALTRAP.

Cardiac failure and ejection fraction decreased

Cardiac failure and ejection fraction decreased have been reported in patients treated with ZALTRAP. Baseline and periodic evaluations of left ventricular function should be considered while the patient is receiving Zaltrap. Patients should be monitored for signs and symptoms of cardiac failure and ejection fraction decreased. Discontinue ZALTRAP in patients who experience cardiac failure and ejection fraction decreased.

Thrombotic and embolic events

Arterial thromboembolic events (ATE)

ATE (including transient ischaemic attack, cerebrovascular accident, angina pectoris, intracardiac thrombus, myocardial infarction, arterial embolism, and ischaemic colitis) have been observed in patients treated with aflibercept.

Aflibercept treatment should be discontinued in patients who experience an ATE.

Venous thromboembolic events (VTE)

VTE including deep vein thrombosis (DVT) and pulmonary embolism (infrequently fatal) have been reported in patients treated with aflibercept.

ZALTRAP should be discontinued in patients with life-threatening (Grade 4) thromboembolic events (including pulmonary embolism). Patients with Grade 3 DVT should be treated with anticoagulation as clinically indicated, and aflibercept therapy should be continued. In the event of recurrence, despite appropriate anticoagulation, aflibercept treatment should be discontinued. Patients with thromboembolic events of Grade 3 or lower need to be closely monitored.

Proteinuria

Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) have been observed in patients treated with aflibercept.

Proteinuria should be monitored by urine dipstick analysis and/or urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria before each aflibercept administration. Patients with a dipstick of >2+ for protein or a UPCR >1 or a protein/creatinine ratio (PCR) >100 mg/mmol should undergo a 24-hour urine collection.

Aflibercept administration should be suspended for >2 grams of proteinuria/24 hours and restarted when proteinuria is <2 grams/24 hours. If there is recurrence, the administration should be suspended until <2 grams/24 hours and then the dose reduced to 2 mg/kg. Aflibercept treatment should be discontinued in patients who develop nephrotic syndrome or TMA.

Neutropenia and neutropenic complications

A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) has been observed in patients treated with the ZALTRAP/FOLFIRI regimen.

Monitoring of complete blood count (CBC) with differential count is recommended at baseline and prior to initiation of each cycle of aflibercept. Administration of ZALTRAP/FOLFIRI should be delayed until neutrophil count is >1.5 x 10⁹/L. Therapeutic use of G-CSF at first occurrence of grade >3 neutropenia and secondary prophylaxis may be considered in patients who may be at increased risk for neutropenia complications.

Diarrhoea and dehydration

A higher incidence of severe diarrhoea has been observed in patients treated with the ZALTRAP/FOLFIRI regimen.

Dose modification of FOLFIRI regimen , anti-diarrhoeal medicinal products, and rehydration as needed should be instituted.

Hypersensitivity reactions

In the pivotal study of MCRC patients, severe hypersensitivity reactions have been reported in patients treated with the ZALTRAP/FOLFIRI regimen.

In the event of a severe hypersensitivity reaction (including bronchospasm, dyspnoea, angioedema, and anaphylaxis), aflibercept should be discontinued and appropriate medical measures should be administered.

In the event of a mild to moderate hypersensitivity reaction to ZALTRAP (including flushing, rash, urticaria, and pruritus), aflibercept should be temporarily suspended until the reaction is resolved. Treatment with corticosteroids and/or antihistamines can be initiated as clinically indicated. Pre-treatment with corticosteroids and/or antihistamines may be considered in subsequent cycles. Caution should be used when retreating patients with prior hypersensitivity reactions as recurrent hypersensitivity reactions have been observed in some patients despite prophylaxis, including corticosteroids.

Compromised wound healing

Aflibercept impaired wound healing in animal models.

Potential for compromised wound healing (wound dehiscence, anastomotic leakage) has been reported with aflibercept.

Aflibercept should be suspended for at least 4 weeks prior to elective surgery.

It is recommended that aflibercept not be initiated for at least 4 weeks following major surgery and not until the surgical wound is fully healed. For minor surgery such as central venous access port placement, biopsy, and tooth extraction, aflibercept may be initiated/restarted once the surgical wound is fully healed. Aflibercept should be discontinued in patients with compromised wound healing requiring medical intervention.

Osteonecrosis of the jaw (ONJ)

Cases of ONJ have been reported in cancer patients treated with Zaltrap, several of whom had received prior or concomitant treatment with intravenous bisphosphonates, for which ONJ is an identified risk. Caution should be exercised when Zaltrap and intravenous bisphosphonates are administered concurrently or sequentially.

Invasive dental procedures are also an identified risk factor. A dental examination and appropriate preventive dentistry should be considered prior to starting the treatment with Zaltrap. Invasive dental procedures should, if possible, be avoided in patients treated with Zaltrap and who have previously received or are receiving intravenous bisphosphonates.

Posterior reversible encephalopathy syndrome (PRES)

PRES was not reported in the pivotal phase III study of MCRC patients. In other studies, PRES was reported in patients treated with aflibercept as monotherapy and in combination with other chemotherapies.

PRES may present with altered mental status, seizure, nausea, vomiting, headache, or visual disturbances. The diagnosis of PRES is confirmed by brain Magnetic Resonance Imaging (MRI).

Aflibercept should be discontinued in patients that develop PRES.

Older people

Older people patients >65 years had an increased risk of diarrhoea, dizziness, asthenia, weight loss and dehydration. Careful monitoring is recommended in order to rapidly detect and treat signs and symptoms of diarrhoea and dehydration and to minimize potential risk.

Renal impairment

There are very limited data available for patients with severe renal impairment treated with aflibercept. No dose adjustment is required for aflibercept.

Performance status and co-morbidities

Patients with ECOG performance status >2 or having significant co-morbidities may be at greater risk for a poor clinical outcome and should be carefully monitored for early clinical deterioration.

Off-label intravitreal use

ZALTRAP is a hyperosmotic solution, which is not formulated for compatibility with the intraocular environment. ZALTRAP must not be administered as an intravitreal injection.

Injection with Wetlia has a minor influence on the ability to drive and use machines due to possible temporary visual disturbances associated either with the injection or the eye examination. Patients should not drive or use machines until their visual function has recovered sufficiently.

ZALTRAP has no or negligible influence on the ability to drive and use machines. If patients are experiencing symptoms that affect their vision or concentration, or their ability to react, they should be advised not to drive or use machines.

The following serious adverse reactions are discussed elsewhere in the labeling:

• Hemorrhage
• Gastrointestinal Perforation
• Compromised Wound Healing
• Fistula Formation
• Hypertension
• Arterial Thromboembolic Events
• Proteinuria
• Neutropenia and Neutropenic Complications
• Diarrhea and Dehydration
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

Clinical Trial Experience

Because clinical trials are conducted under varying designs and in different patient populations, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.

The safety of Wetlia in combination with FOLFIRI was evaluated in 1216 previously treated patients with metastatic colorectal cancer (Study 1) who were treated with Wetlia 4 mg per kg intravenous (N=611) or placebo (N=605) every two weeks (one cycle) in a randomized (1:1), double-blind, placebo-controlled Phase 3 study. Patients received a median of 9 cycles of Wetlia/FOLFIRI or 8 cycles of placebo/FOLFIRI.

The most common adverse reactions (all grades, ≥ 20% incidence) reported at a higher incidence (2% or greater between-arm difference) in the Wetlia/FOLFIRI arm , in order of decreasing frequency, were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache (see Table 1).

The most common Grade 3-4 adverse reactions ( ≥ 5%) reported at a higher incidence (2% or greater between-arm difference) in the Wetlia/FOLFIRI arm, in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia (see Table 1).

The most frequent adverse reactions leading to permanent discontinuation in ≥ 1% of patients treated with Wetlia/FOLFIRI regimen were asthenia/fatigue, infections, diarrhea, dehydration, hypertension, stomatitis, venous thromboembolic events, neutropenia, and proteinuria.

The Wetlia dose was reduced and/or omitted in 17% of patients compared to placebo-dose modification in 5% of patients. Cycle delays > 7 days occurred in 60% of patients treated with Wetlia/FOLFIRI compared with 43% of patients treated with placebo/FOLFIRI.

The most common adverse reactions and laboratory abnormalities during study treatment in Study 1 where the incidence was ≥ 5% (all grades) in patients receiving Wetlia in combination with FOLFIRI and which occurred at ≥ 2% higher frequency in patients treated with Wetlia/FOLFIRI compared to placebo/FOLFIRI are shown in Table 1.

Table 1: Selected Adverse Reactions and Laboratory Findings in Study 1:

Infections occurred at a higher frequency in patients receiving Wetlia/FOLFIRI (46%, all grades; 12%, Grade 3-4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3-4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection.

In patients with mCRC, severe hypersensitivity reactions have been reported with Wetlia/FOLFIRI (0.3%) and placebo/FOLFIRI (0.5%).

In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients treated with Wetlia/FOLFIRI and 7% of patients treated with placebo/FOLFIRI. Grade 3-4 VTE occurred in 8% of patients treated with Wetlia/FOLFIRI and in 6% of patients treated with placebo/FOLFIRI. Pulmonary embolism occurred in 5% of patients treated with Wetlia/FOLFIRI and 3.4% of patients treated with placebo/FOLFIRI.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. In patients with various cancers across 15 studies, 1.4% (41/2862) of patients tested positive for anti-product antibody (APA) at baseline. The incidence of APA development was 3.1% (53/1687) in patients receiving intravenous ziv-aflibercept and 1.7% (19/1134) in patients receiving placebo. Among patients who tested positive for APA and had sufficient samples for further testing, neutralizing antibodies were detected in 17 of 48 ziv-aflibercept-treated patients and in 2 of 40 patients receiving placebo.

The mean free ziv-aflibercept trough concentrations were lower in patients with positive neutralizing antibodies than in the overall population. The impact of neutralizing antibodies on efficacy and safety could not be assessed based on limited available data.

Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Wetlia with the incidence of antibodies to other products may be misleading.

Post Marketing Experience

The following adverse reactions have been identified during post-approval use of Wetlia. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Musculoskeletal and connective tissue disorders: Osteonecrosis of the jaw

Cardiac disorders: Cardiac failure, Ejection fraction decreased

Summary of the safety profile

A total of 3,102 patients constituted the safety population in the eight phase III studies. Among those, 2,501 patients were treated with the recommended dose of 2 mg.

Serious ocular adverse reactions in the study eye related to the injection procedure have occurred in less than 1 in 1,900 intravitreal injections with Wetlia and included blindness, endophthalmitis, retinal detachment, cataract traumatic, cataract, vitreous haemorrhage, vitreous detachment, and intraocular pressure increased.

The most frequently observed adverse reactions (in at least 5% of patients treated with Wetlia) were conjunctival haemorrhage (25%), visual acuity reduced (11%), eye pain (10%), cataract (8%), intraocular pressure increased (8%), vitreous detachment (7%), and vitreous floaters (7%).

Tabulated list of adverse reactions

The safety data described below include all adverse reactions from the eight phase III studies in the indications wet AMD, CRVO, BRVO, DME and myopic CNV with a reasonable possibility of causality to the injection procedure or medicinal product.

The adverse reactions are listed by system organ class and frequency using the following convention:

Very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (> 1/10,000 to < 1/1,000)

Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness.

Table 1: All treatment-emergent adverse drug reactions reported in patients in phase III studies (pooled data of the phase III studies for the indications wet AMD, CRVO, BRVO, DME and myopic CNV) or during post-marketing surveillance

* Conditions known to be associated with wet AMD. Observed in the wet AMD studies only.

** Culture positive and culture negative endophthalmitis

*** During the post-marketing period, reports of hypersensitivity included rash, pruritus, urticaria, and isolated cases of severe anaphylactic/anaphylactoid reactions.

Description of selected adverse reactions

In the wet AMD phase III studies, there was an increased incidence of conjunctival haemorrhage in patients receiving anti-thrombotic agents. This increased incidence was comparable between patients treated with ranibizumab and Wetlia.

Arterial thromboembolic events (ATEs) are adverse events potentially related to systemic VEGF inhibition. There is a theoretical risk of arterial thromboembolic events, including stroke and myocardial infarction, following intravitreal use of VEGF inhibitors.

A low incidence rate of arterial thromboembolic events was observed in the Wetlia clinical trials in patients with AMD, DME, RVO and myopic CNV. Across indications no notable difference between the groups treated with aflibercept and the respective comparator groups were observed.

As with all therapeutic proteins, there is a potential for immunogenicity with Wetlia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Summary of the safety profile

The safety of ZALTRAP in combination with FOLFIRI was evaluated in 1216 patients previously treated for metastatic colorectal cancer, of which 611 patients were treated with ZALTRAP 4 mg/kg every two weeks (one cycle) and 605 patients were treated with placebo/FOLFIRI in a phase III study. Patients received a median number of 9 cycles of the ZALTRAP/FOLFIRI regimen.

The most common adverse reactions (all grades, >20% incidence) reported at least 2% greater incidence for the ZALTRAP/FOLFIRI regimen as compared to the placebo/FOLFIRI regimen in order of decreasing frequency were leucopenia, diarrhoea, neutropenia, proteinuria, increased aspartate aminotransferase (AST), stomatitis, fatigue, thrombocytopenia, increased alanine aminotransferase (ALT), hypertension, weight loss, decreased appetite, epistaxis, abdominal pain, dysphonia, increased serum creatinine, and headache (see Table 1).

The most common reported grades 3-4 reactions (>5% incidence) reported at least 2% greater incidence for the ZALTRAP/FOLFIRI regimen as compared to the placebo/FOLFIRI regimen in order of decreasing frequency, were neutropenia, diarrhoea, hypertension, leucopenia, stomatitis, fatigue, proteinuria, and asthenia (see Table 1).

The most frequent adverse reactions leading to permanent discontinuation in >1% of patients treated with the ZALTRAP/FOLFIRI regimen were vascular disorders (3.8%) including hypertension (2.3%), infections (3.4%), asthenia/fatigue (1.6%, 2.1%),diarrhoea (2.3%), dehydration (1%), stomatitis (1.1%), neutropenia (1.1%), proteinuria (1.5%), and pulmonary embolism (1.1%).

Tabulated summary of adverse reactions

Adverse reactions and laboratory abnormalities reported in patients treated with the ZALTRAP/FOLFIRI regimen compared to patients treated with the placebo/FOLFIRI regimen are listed in Table 1 according to MedDRA system organ class and frequency categories. Adverse reactions in Table 1 are defined as either any adverse clinical reaction or laboratory abnormality having >2% greater incidence (all grades) in the aflibercept treatment group in comparison to the placebo treatment group in the MCRC study including those that do not meet this threshold but were consistent with the anti-VEGF class and were seen in any study with aflibercept. Intensity of the adverse reactions is graded according to NCI CTC version 3.0 (grade >3 = G>3). Frequencies are based on all grades and defined as: very common (>1/10), common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Table 1 - Adverse reactions reported in patients treated with the ZALTRAP/FOLFIRI regimen from the MCRC study

In the pivotal MCRC study, anaemia, nausea, vomiting, constipation, alopecia, increased alkaline phosphatase, and hyperbilirubinaemia occurred in >20% of patients. These were comparable between groups, and the difference between groups did not exceed >2% incidence for the ZALTRAP/FOLFIRI regimen.

Description of selected adverse reactions

Haemorrhage

Patients treated with ZALTRAP have an increased risk of haemorrhage, including severe and sometimes fatal haemorrhagic events. In the pivotal study of MCRC patients, episodes of bleeding/haemorrhage (all grades) was reported in 37.8% of patients treated with the ZALTRAP/FOLFIRI regimen compared to 19.0% of patients treated with the placebo/FOLFIRI regimen. The most common reported form of bleeding was minor (grade 1-2) epistaxis occurring in 27.7% of patients treated with the ZALTRAP/FOLFIRI regimen. Grade 3-4 haemorrhage including GI haemorrhage, haematuria, and post-procedural haemorrhage was reported in 2.9% of patients receiving the ZALTRAP/FOLFIRI regimen compared with 1.7% of patients receiving the placebo/FOLFIRI regimen. In other studies, severe intracranial haemorrhage and pulmonary haemorrhage/haemoptysis including fatal events have occurred in patients receiving ZALTRAP.

Gastrointestinal perforation

GI perforation including fatal GI perforation has been reported in patients treated with ZALTRAP. In the pivotal study of MCRC patients, GI perforation (all grades) was reported in 3 of 611 patients (0.5%) treated with the ZALTRAP/FOLFIRI regimen and 3 of 605 patients (0.5%) treated with the placebo/FOLFIRI regimen. Grade 3-4 GI perforation events occurred in all 3 patients (0.5%) treated with the ZALTRAP/FOLFIRI regimen and in 2 patients (0.3%) treated with the placebo/FOLFIRI regimen. Across the three Phase III placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of GI perforation (all grades) was 0.8% for patients treated with ZALTRAP and 0.3% for patients treated with placebo. Grade 3-4 GI perforation events occurred in 0.8% of patients treated with ZALTRAP and 0.2% of patients treated with placebo.

Fistula formation

Fistula formation involving GI and non-GI sites has occurred in patients treated with ZALTRAP. In the pivotal study of MCRC patients, fistulas (anal, enterovesical, enterocutaneous, colovaginal, intestinal sites) were reported in 9 of 611 patients (1.5%) treated with the ZALTRAP/FOLFIRI regimen and 3 of 605 patients (0.5%) treated with the placebo/FOLFIRI regimen. Grade 3 GI fistula formation occurred in 2 patients treated with ZALTRAP (0.3%) and in 1 placebo-treated patient (0.2%). Across the three Phase III placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of fistula (all grades) was 1.1% for patients treated with ZALTRAP and 0.2% for patients treated with placebo. Grade 3-4 fistula occurred in 0.2% of patients treated with ZALTRAP and 0.1% of patients treated with placebo.

Hypertension

In the pivotal study of MCRC patients, hypertension (all grades) has been reported in 41.2% of patients treated with ZALTRAP/FOLFIRI and 10.7% of patients treated with placebo/FOLFIRI. An increased risk of grade 3-4 hypertension (including hypertension and one case of essential hypertension) has been observed in patients receiving the ZALTRAP/FOLFIRI regimen. Grade 3 hypertension (requiring adjustment in existing anti-hypertensive therapy or treatment with more than one medicinal product) was reported in 1.5% of patients treated with the placebo/FOLFIRI regimen and 19.1% of patients treated with the ZALTRAP/FOLFIRI regimen. Grade 4 hypertension (hypertensive crisis) was reported in 1 patient (0.2%) treated with the ZALTRAP/FOLFIRI regimen. Among those patients treated with the ZALTRAP/FOLFIRI regimen developing grade 3-4 hypertension, 54% had onset during the first two cycles of treatment.

Thrombotic and embolic events

Arterial thromboembolic events

In the pivotal study of MCRC patients, ATE (including transient ischaemic attack, cerebrovascular accident, angina pectoris, intracardiac thrombus, myocardial infarction, arterial embolism, and ischaemic colitis) were reported in 2.6% of patients treated with the ZALTRAP/FOLFIRI regimen and 1.5% of patients treated with the placebo/FOLFIRI regimen. Grade 3-4 events occurred in 11 patients (1.8%) treated with the ZALTRAP/FOLFIRI regimen and 3 patients (0.5%) treated with the placebo/FOLFIRI regimen. Across the three Phase III placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of ATE (all grades) was 2.3% for patients treated with ZALTRAP and 1.7% for patients treated with placebo. Grade 3-4 ATE occurred in 1.7% of patients treated with ZALTRAP and 1.0% of patients treated with placebo.

Venous thromboembolic events

Venous thromboembolic events (VTE) include deep venous thrombosis and pulmonary embolism. In the pivotal study of MCRC patients, all grades VTE occurred in 9.3% of patients treated with the ZALTRAP/FOLFIRI regimen and 7.3% of patients treated with the placebo/FOLFIRI regimen. Grade 3-4 VTE occurred in 7.9% of patients treated with the ZALTRAP/FOLFIRI regimen and in 6.3% of patients treated with the placebo/FOLFIRI regimen. Pulmonary embolism occurred in 4.6% of patients treated with the ZALTRAP/FOLFIRI regimen and 3.5% of patients treated with the placebo/FOLFIRI regimen. Across the three Phase III placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of VTE (all grades) was 7.1% for patients treated with ZALTRAP and 7.1% for patients treated with placebo.

Proteinuria

In the pivotal study of MCRC patients, proteinuria (compiled from clinical and laboratory data) was reported in 62.2% patients treated with the ZALTRAP/FOLFIRI regimen compared to 40.7% patients treated with the placebo/FOLFIRI regimen. Grade 3-4 proteinuria occurred in 7.9% of patients treated with the ZALTRAP/FOLFIRI regimen compared to 1.2% of patients treated with the placebo/FOLFIRI regimen. Nephrotic syndrome occurred in 2 patients (0.5%) treated with the ZALTRAP/FOLFIRI regimen compared to none of the patients treated with the placebo/FOLFIRI regimen. One patient treated with the ZALTRAP/FOLFIRI regimen presenting with proteinuria and hypertension was diagnosed with thrombotic microangiopathy (TMA). Across the three Phase III placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of nephrotic syndrome was 0.5% of patients treated with ZALTRAP and 0.1% of patients treated with placebo.

Neutropenia and neutropenic complications

In the pivotal study of MCRC patients, neutropenia (all grades) has been reported in 67.8% of patients treated with ZALTRAP/FOLFIRI and 56.3% of patients treated with placebo/FOLFIRI. Grade 3-4 neutropenia was observed in 36.7% of patients treated with the ZALTRAP/FOLFIRI regimen compared to 29.5% patients treated with the placebo/FOLFIRI regimen. The most common grade 3-4 neutropenic complication was the occurrence of febrile neutropenia in 4.3% of patients treated with the ZALTRAP/FOLFIRI regimen compared to 1.7% of patients treated with the placebo/FOLFIRI regimen. Grade 3-4 neutropenic infection/sepsis occurred in 1.5% of patients treated with the ZALTRAP/FOLFIRI regimen and 1.2% of patients treated with the placebo/FOLFIRI regimen.

Infections

Infections occurred at a higher frequency in patients receiving the ZALTRAP/FOLFIRI regimen (46.2%, all grades; 12.3%, grade 3-4) than in patients receiving the placebo/FOLFIRI regimen (32.7%, all grades; 6.9%, grade 3-4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection.

Diarrhoea and dehydration

In the pivotal study of MCRC patients, diarrhoea (all grades) has been observed in 69.2% of patients treated with ZALTRAP/FOLFIRI and 56.5% of patients treated with placebo/FOLFIRI. Dehydration (all grades) has been observed in 9.0% of patients treated with ZALTRAP/FOLFIRI and 3.0% of patients treated with placebo/FOLFIRI. Grade 3-4 diarrhoea was reported in 19.3% of patients treated with the ZALTRAP/FOLFIRI regimen compared to 7.8% of patients treated with the placebo/FOLFIRI regimen. Grade 3-4 dehydration was reported in 4.3% of patients treated with the ZALTRAP/FOLFIRI regimen compared to 1.3% of patients treated with the placebo/FOLFIRI regimen.

Hypersensitivity reactions

In the pivotal study of MCRC patients, severe hypersensitivity reactions have been reported in 0.3% of patients treated with the ZALTRAP/FOLFIRI regimen and 0.5% of patients treated with the placebo/FOLFIRI regimen.

Compromised wound healing

Treatment with ZALTRAP is associated with potential for compromised wound healing (wound dehiscence, anastomotic leakage). In the pivotal study for MCRC, compromised wound healing was reported in 3 patients (0.5%) treated with the ZALTRAP/FOLFIRI regimen and 5 patients (0.8%) treated with the placebo/FOLFIRI regimen. Grade 3 compromised wound healing was reported in 2 patients (0.3%) treated with the ZALTRAP/FOLFIRI regimen and in none of the patients treated with the placebo/FOLFIRI regimen. Across the three Phase III placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of compromised wound healing (all grades) was 0.5% for patients treated with ZALTRAP and 0.4% for patients treated with placebo. Grade 3-4 compromised wound healing occurred in 0.2% of patients treated with ZALTRAP and none of patients treated with placebo.

Posterior reversible encephalopathy syndrome (PRES)

PRES was not reported in the pivotal Phase III study of MCRC patients. In other studies, PRES was reported in patients treated with monotherapy ZALTRAP (0.5%) and in combination with other chemotherapies.

Additional adverse reactions and laboratory abnormalities reported with a >5% difference (all grades) in patients treated with the ZALTRAP/FOLFIRI regimen versus the placebo/FOLFIRI regimen

The following adverse reactions and laboratory abnormalities were reported with a >5% difference (all grades) in patients treated with the ZALTRAP/FOLFIRI regimen versus the placebo/FOLFIRI regimen (in order of decreasing frequency): leucopenia (78.3% versus 72.4% all grades; 15.6% versus 12.2% Grades 3-4), increased AST (57.5% versus 50.2% all grades; 3.1% versus 1.7% Grades 3-4), stomatitis (50.1% versus 32.9% all grades; 12.8% versus 4.6% Grades 3-4), fatigue (47.8% versus 39.0% all grades; 12.6% versus 7.8% Grade 3-4), thrombocytopenia (47.4% versus 33.8% all grades; 3.3% versus 1.7% Grades 3-4), increased ALT (47.3% versus 37.1% all grades; 2.7% versus 2.2% Grades 3-4), decreased appetite (31.9% versus 23.8% all grades; 3.4% versus 1.8% Grade 3-4), weight loss (31.9% versus 14.4% all grades; 2.6% versus 0.8% Grades 3-4), dysphonia (25.4% versus 3.3% all grades; 0.5% versus 0 Grades 3-4), headache (22.3% versus 8.8% all grades; 1.6% versus 0.3% Grades 3-4), asthenia (18.3% versus 13.2% all grades; 5.1% versus 3.0% Grades 3-4), Palmar-Plantar Erythrodysaesthesia syndrome (11.0% versus 4.3% all grades; 2.8% versus 0.5% Grades 3-4), and skin hyperpigmentation (8.2% versus 2.8% all grades; 0 versus 0 Grades 3-4).

Paediatric population

The safety in paediatric patients has not been established.

Other special populations

Older people

Of the 611 patients treated with the ZALTRAP/FOLFIRI regimen in the pivotal study of MCRC patients, 172 (28.2%) were aged >65 and <75 and 33 (5.4%) were age >75. Older people (>65 years of age) may be more likely to experience adverse reactions. The incidence of diarrhoea, dizziness, asthenia, weight decrease, and dehydration was increased by >5% in older people compared to younger patients. Older people should be closely monitored for the development of diarrhoea and potential dehydration.

Renal impairment

In patients receiving ZALTRAP, the adverse reactions in patients with mild renal impairment at baseline in three Phase III placebo-controlled clinical studies (N=352) were comparable with those of patients without renal impairment (N=642). A limited number of patients having moderate/severe renal impairment at baseline (N=49) were treated with ZALTRAP. In these patients, non-renal events were generally comparable between patients with renal impairment and those without renal impairment, except a >10% higher incidence in dehydration (all grades) was noted.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity with ZALTRAP.

Overall across all clinical oncology studies, similar incidence of low titre anti-drug antibody (ADA) responses (post baseline) in the ADA assay were observed in both patients treated with placebo and ZALTRAP (3.3% and 3.8%, respectively). High-titre antibody responses to aflibercept were not detected in any patients. Seventeen (17) patients treated with ZALTRAP (1.6 %) and two (2) placebo-treated patients (0.2%) were also positive in the neutralising antibody assay. In the pivotal study of MCRC patients, positive responses in the ADA assay were observed at higher levels in patients treated with the placebo/FOLFIRI regimen [18/526 (3.4%)] than with the ZALTRAP/FOLFIRI regimen [8/521 (1.5%)]. Positive results in the neutralising antibody assay in the MCRC pivotal study were also higher in patients treated with the placebo/FOLFIRI regimen [2/526 (0.38%)] than with the ZALTRAP/FOLFIRI regimen [1/521 (0.19%)]. There was no observed impact on the pharmacokinetic profile of aflibercept in patients who were positive in the immunogenicity assays.

Given the similar ADA assay results in patients treated with placebo or ZALTRAP, the actual incidence of immunogenicity with ZALTRAP based on these assays is likely to be overestimated.

Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medicinal products, and underlying disease. For these reasons, comparison of the incidence of antibodies to ZALTRAP with the incidence of antibodies to other products may be misleading.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the national reporting system listed below.

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

There have been no cases of overdose reported with Wetlia. There is no information on the safety of Wetlia given at doses exceeding 7 mg per kg every 2 weeks or 9 mg per kg every 3 weeks.

In clinical trials, doses of up to 4 mg in monthly intervals have been used and isolated cases of overdoses with 8 mg occurred.

Overdosing with increased injection volume may increase intraocular pressure. Therefore, in case of overdose, intraocular pressure should be monitored and if deemed necessary by the treating physician, adequate treatment should be initiated.

There is no information on the safety of aflibercept given at doses exceeding 7 mg/kg every 2 weeks or 9 mg/kg every 3 weeks. The most commonly observed adverse reactions at these doses were similar to those observed at the therapeutic dose.

There is no specific antidote to ZALTRAP overdose. Cases of overdose should be managed by appropriate supportive measures particularly with regard to monitoring and treatment of hypertension and proteinuria. The patient should remain under close medical supervision to monitor any adverse reactions.

Pharmacotherapeutic group: Ophthalmologicals / Antineovascularisation agents

ATC code: S01LA05

Aflibercept is a recombinant fusion protein consisting of portions of human VEGF receptor 1 and 2 extracellular domains fused to the Fc portion of human IgG1.

Aflibercept is produced in Chinese hamster ovary (CHO) K1 cells by recombinant DNA technology.

Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF with higher affinity than their natural receptors, and thereby can inhibit the binding and activation of these cognate VEGF receptors.

Mechanism of action

Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are members of the VEGF family of angiogenic factors that can act as potent mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF acts via two receptor tyrosine kinases; VEGFR-1 and VEGFR-2, present on the surface of endothelial cells. PlGF binds only to VEGFR-1, which is also present on the surface of leucocytes. Excessive activation of these receptors by VEGF-A can result in pathological neovascularisation and excessive vascular permeability. PlGF can synergize with VEGF-A in these processes, and is also known to promote leucocyte infiltration and vascular inflammation.

Pharmacodynamic effects

wet AMD

Wet AMD is characterised by pathological choroidal neovascularisation (CNV). Leakage of blood and fluid from CNV may cause retinal thickening or oedema and/or sub-/intra-retinal haemorrhage, resulting in loss of visual acuity.

In patients treated with Wetlia (one injection per month for three consecutive months, followed by one injection every 2 months), central retinal thickness [CRT] decreased soon after treatment initiation, and the mean CNV lesion size was reduced, consistent with the results seen with ranibizumab 0.5 mg every month.

In the VIEW1 study there were mean decreases in CRT on optical coherence tomography (OCT) (-130 and -129 microns at week 52 for the Wetlia 2 mg every two months and ranibizumab 0.5 mg every month study groups, respectively). Also at the 52 week time point, in the VIEW2 study there were mean decreases in CRT on OCT (-149 and -139 microns for the Wetlia 2 mg every two months and ranibizumab 0.5 mg every month study groups, respectively).

The reduction of CNV size and reduction in CRT were generally maintained in the second year of the studies.

Macular oedema secondary to CRVO and BRVO

In CRVO and BRVO, retinal ischaemia occurs and signals the release of VEGF which in turn destabilises the tight junctions, and promotes endothelial cell proliferation. Up-regulation of VEGF is associated with the breakdown of the blood retina barrier, increased vascular permeability, retinal oedema, and neovascularisation complications.

In patients treated with 6 consecutive monthly injections of Wetlia 2mg, there was a consistent, rapid and robust morphologic response (as measured by improvements in mean CRT) observed. At week 24, the reduction in CRT was statistically superior versus control in all three studies (COPERNICUS in CRVO: -457 vs. -145 microns; GALILEO in CRVO: -449 vs. -169 microns; VIBRANT in BRVO: -280 vs. -128 microns).

This decrease from baseline in CRT was maintained to the end of each study, week 100 in COPERNICUS, week 76 in GALILEO and week 52 in VIBRANT.

Diabetic macular oedema

Diabetic macular oedema is a consequence of diabetic retinopathy and is characterised by increased vasopermeability and damage to the retinal capillaries which may result in loss of visual acuity.

In patients treated with Wetlia, the majority of whom were classified as having Type II diabetes, a rapid and robust response in morphology (CRT, DRSS level) was observed.

In the VIVID^DME and the VISTA^DME studies, a statistically significant greater mean decrease in CRT from baseline to week 52 was observed in patients treated with Wetlia than with the laser control, -192.4 and -183.1 microns for the 2Q8 Wetlia groups and -66.2 and -73.3 microns for the control groups, respectively. At week 100 the decrease was maintained with -195.8 and -191.1 microns for the 2Q8 Wetlia groups and -85.7 and -83.9 microns for the control groups, in the VIVID^DME and VISTA^DME studies, respectively.

A > 2 step improvement in DRSS was assessed in a pre-specified manner in VIVID^DME and VISTA^DME. The DRSS score was gradable in 73.7% of the patients in VIVID-^DME and 98.3% of the patients in VISTA^DME. At week 52, 27.7% and 29.1% of the Wetlia 2Q8 groups, and 7.5% and 14.3% of the control groups experienced a >2 step improvement in the DRSS. At week 100, the respective percentages were 32.6% and 37.1% of the Wetlia 2Q8 groups and 8.2% and 15.6% of the control groups.

Myopic choroidal neovascularisation

Myopic choroidal neovascularisation (myopic CNV) is a frequent cause of vision loss in adults with pathologic myopia. It develops as a wound healing mechanism consequent to Bruch's membrane ruptures and represents the most vision-threatening event in pathologic myopia.

In patients treated with Wetlia in the MYRROR study (one injection given at start of therapy, with additional injections given in case of disease persistence or recurrence), CRT decreased soon after treatment initiation favouring Wetlia at week 24 (-79 microns and -4 microns for the Wetlia 2 mg treatment group and the control group, respectively), which was maintained through week 48. In addition, the mean CNV lesion size decreased.

Clinical efficacy and safety

wet AMD

The safety and efficacy of Wetlia were assessed in two randomised, multi-centre, double-masked, active-controlled studies in patients with wet AMD (VIEW1 and VIEW2) with a total of 2,412 patients treated and evaluable for efficacy (1,817 with Wetlia). Patient ages ranged from 49 to 99 years with a mean of 76 years. In these clinical studies, approximately 89% (1,616/1,817) of the patients randomised to treatment with Wetlia were 65 years of age or older, and approximately 63% (1,139/1,817) were 75 years of age or older. In each study, patients were randomly assigned in a 1:1:1:1 ratio to 1 of 4 dosing regimens:

1) Wetlia administered at 2 mg every 8 weeks following 3 initial monthly doses (Wetlia 2Q8);

2) Wetlia administered at 2 mg every 4 weeks (Wetlia 2Q4);

3) Wetlia administered at 0.5 mg every 4 weeks (Wetlia 0.5Q4); and

4) ranibizumab administered at 0.5 mg every 4 weeks (ranibizumab 0.5Q4).

In the second year of the studies, patients continued to receive the initially randomised dosage but on a modified dosing schedule guided by assessment of visual and anatomic outcomes with a protocol-defined maximum dosing interval of 12 weeks.

In both studies, the primary efficacy endpoint was the proportion of patients in the Per Protocol Set who maintained vision, i.e. losing fewer than 15 letters of visual acuity at week 52 from baseline.

In the VIEW1 study, at week 52, 95.1% of patients in the Wetlia 2Q8 group maintained vision compared to 94.4% patients in the ranibizumab 0.5Q4 group. In the VIEW2 study, at week 52, 95.6% of patients in the Wetlia 2Q8 group maintained vision compared to 94.4% patients in the ranibizumab 0.5Q4 group. In both studies Wetlia was shown to be non-inferior and clinically equivalent to the ranibizumab 0.5Q4 group.

Detailed results from the combined analysis of both studies are shown in Table 2 and Figure 1 below.

Table 2: Efficacy outcomes at week 52 (primary analysis) and week 96; combined data from the VIEW1 and VIEW2 studies^B)

^A) BCVA: Best Corrected Visual Acuity

ETDRS: Early Treatment Diabetic Retinopathy Study

LS: Least square means derived from ANCOVA

PPS: Per Protocol Set

^B) Full Analysis Set (FAS), Last Observation Carried Forward (LOCF) for all analyses except proportion of patients with maintained visual acuity at week 52 which is PPS

^C) The difference is the value of the Wetlia group minus the value of the ranibizumab group. A positive value favours Wetlia.

^D) Confidence interval (CI) calculated by normal approximation

^E) After treatment initiation with three monthly doses

^F) A confidence interval lying entirely above -10% indicates a non-inferiority of Wetlia to ranibizumab

Figure 1. Mean Change in Visual Acuity from Baseline to Week 96 for the Combined Data from the View1 and View2 Studies

In combined data analysis of VIEW1 and VIEW2 Wetlia demonstrated clinically meaningful changes from baseline in pre-specified secondary efficacy endpoint National Eye Institute Visual Function Questionnaire (NEI VFQ-25) without clinically meaningful differences to ranibizumab. The magnitude of these changes was similar to that seen in published studies, which corresponded to a 15-letter gain in Best Corrected Visual Acuity (BCVA).

In the second year of the studies, efficacy was generally maintained through the last assessment at week 96, and 2-4% of patients required all injections on a monthly basis, and a third of patients required at least one injection with a treatment interval of only one month.

Decreases in mean CNV area were evident in all dose groups in both studies.

Efficacy results in all evaluable subgroups (e.g. age, gender, race, baseline visual acuity, lesion type, lesion size) in each study and in the combined analysis were consistent with the results in the overall populations.

Macular oedema secondary to CRVO

The safety and efficacy of Wetlia were assessed in two randomised, multi-centre, double-masked, sham-controlled studies in patients with macular oedema secondary to CRVO (COPERNICUS and GALILEO) with a total of 358 patients treated and evaluable for efficacy (217 with Wetlia). Patient ages ranged from 22 to 89 years with a mean of 64 years. In the CRVO studies, approximately 52% (112/217) of the patients randomised to treatment with Wetlia were 65 years of age or older, and approximately 18% (38/217) were 75 years of age or older. In both studies, patients were randomly assigned in a 3:2 ratio to either 2 mg Wetlia administered every 4 weeks (2Q4), or the control group receiving sham injections every 4 weeks for a total of 6 injections.

After 6 consecutive monthly injections, patients received treatment only if they met pre-specified retreatment criteria, except for patients in the control group in the GALILEO study who continued to receive sham (control to control) until week 52. From this timepoint all patients were treated if pre-specified criteria were met.

In both studies, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA at week 24 compared to baseline. A secondary efficacy variable was change in visual acuity at week 24 compared to baseline.

The difference between treatment groups was statistically significant in favour of Wetlia in both studies. The maximal improvement in visual acuity was achieved at month 3 with subsequent stabilisation of visual acuity and CRT until month 6. The statistically significant difference was maintained through week 52.

Detailed results from the analysis of both studies are shown in Table 3 and Figure 2 below.

Table 3: Efficacy outcomes at week 24, week 52 and week 76/100 (Full Analysis Set with LOCF^C)) in COPERNICUS and GALILEO studies

^A) Difference is Wetlia 2 mg Q4 weeks minus control

^B) Difference and confidence interval (CI) are calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for region (America vs. rest of the world for COPERNICUS and Europe vs. Asia/Pacific for GALILEO) and baseline BCVA category (> 20/200 and ≤ 20/200)

^C) BCVA: Best Corrected Visual Acuity

ETDRS: Early Treatment Diabetic Retinopathy Study

LOCF: Last Observation Carried Forward

SD: Standard deviation

LS: Least square means derived from ANCOVA

^D) LS mean difference and confidence interval based on an ANCOVA model with factors treatment group, region (America vs. rest of the world for COPERNICUS and Europe vs. Asia/Pacific for GALILEO) and baseline BCVA category (> 20/200 and ≤ 20/200)

^E) In COPERNICUS study, control group patients could receive Wetlia on an as-needed basis as frequently as every 4 weeks during week 24 to week 52; patients had visits every 4 weeks.

^F) In COPERNICUS study, both control group and Wetlia 2mg patients received Wetlia 2 mg on an as-needed basis as frequently as every 4 weeks starting from week 52 to week 96; patients had mandatory quarterly visits but may have been seen as frequently as every 4 weeks if necessary.

^G) In GALILEO study, both control group and Wetlia 2mg patients received Wetlia 2 mg on an as-needed basis every 8 weeks starting from week 52 to week 68; patients had mandatory visits every 8 weeks.

Figure 2: Mean Change from Baseline to Week 76/100 in Visual Acuity by Treatment Group for the COPERNICUS and GALILEO Studies (Full Analysis Set)

In GALILEO, 86.4% (n=89) of the Wetlia group and 79.4% (n=54) of the sham group had perfused CRVO at baseline. At week 24, this was 91.8% (n=89) in the Wetlia group and 85.5% (n=47) in the sham group. These proportions were maintained at week 76, with 84.3% (n=75) in the Wetlia group and 84.0% (n=42) in the sham group.

In COPERNICUS, 67.5% (n = 77) of the Wetlia group and 68.5% (n = 50) of the sham group had perfused CRVO at baseline. At week 24, this was 87.4% (n = 90) in the Wetlia group and 58.6% (n = 34) in the sham group. These proportions were maintained at week 100 with 76.8 % (n = 76) in the Wetlia group and 78% (n = 39) in the sham group. Patients in the sham group were eligible to receive Wetlia from week 24.

The beneficial effect of Wetlia treatment on visual function was similar in the baseline subgroups of perfused and non-perfused patients. Treatment effects in other evaluable subgroups (e.g. age, gender, race, baseline visual acuity, CRVO duration) in each study were in general consistent with the results in the overall populations.

In combined data analysis of GALILEO and COPERNICUS, Wetlia demonstrated clinically meaningful changes from baseline in pre-specified secondary efficacy endpoint National Eye Institute Visual Function Questionnaire (NEI VFQ-25). The magnitude of these changes was similar to that seen in published studies, which corresponded to a 15-letter gain in Best Corrected Visual Acuity (BCVA).

Macular oedema secondary to BRVO

The safety and efficacy of Wetlia were assessed in a randomised, multi-centre, double-masked, active-controlled study in patients with macular oedema secondary to BRVO (VIBRANT) which included Hemi-Retinal Vein Occlusion. A total of 181 patients were treated and evaluable for efficacy (91 with Wetlia). Patient ages ranged from 42 to 94 years with a mean of 65 years. In the BRVO study, approximately 58% (53/91) of the patients randomised to treatment with Wetlia were 65 years of age or older, and approximately 23% (21/91) were 75 years of age or older. In the study, patients were randomly assigned in a 1:1 ratio to either 2 mg Wetlia administered every 8 weeks following 6 initial monthly injections or laser photocoagulation administered at baseline (laser control group). Patients in the laser control group could receive additional laser photocoagulation (called 'rescue laser treatment') beginning at week 12 with a minimum interval of 12 weeks. Based on pre-specified criteria, patients in the laser group could receive rescue treatment with Wetlia 2mg from week 24, administered every 4 weeks for 3 months followed by every 8 weeks.

In the VIBRANT study, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA at week 24 compared to baseline and the Wetlia group was superior to laser control.

A secondary efficacy endpoint was change in visual acuity at week 24 compared to baseline, which was statistically significant in favour of Wetlia in the VIBRANT study. The course of visual improvement was rapid and peaked at 3 months with maintenance of the effect until month 12.

In the laser group 67 patients received rescue treatment with Wetlia beginning at week 24 (Active Control/ Wetlia 2mg group), which resulted in improvement of visual acuity by about 5 letters from week 24 to 52.

Detailed results from the analysis of the VIBRANT study are shown in Table 4 and Figure 3 below.

Table 4: Efficacy outcomes at week 24 and week 52 (Full Analysis Set with LOCF) in VIBRANT study

^A) Difference is Wetlia 2 mg Q4 weeks minus Laser Control

^B) Difference and 95% CI are calculated using Mantel-Haenszel weighting scheme adjusted for region (North America vs. Japan) and baseline BCVA category (> 20/200 and ≤ 20/200)

^C) LS mean difference and 95% CI based on an ANCOVA model with treatment group, baseline BCVA category (> 20/200 and ≤ 20/200) and region (North America vs. Japan) as fixed effects, and baseline BCVA as covariate

^D) From week 24 on the treatment interval in the Wetlia treatment group was extended for all subjects from 4 weeks to 8 weeks through week 48.

^E) Beginning at week 24 subjects in the Laser Group could receive rescue treatment with Wetlia, if they met at least one pre-specified eligibility criterion. At total of 67 subjects in this group received Wetlia rescue treatment. The fixed regimen for Wetlia rescue was three times Wetlia 2mg every 4 weeks followed by injections every 8 weeks.

^F) Nominal p-value

Figure 3: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 52 in VIBRANT Study

At baseline, the proportion of perfused patients in the Wetlia and laser groups was 60% and 68%, respectively. At week 24 these proportions were 80% and 67%, respectively. In the Wetlia group the proportion of perfused patients was maintained through week 52. In the laser group, where patients were eligible for rescue treatment with Wetlia from week 24, the proportion of perfused patients increased to 78% by week 52.

Diabetic macular oedema

The safety and efficacy of Wetlia were assessed in two randomised, multi-centre, double-masked, active-controlled studies in patients with DME (VIVID^DME and VISTA^DME). A total of 862 patients were treated and evaluable for efficacy, 576 with Wetlia. Patient ages ranged from 23 to 87 years with a mean of 63 years. In the DME studies, approximately 47% (268/576) of the patients randomised to treatment with Wetlia were 65 years of age or older, and approximately 9% (52/576) were 75 years of age or older. The majority of patients in both studies had Type II diabetes.

In both studies, patients were randomly assigned in a 1:1:1 ratio to 1 of 3 dosing regimens:

1) Wetlia administered 2 mg every 8 weeks following 5 initial monthly injections (Wetlia 2Q8);

2) Wetlia administered 2 mg every 4 weeks (Wetlia 2Q4); and

3) macular laser photocoagulation (active control).

Beginning at week 24, patients meeting a pre-specified threshold of vision loss were eligible to receive additional treatment: patients in the Wetlia groups could receive laser and patients in the control group could receive Wetlia.

In both studies, the primary efficacy endpoint was the mean change from baseline in BCVA at week 52 and both Wetlia 2Q8 and Wetlia 2Q4 groups demonstrated statistical significance and were superior to the control group. This

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XX44

Mechanism of action

Vascular endothelial growth factor A and B (VEGF-A, VEGF-B), and placental growth factor (PlGF) are members of the VEGF family of angiogenic factors that can act as potent mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF-A acts via two receptor tyrosine kinases, VEGFR-1 and VEGFR-2, present on the surface of endothelial cells. PlGF and VEGF-B bind only to VEGFR-1, which is also present on the surface of leucocytes. Excessive activation of these receptors by VEGF-A can result in pathological neovascularisation and excessive vascular permeability. PlGF is also linked to pathological neovascularisation and recruitment of inflammatory cells into tumours.

Aflibercept, also known as VEGF TRAP in the scientific literature, is a recombinant fusion protein consisting of VEGF-binding portions from the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of the human IgG1. Aflibercept is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) K-1 mammalian expression system. Aflibercept is a dimeric glycoprotein with a protein molecular weight of 97 kilodaltons (kDa) and contains glycosylation, constituting an additional 15% of the total molecular mass, resulting in a total molecular weight of 115 kDa.

Aflibercept acts as a soluble decoy receptor that binds to VEGF-A, with higher affinity than its native receptors, as well as the related ligands PlGF and VEGF-B. By acting as a ligand trap, aflibercept prevents binding of endogenous ligands to their cognate receptors and thereby blocks receptor mediated signaling.

Aflibercept blocks the activation of VEGF receptors and the proliferation of endothelial cells, thereby inhibiting the growth of new vessels that supply tumours with oxygen and nutrients.

Aflibercept binds to human VEGF-A (equilibrium dissociation constant K_D of 0.5 pM for VEGF-A₁₆₅ and 0.36 pM for VEGF-A₁₂₁), to human PlGF (K_D of 39 pM for PlGF-2), and to human VEGF-B (K_D of 1.92 pM) to form a stable, inert complex which has no detectable biological activity.

Pharmacodynamic effects

Administration of aflibercept to mice bearing xenotransplant or allotransplant tumours inhibited the growth of various cancer types.

Clinical efficacy and safety

The efficacy and safety of ZALTRAP were evaluated in a randomised, double-blind, placebo-controlled study in patients with metastatic colorectal cancer who had previously been treated with an oxaliplatin-based treatment with or without prior bevacizumab. A total of 1226 patients were randomised (1:1) to receive either ZALTRAP (N=612; 4 mg/kg as a 1 hour intravenous infusion on day 1) or placebo (N=614), in combination with 5-fluouracil plus irinotecan [FOLFIRI: irinotecan 180 mg/m² intravenous infusion over 90 minutes and folinic acid (dl racemic) 400 mg/m² intravenous infusion over 2 hours at the same time on day 1 using a Y-line, followed by 5-FU 400 mg/m² intravenous bolus, followed by 5-FU 2400 mg/m² continuous intravenous infusion over 46-hours]. The treatment cycles on both arms were repeated every 2 weeks. Patients were treated until disease progression or unacceptable toxicity. The primary efficacy endpoint was overall survival. Treatment assignment was stratified by the ECOG performance status (0 versus 1 versus 2) and according to prior therapy with bevacizumab (yes or no).

Demographics were well balanced between the treatment arms (age, race, ECOG performance status, and prior bevacizumab status). Of the 1226 patients randomised in the study, the median age was 61 years, 58.6% were male, 97.8% had a baseline ECOG performance status (PS) of 0 or 1, and 2.2% had a baseline ECOG performance status (PS) of 2. Among the 1226 randomised patients, 89.4% and 90.2% of patients treated with the placebo/FOLFIRI and ZALTRAP/FOLFIRI regimens, respectively, received prior oxaliplatin-based combination chemotherapy in the metastatic/advanced setting. Approximately 10% of patients (10.4% and 9.8% of patients treated with the placebo/FOLFIRI and ZALTRAP/FOLFIRI regimens, respectively) received prior oxaliplatin-based adjuvant chemotherapy and progressed on or within 6 months of completion of adjuvant chemotherapy. Oxaliplatin-based regimens were administered in combination with bevacizumab in 373 patients (30.4%).

Overall efficacy results for the ZALTRAP/FOLFIRI regimen versus the placebo/FOLFIRI regimen are summarised in Figure 1 and Table 2.

Figure 1 - Overall survival (months) - Kaplan-Meier curves by treatment group - ITT population

Table 2 - Main efficacy endpoints^a - ITT population

^a Stratified on ECOG performance status (0 versus 1 versus 2) and prior bevacizumab (yes versus no).

^b PFS (based on tumour assessment by the IRC): Significance threshold is set to 0.0001

^c Overall objective response rate by IRC

Analyses for Overall survival (OS) and Progression Free Survival (PFS) by stratification factors were performed. A numerically lower treatment effect on OS with the ZALTRAP/FOLFIRI regimen was reported for patients with prior bevacizumab as compared to patients without prior bevacizumab exposure, with no evidence of heterogeneity in treatment effect (non significant interaction test). Results by prior bevacizumab exposure are summarised in Table 3.

Table 3 - OS and PFS by prior bevacizumab exposure^a - ITT population

^a As determined per IVRS

Analysis for OS and PFS by ECOG PS was also performed. The hazard ratio (95% CI) of overall survival was 0.77 (0.64 to 0.93) for ECOG performance status 0 and 0.87 (0.71 to 1.06) for ECOG performance status 1. The hazard ratio (95% CI) of progression free survival was 0.76 (0.63 to 0.91) for ECOG performance status 0 and 0.75 (0.61 to 0.92) for ECOG performance status 1.

Post-hoc analyses excluding patients who progressed during or within 6 months of adjuvant therapy for patients with or without prior bevacizumab treatment are summarised in Table 4.

Table 4 - Post-hoc analyses excluding adjuvant patients^a,b

^a As determined per IVRS

^b Overall survival in ITT population excluding patients who progressed during or within 6 months of adjuvant therapy demonstrated an HR (95% CI) of 0.78 (0.68 to 0.90) [median OS (95% CI) with Placebo/FOLFIRI 11.9 months (10.88 to 13.01) and with ZALTRAP/FOLFIRI 13.8 months (12.68 to 15.44)]

Other subgroup analyses for overall survival and progression free survival according to age (<65; >65), gender, presence of liver metastasis only, history of prior hypertension, and number of organs involved, showed a treatment effect favouring the ZALTRAP/FOLFIRI regimen over the placebo/FOLFIRI regimen.

In sub-group analysis of overall survival, a benefit consistent with the overall population was observed in patients <65 years old and >65 years old who received the ZALTRAP/FOLFIRI regimen.

Exploratory biomarker analyses were undertaken in the VELOUR trial including analyses of RAS mutational status in 482 of 1226 patients (n= 240 aflibercept; 242 placebo). In patients with RAS wild type tumours the HR (95% CI) for overall survival (OS) was 0.7 (0.5-1.0) with a median OS of 16.0 months for patients treated with aflibercept, and 11.7 mo for the patients treated with placebo. Corresponding data in patients with RAS mutant type tumours showed a HR for OS of 0.9 (0.7-1.2) with median 12.6 and 11.2 months for aflibercept and placebo, respectively. These data are exploratory and the statistical interaction test was non-significant (lack of evidence for heterogeneity in treatment effect between the RAS wild-type and RAS mutant subgroups).

Paediatric population

).

Plasma concentrations of free and VEGF-bound ziv-aflibercept were measured using specific enzyme-linked immunosorbent assays (ELISAs). Free ziv-aflibercept concentrations appear to exhibit linear pharmacokinetics in the dose range of 2-9 mg/kg. Following 4 mg/kg every two weeks intravenous administration of Wetlia, the elimination half-life of free ziv-aflibercept was approximately 6 days (range 4-7 days). Steady state concentrations of free ziv-aflibercept were reached by the second dose. The accumulation ratio for free ziv-aflibercept was approximately 1.2 after administration of 4 mg/kg every two weeks.

Wetlia is administered directly into the vitreous to exert local effects in the eye.

Absorption / Distribution

Aflibercept is slowly absorbed from the eye into the systemic circulation after intravitreal administration and is predominately observed in the systemic circulation as an inactive, stable complex with VEGF; however only “free aflibercept” is able to bind endogenous VEGF.

In a pharmacokinetic sub-study in 6 neovascular wet AMD patients with frequent sampling, maximum plasma concentrations of free aflibercept (systemic C_max) were low, with a mean of approximately 0.02 microgram/ml (range 0 to 0.054) within 1 to 3 days after a 2 mg intravitreal injection, and were undetectable two weeks following dosage in almost all patients. Aflibercept does not accumulate in the plasma when administered intravitreally every 4 weeks.

The mean maximum plasma concentration of free aflibercept is approximately 50 to 500 times below the aflibercept concentration required to inhibit the biologic activity of systemic VEGF by 50% in animal models, in which blood pressure changes were observed after circulating levels of free aflibercept attained approximately 10 microgram/ml and returned to baseline when levels fell below approximately 1 microgram/ml. It is estimated that after intravitreal administration of 2 mg to patients, the mean maximum plasma concentration of free aflibercept is more than 100-fold lower than the concentration of aflibercept required to half-maximally bind systemic VEGF (2.91 microgram/ml) in a study of healthy volunteers. Therefore, systemic pharmacodynamic effects such as blood pressure changes are unlikely.

In pharmacokinetic sub-studies in patients with CRVO, BRVO, DME or myopic CNV mean C_max of free aflibercept in plasma were similar with values in the range of 0.03 to 0.05 microgram/ml and individual values not exceeding 0.14 microgram/ml. Thereafter, plasma concentrations of free aflibercept declined to values below or close to the lower limit of quantitation generally within one week; undetectable concentrations were reached before the next administration after 4 weeks in all patients.

Elimination

As Wetlia is a protein-based therapeutic, no metabolism studies have been conducted.

Free aflibercept binds VEGF to form a stable, inert complex. As with other large proteins, both free and bound aflibercept are expected to be cleared by proteolytic catabolism.

Renal impairment

No special studies in patients with renal impairment have been conducted with Wetlia.

Pharmacokinetic analysis of patients in the VIEW2 study, of which 40% had renal impairment (24% mild, 15% moderate, and 1% severe), revealed no differences with respect to plasma concentrations of active drug after intravitreal administration every 4 or 8 weeks.

Similar results were seen in patients with CRVO in the GALILEO study, in patients with DME in the VIVID^DME study, and in patients with myopic CNV in the MYRROR study.

The pharmacokinetic properties described below have to a large extent been derived from a population pharmacokinetic analysis with data from 1507 patients with various types of advanced malignancies.

Absorption

In preclinical tumour models, biologically active doses of aflibercept correlated with those necessary to produce circulating concentrations of free aflibercept in excess of VEGF-bound aflibercept. Circulating concentrations of VEGF-bound aflibercept increase with the aflibercept dose until most available VEGF is bound. Further increases in the aflibercept dose resulted in dose-related increases in circulating free aflibercept concentrations but only small further increases in the VEGF-bound aflibercept concentration.

In patients, ZALTRAP is administered at the dose of 4 mg/kg intravenously every two weeks for which there is an excess of circulating free aflibercept compared to VEGF-bound aflibercept.

At the recommended dose regimen of 4 mg/kg every two weeks, concentration of free aflibercept were near steady-state levels by the second cycle of treatment with essentially no accumulation (accumulation ratio of 1.2 at steady-state compared to the first administration).

Distribution

The volume of distribution of free aflibercept at steady-state is approximately 8 litres.

Biotransformation

No metabolism studies have been conducted with aflibercept since it is a protein. Aflibercept is expected to degrade to small peptides and individual amino acids.

Elimination

Free aflibercept is primarily cleared by binding to endogenous VEGF to form a stable, inactive complex. As with other large proteins, both free and bound aflibercept, are expected to be cleared, more slowly, by other biological mechanisms, such as proteolytic catabolism.

At doses greater than 2 mg/kg, free aflibercept clearance was approximately 1.0 L/day with a terminal half-life of 6 days.

High molecular weight proteins are not cleared by the renal route, therefore renal elimination of aflibercept is expected to be minimal.

Linearity/non-linearity

Consistent with target-mediated drug disposition, free aflibercept exhibits a faster (non-linear) clearance at doses below 2 mg/kg, likely due to the high affinity binding of aflibercept to endogenous VEGF. Linear clearance observed in the dose range of 2 to 9 mg/kg is likely due to non saturable biological mechanisms of elimination such as protein catabolism.

Other special populations

Older people

There was no effect of age on the pharmacokinetics of free aflibercept.

Race

No effect of race was identified in the population analysis.

Gender

Gender was the most significant covariate for explaining the interindividual variability of free aflibercept clearance and volume with a 15.5% higher clearance and a 20.6% higher volume of distribution in males than in females. These differences do not affect exposure due to weight-based dosing and no dose modifications based on gender are required.

Weight

Weight had an effect on free aflibercept clearance and volume of distribution resulting with a 29% increase in aflibercept exposure in patients weighing >100 kg.

Hepatic impairment

There have been no formal studies with ZALTRAP in patients with hepatic impairment. In a population pharmacokinetic analysis with data from 1507 patients with various types of advanced malignancies receiving ZALTRAP with or without chemotherapy, 63 patients with mild hepatic impairment (total bilirubin >1.0 x - 1.5 x ULN and any AST) and 5 patients with moderate hepatic impairment (total bilirubin >1.5 x - 3 x ULN and any AST) were treated with ZALTRAP. In these mild and moderate hepatic impairment patients, there was no effect on clearance of aflibercept. There are no data available for patients with severe hepatic impairment (total bilirubin >3 x ULN and any AST).

Renal impairment

There have been no formal studies with ZALTRAP in patients with renal impairment. A population pharmacokinetic analysis was conducted with data from 1507 patients with various types of advanced malignancies receiving ZALTRAP with or without chemotherapy. This population included; 549 patients with mild renal impairment (CL_CR between 50-80 ml/min), 96 patients with moderate renal impairment (CL_CR between 30-50 ml/min), and 5 patients with severe renal impairment (CL_CR <30 ml/min). This population pharmacokinetic analysis revealed no clinically meaningful differences in clearance or systemic exposure (AUC) of free aflibercept in patients with moderate and mild renal impairment at the 4 mg/kg dose of ZALTRAP as compared to the overall population studied. No conclusion can be drawn for patients with severe renal impairment due to very limited data available. In the few patients with severe renal impairment, drug exposure was similar to that observed in patients with normal renal function.

Effects in non-clinical studies on repeated dose toxicity were observed only at systemic exposures considered substantially in excess of the maximum human exposure after intravitreal administration at the intended clinical dose indicating little relevance to clinical use.

Erosions and ulcerations of the respiratory epithelium in nasal turbinates in monkeys treated with aflibercept intravitreally were observed at systemic exposures in excess of the maximum human exposure. The systemic exposure based on C_max and AUC for free aflibercept were approximately 200- and 700-fold higher, respectively, when compared to corresponding values observed in humans after an intravitreal dose of 2 mg. At the No Observed Adverse Effect Level (NOAEL) of 0.5 mg/eye in monkeys the systemic exposure was 42- and 56-fold higher based on C_max and AUC, respectively.

No studies have been conducted on the mutagenic or carcinogenic potential of aflibercept.

An effect of aflibercept on intrauterine development was shown in embryo-foetal development studies in pregnant rabbits with intravenous (3 to 60 mg/kg) as well as subcutaneous (0.1 to 1 mg/kg) administration. The maternal NOAEL was at the dose of 3 mg/kg or 1 mg/kg, respectively. A developmental NOAEL was not identified. At the 0.1 mg/kg dose, the systemic exposures based on C_max and cumulative AUC for free aflibercept were approximately 17- and 10-fold higher, respectively, when compared to corresponding values observed in humans after an intravitreal dose of 2 mg.

Effects on male and female fertility were assessed as part of a 6-month study in monkeys with intravenous administration of aflibercept at doses ranging from 3 to 30 mg/kg. Absent or irregular menses associated with alterations in female reproductive hormone levels and changes in sperm morphology and motility were observed at all dose levels. Based on C_max and AUC for free aflibercept observed at the 3 mg/kg intravenous dose, the systemic exposures were approximately 4,900-fold and 1,500-fold higher, respectively, than the exposure observed in humans after an intravitreal dose of 2 mg. All changes were reversible.

Animal toxicology and pharmacology

Weekly/every two weeks intravenous administration of aflibercept to cynomolgus monkeys for up to 6 months resulted in changes in the bone (effects on growth plate and the axial and appendicular skeleton), nasal cavity, kidney, ovary, and adrenal gland. Most aflibercept-related findings were noted from the lowest dose tested corresponding to plasma exposures close to those in patients at the therapeutic dose. Most aflibercept-induced effects were reversible after a 5-month drug free period with the exception of skeletal and nasal cavity findings. Most findings were considered to be related to the pharmacological activity of aflibercept.

Aflibercept administration resulted in a delay in wound healing in rabbits. In full-thickness excisional and incisional skin wound models, aflibercept administration reduced fibrous response, neovascularisation, epidermal hyperplasia/re-epithelialisation, and tensile strength. Aflibercept increased blood pressure in normotensive rodents.

Carcinogenesis and mutagenesis

No studies have been conducted to evaluate carcinogenicity or mutagenicity of aflibercept.

Impairment of fertility

No specific studies with aflibercept have been conducted in animals to evaluate the effect on fertility.

However, results from a repeat dose toxicity study suggest there is a potential for aflibercept to impair reproductive function and fertility. In sexually mature female cynomolgus monkeys inhibition of ovarian function and follicular development was evidenced. These animals also lost normal menstrual cycling. In sexually mature male cynomolgus monkeys a decrease in sperm motility and an increase in incidence of morphological abnormalities of spermatozoa were observed. There was no margin of exposure to patients in relation to these effects. These effects were fully reversible within 8-18 weeks after the last injection.

Reproductive and developmental toxicology

Aflibercept has been shown to be embryotoxic and teratogenic when administered intravenously to pregnant rabbits every 3 days during the organogenesis period (gestation days 6 to 18) at doses approximately 1 to 15 times the human dose of 4 mg/kg every 2 weeks. Observed effects included decreases in maternal body weights, an increased number of foetal resorptions, and an increased incidence of external, visceral, and skeletal foetal malformations.

The vial is for single use in one eye only.

Since the vial contains more volume (100 microlitres) than the recommended dose (50 microlitres), a part of the volume contained in the vial has to be discarded prior to the administration.

The solution should be inspected visually for any foreign particulate matter and/or discolouration or any variation in physical appearance prior to administration. In the event of either being observed, discard the medicinal product.

For the intravitreal injection, a 30 G x ½ inch injection needle should be used.

Instructions for use of vial:

ZALTRAP is a sterile, preservative-free and non-pyrogenic concentrate, therefore the solution for infusion should be prepared by a healthcare professional using safe-handling procedures and aseptic technique.

Caution should be exercised when handling ZALTRAP, taking into account the use of containment devices, personal protective equipment (e.g. gloves), and preparation procedures.

Preparation of the infusion solution

- Inspect the ZALTRAP vial visually prior to use. The concentrate solution must be clear and without particles.

- Based on the required dose for the patient, withdraw the necessary volume of ZALTRAP concentrate from the vial. More than one vial could be needed for the preparation of the infusion solution.

- Dilute it to the required administration volume with sodium chloride 9 mg/ml (0.9%) solution or 5% glucose solution for infusion. The concentration of the final ZALTRAP solution for intravenous infusion should be kept within the range of 0.6 mg/ml to 8 mg/ml of aflibercept.

- PVC containing DEHP infusion bags or polyolefin infusion bags should be used.

- The diluted solution should be inspected visually for particulate matter and discolouration prior to administration. If any discolouration or particulate matter is observed, the reconstituted solution should be discarded.

- ZALTRAP is a single-use vial. Do not re-enter the vial after the initial puncture. Any unused concentrate should be discarded.

Administration of the infusion solution

Diluted solutions of ZALTRAP should be administered using infusion sets containing a 0.2 micron polyethersulfone filter.

The infusion sets should be made of one of the following materials:

- polyvinyl chloride (PVC) containing bis(2-ethylhexyl) phthalate (DEHP)

- DEHP free PVC containing trioctyl-trimellitate (TOTM)

- polypropylene

- polyethylene lined PVC

- polyurethane

Filters made of polyvinylidene fluoride (PVDF) or nylon must not be used.

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.