Bayer Supplement - Nov 14

Supplement November 2014

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Bayer Health Care Satellite Symposium 12 September 2014, London, UK 14th EURETINA Congress

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VIVID Diabetic Macular Edema: When Every Letter Counts

VISTA This article has been produced on behalf of Bayer Healthcare and reports a Bayer-funded and organised symposium.

Prescribing information can be found on back cover

Chairman’s Introduction

rof Jean-François Korobelnik MD, chief of the Ophthalmology Department, University Hospital (CHU) Bordeaux, France, chaired Bayer Healthcare’s Satellite Symposium “DME: When Every Letter Counts” held on 12 September at the 14th EURETINA Congress in London, United Kingdom.

“Early diagnosis of diabetic macular edema (DME) is critical, and if not treated rigorously, there is a high risk of serious loss of visual function or even blindness,” said Prof Korobelnik.

The good news, however, is that clinicians now have an additional tool to add to their treatment armamentarium with the recent approval by the European Commission of Eylea® (aflibercept solution for injection) for the treatment of visual impairment due to DME. “The results of two phase III studies were very encouraging with the majority of patients with visual impairment due to DME experiencing a significant two-line improvement in visual acuity with aflibercept solution for injection,” Prof Korobelnik said.

Discussing the approved European protocol, he explained that Eylea® is recommended at 2.0mg, equivalent to 50 microlitres, with the treatment for DME initiated with one injection per month for five consecutive doses, followed by one injection every two months.

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“There is no requirement for monitoring between the injections.

After the first year, the treatment interval may be extended based on visual, functional and anatomical outcomes,” he said. The licence states: “If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, Eylea® should be discontinued.”

Prof Korobelnik said that the symposium would focus on a number of key topics relevant to patients with DME and their treating physicians: • The issues faced by patients with diabetes and the impact of the disease on their lifestyles; • The benefits of proactive management for comorbidities associated with diabetes, including DME; • Present clinical trial data supporting proactive anti-vascular endothelial growth factor (anti-VEGF) treatment regimens for the management of DME. The symposium would conclude with a panel discussion and interactive question-and-answer session on the impact of PRN, fixed and treat-and-extend regimens for DME on patients and clinics, said Prof Korobelnik.

What ophthalmologists need to know about diabetes Marc Evans MD, consultant physician, University Hospital Llandough, Cardiff, UK

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eople with diabetes are accustomed to a proactive approach in the management of the disease, so it is only logical that DME should also be treated in a similarly proactive fashion, according to Marc Evans MD. “Successful diabetes care involves a proactive approach and we know that early and sustained tight glycaemic control reduces microvascular risks and helps prevent later macrovascular complications. Research has shown that an investment in better, early, proactive management results in lower total healthcare costs, so it makes sense that DME should also be treated proactively,1” he said.

Dr Evans reminded the audience that the burden of diabetes is increasing globally.

“Not only is diabetes an extremely common condition it is also an extremely expensive one,” he said. An estimated 380 million people worldwide are now classified as diabetic, the vast majority of them with Type II diabetes. The economic costs are also staggering, with current diabetes-related healthcare accounting for 11 per cent of total healthcare expenditure worldwide at around $548bn, a figure expected to rise to $627bn by 2035.2 Importantly this average prevalence estimate does not reflect some of the rapid increase in prevalence in different parts of the world and different ethnicities, said Dr Evans. For instance, the increase in diabetes in Africa is 80 per cent, while it is approaching 95 per cent in the Middle East region. All of these costs are going to cause huge stresses on healthcare systems, he warned.

“The important thing to remember when it comes to the costs of diabetes is that the majority, in fact 80 per cent of the costs, are related to managing the complications. From a health economic perspective there is, therefore, an unquestionable imperative to be proactive in terms of managing patients to reduce the burden of complications,” he said.

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Diabetic Macular Edema: When Every Letter Counts

Glucose control critical While complications associated with diabetes are multifactorial, Dr Evans explained that a very robust evidence base exists to show that chronic hyperglycaemia and glucose excursions can seriously affect a variety of tissues including cardiovascular, neural and retinal tissues.1 “From the perspective of the disease burden we know that someone is diagnosed with diabetes globally every five seconds, someone dies from diabetes-related causes every 10 seconds and someone loses a limb to diabetes every 30 seconds,” he said.2 With this increase in prevalence, people of younger ages are being increasingly diagnosed with Type II diabetes and there is also an increase in the prevalence of Type I diabetes, said Dr Evans.

“Many theories such as environmental, dietary and lifestyle factors have been proposed to account for this increase. Because of this, patients are going to be exposed to risk factors for a longer period of time and so our approach is to be proactive, to minimise their exposure to these risk factors and to reduce their burden of complications,” he said.

The result of this proactive approach is that patients will be seen frequently by many healthcare professionals from diabetologists, primary care physicians, dieticians, diabetes nurse specialists and educators, said Dr Evans.

“This means that diabetes care and the delivery of optimal diabetes care is extremely resource intensive. From a therapeutic perspective, any innovation that can reduce the frequency or the need for healthcare professional contacts while maintaining clinical outcomes is an extremely important and valuable innovation from the health-economic as well as the patient perspective,” he said.

Patient awareness Dr Evans noted that patient source data has shown that 63 per cent of people when diagnosed with diabetes are fully aware that the condition is associated with some future health problems.3 “About 25 per cent were concerned that they might develop specific complications, whereas nine per cent were not really concerned by the health implications. And it is this nine per cent that we really need to be thinking about in terms of our educational strategies,” he said.

Interestingly, when patients were quizzed about which potential complication concerned them the most, vision loss came top of the list with 50 per cent compared to 21 per cent for cardiac complications, 11 per cent for renal, 10 per cent for circulation and nine per cent for feet and legs.3 Hypoglycaemia was another major concern for people with diabetes, said Dr Evans, noting that for many patients symptomatically having a low blood sugar level is the factor that most evidently differentiates them from someone without diabetes.

“One of the major objectives that we have, therefore, in treating diabetes is to maintain quality of life and as such limit the fear associated with the development of complications and also limit the fear of treatment-related morbidity such as hypoglycaemia,” he said.

With that in mind, patients with diabetes are accustomed to a proactive approach to disease management, explained Dr Evans.

“We often talk to them about diet and exercise, we focus on riskfactor monitoring and modification, we look at glucose monitoring and we talk proactively about the need to maximise therapy adherence and to take the medication at the right time in order to maximise the effect,” he said.

Dr Evans said that many structured education programmes are now in place for patients with Type II and Type I diabetes, all focusing on patient empowerment and the proactive need for patients to know their blood pressure and glucose levels in order to maximise the outcomes and reduce their risk of complications.

Patient input critical for success Nevertheless, while the physician and diabetologist can play a key role in educating and treating the patient, the cornerstone of diabetes care has to come from the patient’s own lifestyle modification, pointed out Dr Evans.

“About half of patients when diagnosed find it very difficult to change their diet. In quality-of-life terms if you ask someone with diabetes what is the worst thing about the disease they will usually reply that it is not being able to eat what they want. Only about 40 per cent of people when diagnosed actually increased their exercise and just 51 per cent changed their diet.4 So from our perspective, addressing these lifestyle issues is a big consideration,” he said.

The importance of treating patients proactively to minimise the risk of complications such as hyperglycaemia, hypoglycaemia, hypertension and dyslipidaemia should not be underestimated, said Dr Evans.

“Hypoglycaemia is a major concern for us as diabetologists because we are now aware that it is not only bad from the quality-of-life perspective but it is also causally associated with sudden explained

“About 25 per cent were concerned that they might develop specific complications, whereas nine per cent were not really concerned by the health implications” death in diabetes and increased risk of atrial fibrillation which is an independent risk factor for stroke. Furthermore, it is also associated with progression of microvascular complications and, in particular, adverse outcomes from a retinopathy perspective,” he said.5

Success-driven approach In terms of treating blood glucose in diabetes, these days we focus on a success-driven approach, said Dr Evans, trying to escalate therapies in such a way as to maintain patients’ blood glucose levels at the desired target of an HbA1c level of less than seven per cent.

“In other words we are proactively escalating therapy in order to minimise exposure to high blood glucose levels. Because what we know is that diabetes is a progressive condition and the longer you have, whether it is Type I or Type II diabetes, the more treatment you will require. So more therapies are required and in order to maximise outcomes, we as a specialty are very focused on being proactive in terms of escalating these treatments in a success-based approach to avoid excursions of blood glucose levels,” he said.

Dr Evans noted that the rationale for proactive treatment in diabetic patients is amply supported by clinical trial evidence showing the long-term benefits of controlling blood glucose levels in terms of macrovascular complications and all-cause mortality.6 In terms of managing blood glucose control, one of the major barriers relates to hypoglycaemia, said Dr Evans, with many patients failing to achieve optimal levels of glucose control due to fear of hypoglycaemia.

“In a survey published by Mark Peyrot a few years ago, threequarters of either primary care physicians or specialists said that they would treat their patients more aggressively if there was no risk of hypoglycaemia and the potential adverse consequences,”7 he said.

Summing up, Dr Evans said that all the evidence pointed to proactive treatment as being the most effective way to treat patients with diabetes.

“An investment in better early proactive intervention from the perspective of multiple risk factors is key to delivering optimal clinical outcomes and optimal economic outcomes. People with diabetes are very used to being managed in this way and therefore it is logical to consider an approach to DME in a similar way,” he concluded.

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VIVID/VISTA and the evidence for a proactive anti-VEGF treatment regimen Jennifer Arnold MBBS, FRANZCO (chair), consultant ophthalmologist at Marsden Eye Specialists, Parramatta, New South Wales, Australia he compelling evidence from the recent VIVID/VISTA clinical trials on the efficacy and role of aflibercept in DME was discussed by Jennifer Arnold MBBS, FRANZCO. Noting that DME is common in people with diabetes, Dr Arnold said that the prevalence rate ranges from around one per cent to 12 per cent of all people with diabetes.8 Furthermore, a recent UK study showed that at least 40 per cent of people with DME had some form of visual impairment.9 “There is a range of pathogenic mechanisms and steps that precede from chronic hyperglycaemia through the vascular effects down to the vision loss. Growth factors such as the vascular endothelial growth factor (VEGF) family and placental growth factor (PIGF) are involved in this pathogenic cascade and therefore present themselves as natural targets for our interventions,” she explained.

The mechanism of action of aflibercept is to bind to both VEGF-A and PIGF in order to prevent their interaction with native VEGF receptors and prevent them from forming complexes, said Dr Arnold.10 “With such a mechanism of action binding VEGF-A and PlGF with higher affinity than their natural receptors, aflibercept has clear potential to be a potent and quite long-lasting blocker,” she said.

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Identical protocols The VIVID and VISTA clinical trials were designed to assess the safety and efficacy of aflibercept, said Dr Arnold. These randomised, multicentre, double-masked phase III trials in patients with clinically significant DME were carried out at 54 centres and 466 patients in the US (VISTA) and 73 centres and 406 patients in the rest of the world (VIVID).11 With identical protocols, patients were randomised into three groups, explained Dr Arnold: one group underwent laser photocoagulation, while the other two groups were given intravitreal injections of aflibercept, either 2.0mg every four weeks or the same dosage every eight weeks but after five consecutive months of a loading dose. The primary endpoints at 52 weeks were mean change in vision, but the treatment was continued out to three years, added Dr Arnold, who presented results from both the 52-week as well as the two-year endpoints in her talk.

Looking at the baseline data, the mean visual acuity scores across all groups was about 60 letters, which is typical in a DME study, said Dr Arnold.

“Importantly, these are not really treatment-naive patients with DME. A good proportion had already had laser treatment and about one in 10 patients in the VIVID study and up to 40 per cent in VISTA had previous anti-VEGF therapy,” she said.

Turning to the results, Dr Arnold noted that the main outcome showed that the two treatment protocols with aflibercept achieved an excellent improvement in baseline vision which was sustained over the two-year follow-up period. The analysis showed statistically significant differences favouring both the aflibercept groups compared with laser (12.5 and 10.7 mean letters of vision gained versus 0.2 letters).

Dr Arnold said it was important to stress that the eyes receiving injections every other month maintained excellent visual acuity gains through the two-year follow-up period.

“It is interesting to note that there is not a great deal of difference between the two aflibercept treatment regimens, indicating comparable efficacy which might reduce the burden of treatment after the initial loading phase. Another point worth noting is that the mean vision takes some time to rise: although by three months a lot of the improvement has occurred, there is still a gain of several further letters over the first year to 12 months.

Thereafter the vision gain is maintained,” she said.

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“There is a range of pathogenic mechanisms and steps that precede from chronic hyperglycaemia through the vascular effects down to the vision loss” Patient improvement In terms of the patients that improved in the study, Dr Arnold said that clinical experience of patients treated with laser shows that only about 10 per cent usually show some visual improvement, whereas this figure was as high as 40 per cent with the aflibercept treatment arms.

Focusing on the safety data, Dr Arnold said that the treatments overall were very well tolerated, with no reports of endophthalmitis in aflibercept-treated eyes.

“We see comparable amounts of non-ocular and ocular adverse events overall. Interestingly, slightly more people in the laser group seemed to progress to retinopathy-related complications

such as neovascularisation and vitreous haemorrhage than the groups in the aflibercept treatment arms,” she said.

She added that studies such as VISTA and VIVID were not powered to detect serious systemic adverse events, and particularly thromboembolic events.

Post-hoc analysis In terms of the optimal treatment regimen to use – whether fixed, treat-and-extend or PRN – Dr Arnold said that there are currently no direct head-to-head clinical studies comparing different treatment regimens. Nevertheless, some helpful pointers to guide clinicians in their treatment choices might be gleaned from a posthoc analysis of the aflibercept proactive study results from the VIVID and VISTA trials and a reactive regimen in the RESTORE ranibizumab study for the treatment of DME. “It is important to stress, however, that this analysis cannot give clinical significance so we need this to interpret these results with caution,” she said.

To make the studies comparable, the same endpoint of mean change in visual acuity was fixed for both studies. Overall the analysis showed that the vision improved in treatment with intravitreal anti-VEGF therapy, whereas no improvement was found with laser treatment in all of the studies.

“There is a slight numerical advantage for the proactive regimen in the VIVID and VISTA trials compared to the more reactive regimen used in RESTORE,” said Dr Arnold.

A further subgroup analysis was carried out for an overlapping range of vision, said Dr Arnold, including patients in the studies that had the same baseline range in a poorer vision group of 39 to 60 letters and also a better vision group of 61 to 73 letters.

“We see for the better vision group that treatment was efficacious whereas laser really did not show much improvement at all. Slightly better outcomes were also found for the proactive aflibercept group compared to RESTORE in this group of patients. Similar results were also found in the poorer vision group of patients, with laser giving some slight improvement of 2.5 to 4 letters and a marginally better result for the proactive aflibercept treatment groups,” she said.

Summing up the data from the various trials, Dr Arnold said that the results showed that treatment with anti-VEGF agents delivers better improvement in visual acuity for patients with DME than laser photocoagulation, the previous standard of care.

“Furthermore, while different treatment regimens have not been directly compared it appears that a proactive regimen for the initiation of treatment may well give slightly improved vision compared to a more reactive measure. Another important takehome message is that aflibercept given at eight-weekly intervals after the initial loading dose acted similarly to the four-weekly regimen, allowing a decreased burden of care for these patients,” she concluded.

“There is a slight numerical advantage for the proactive regimen in the VIVID and VISTA trials compared to the more reactive regimen used in RESTORE”

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Clinical conversations: impact of treatment regimen on patients and clinics Following speaker presentations, the symposium closed with an interactive question-and-answer session involving congress delegates, panel speakers and Sebastian Wolf MD, PhD, Department of Ophthalmology, University of Bern, and moderated by Prof Korobelnik.

A selection of highlights from the session is included below.

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Jean-Francois Korobelnik: What are the risks of over-treatment and under-treatment with PRN, fixed and treat-and-extend treatment regimens in DME?

Sebastian Wolf: In our experience we have treated quite a lot of DME patients intensively and we never have seen any development of atrophy. In terms of the dose of anti-VEGF therapy, I do not think that there is a risk treating these patients intensively with a fixed regimen. Of course, each injection carries a certain risk of inflammation or endophthalmitis but this is a very low risk. On the other hand, to under-treat means that the patient may lose vision.

This is not as critical in diabetes as in AMD because if you retreat patients intensively they tend to recover visual acuity to the same level as before treatment.

Jennifer Arnold: I think the priority, at least initially, when commencing treatment is to try as rapidly as possible to gain the best return to vision for the patient. I think that if we under-treat early in the course of the management, we risk delaying that recovery and perhaps compromising the long-term outcome. I agree with Sebastian Wolf that there is a lot more forgiveness in the retina of a diabetic patient, so you do have some more leeway in that regard. But I would be prioritising particularly early on trying to maximise my outcome.

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Jean-Francois Korobelnik: Which treatment regimen do you think is the most achievable in practice for patients and clinics?

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Jean-Francois Korobelnik: Do you still perform focal or grid laser in focal DME or diffuse DME?

Jennifer Arnold: I find the most achievable is a proactive regimen whether that is a fixed-dose initially or a treat-and-extend regimen.

It gives clarity for the patients who are often working and may find it hard to get to the clinic in the first place. With this approach, they know what it is going to occur and when, and it allows for better planning all around.

Jennifer Arnold: I think the role for laser still exists in our management of DME, but it is a greatly diminished role. I think certainly in patients that have not yet lost vision some focal laser may be used in certain cases. But experience from studies shows that as a first-line therapy for patients with foveal or centreinvolving DME, particularly with vision loss, laser is not the way to start because 10 per cent of those patients do lose sight and we are also delaying the eventual improvement in vision when you get started. So I think the role of laser should be diminished.

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Jean-Francois Korobelnik: How do you treat clinically significant DME without visual impairment?

Sebastian Wolf: Jennifer told us she would think about laser treatment, which I would not do. I would observe these patients.

My feeling is that if we do laser we may do some harm and since we have other good options, we do not need to start with laser if the patient has good vision. We may also treat patients with 20/20 vision with anti-VEGF therapy even if the vision is good, but they are having problems with driving or reading, for instance.

Jennifer Arnold: I would just point out that this is a perfect moment to highlight proactive interaction involving our physicians because we can demonstrate to the patient a threat to their vision with a nice display on OCT scans and really try to get them to go back to their physicians and improve their glucose control.

Marc Evans: I think that is a very good point and one of the areas where diabetes care is lacking is this collaborative approach in terms of maximising these touch points that we often have. In patients who have DME without visual impairment the fear of vision loss is a major determinant of driving improvements in glucose control. Much the same paradigm exists for example in young women with diabetes who become pregnant, where the fear of a pregnancy complication drives a lot of motivation in terms of improving glucose control. I think this sort of situation is one where a combined multidisciplinary approach would really benefit the patient, not only from the DME perspective, but also taking account of multiple other comorbidities.

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Jean-Francois Korobelnik: Isn’t reactive PRN associated with fewer injections than proactive regimens and therefore better for the patient?

Jennifer Arnold: I think really the answer here depends on the staging of the treatment. We are talking about the initiation stage here and certainly with a monthly treatment regimen, more injections are going to be needed in the first 12 months. The RESTORE study, for instance, had around seven in the first year.

With aflibercept, it is possible to use the two-monthly regimen and have a comparable outcome. So you can get comparable treatment injection numbers in the first year, but moving further out I think the proactive approach of treat-and-extend can certainly give the same number as a reactive approach.

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Jean-Francois Korobelnik: What are the criteria for an “unresponsive� eye to anti-VEGF agents?

Jennifer Arnold: It is quite hard to define unresponsive and I think it is usually just the response that is sub-optimal compared to what had been hoped for by the physician and the patient.

That can be in terms of vision or in the anatomy as shown on OCT. I think we certainly cannot always aim for a drylooking macula as with AMD patients. Similarly, we have got to remember that if the vision is not improving it is often because of structural damage, so it really depends on whether I think there is a reversible component.

Sebastian Wolf: We try to do the OCT in the first place and if we see a total loss of photoreceptors we may not do treatment. I think it is interesting to do an intensive starting phase to be sure that nothing is happening. If you do not see anything after five or six injections, then probably it is already too late to rescue the photoreceptors from DME-related damage.

References 1. Shubrook JH. J Am Osteopath Assoc 2014; 114: S6-S13.

2. Data from the International Diabetes Federation, IDF Diabetes Atlas.

6th ed. 2013.

3. Strain D et al. Diabetes Res Clin Pract 2014; Epub ahead of print.

4. Patient likelihood to follow physician’s advice: changed diet in 51% and increased exercise in 40% (Source Strain D et al. Diabetes Res Clin Pract 2014; Epub ahead of print. Time 2 Do More in Diabetes survey. Available at: http://www.novartis.com/downloads/newsroom/ feature-stories/2014/time-2-do-more-infographic.pdf. Accessed September 2014.)

5. Holman RR et al. N Engl J Med 2008; 359: 1577–1589. UKPDS 33 Study Group. Lancet 1998; 352: 837–853.

6. King P, Peacock I and Donnelly R. The UK Prospective Diabetes Study (UKPDS): clinical and therapeutic implications for type 2 diabetes. Br J Clin Pharmacol. Nov 1999; 48(5): 643-648.

7. Peyrot M et al. Diabet Med 2012; 29: 682-689.

8. Chen E et al. Curr Med Res Opin 2010; 26: 1587-1597.

9. Minassian DC et al. Br J Ophthalmol 2012; 96: 345-349.

10. Heier JS et al. 2009; Available at http://www.retinalphysician.com/ articleviewer.aspx?articleid=102898. Accessed July 2014.

11. Korobelnik J-F et al. Ophthalmology 2014; Epub ahead of print.

Contacts Marc Evans: moc.dlrowltn@2snave.cram Sebastian Wolf: sebastian.wolf@insel.ch Jean-Francois Korobelnik: jean-francois.korobelnik@chu-bordeaux.fr Jennifer Arnold: jennifer.arnold@marsdeneye.com

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Eylea® 40 mg/ml solution for injection in a vial (aflibercept) Prescribing Information (Refer to full Summary of Product Characteristics (SmPC) before prescribing) Presentation: 1 ml solution for injection contains 40 mg aflibercept. Each vial contains 100 microlitres, equivalent to 4 mg aflibercept. Indication(s): Treatment of neovascular (wet) age-related macular degeneration (AMD),macular oedema secondary to central retinal vein occlusion (CRVO) and visual impairment due to diabetic macular oedema (DMO) in adults.

Posology & method of administration: For intravitreal injection only. Must be administered according to medical standards and applicable guidelines by a qualified physician experienced in administering intravitreal injections. Each vial should only be used for the treatment of a single eye. The vial contains more than the recommended dose of 2 mg. The extractable volume of the vial (100 microlitres) is not to be used in total. The excess volume should be expelled before injecting. Refer to SmPC for full details. Adults: The recommended dose is 2 mg aflibercept, equivalent to 50 microlitres. For wAMD treatment is initiated with one injection per month for three consecutive doses, followed by one injection every two months. No requirement for monitoring between injections. After the first 12 months of treatment, treatment interval may be extended based on visual and anatomic outcomes. In this case the schedule for monitoring may be more frequent than the schedule of injections. For CRVO, after the initial injection, treatment is given monthly at intervals not shorter than one month, and continues until visual and anatomic outcomes are stable for three monthly assessments.

Thereafter the need for continued treatment should be reconsidered.

Treatment may be continued with gradually increasing treatment intervals to maintain a stable visual and anatomic outcome. Continued treatment is not recommended if no improvement in visual and anatomic outcomes over the first three injections. If treatment is discontinued, monitor visual and anatomic outcomes and resume treatment if these deteriorate. Usually, monitoring should be done at the injection visits. During treatment interval extension until therapy completion, the monitoring schedule should be determined by the treating physician based on the individual patient’s response and may be more frequent than the schedule of injections. For DMO, initiate treatment with one injection/month for 5 consecutive doses, followed by one injection every two months. No requirement for monitoring between injections. After the first 12 months of treatment, the treatment interval may be extended based on visual and anatomic outcomes. The schedule for monitoring should be determined by the treating physician. If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, treatment should be discontinued. Hepatic and/or renal impairment: No specific studies have been conducted. Available data do not suggest a need for a dose adjustment. Elderly population: No special considerations are needed.

Limited experience in those with DMO over 75years old. Paediatric population: No data available. Contra-indications: Hypersensitivity to active substance or any excipient; active or suspected ocular or periocular infection; active severe intraocular inflammation. Warnings & precautions: As with other intravitreal therapies endophthalmitis has been reported. Aseptic injection technique essential. Patients must report any symptoms of endophthalmitis without delay. Increases in intraocular pressure have been seen within 60 minutes of intravitreal injection; special precaution is needed in patients with poorly controlled glaucoma (do not inject while the intraocular pressure is ≥ 30 mmHg). Immediately after injection, monitor intraocular pressure and perfusion of optic nerve head and manage appropriately. There is a potential for immunogenicity as with other therapeutic proteins; patients should report any signs or symptoms of intraocular inflammation e.g pain, photophobia or redness, which may be a clinical sign of hypersensitivity.

Reports of systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events following intravitreal injection of VEGF inhibitors. Safety and efficacy of concurrent use in both eyes have not been systemically studied. Caution in patients with risk factors for development of retinal pigment epithelial tears including large and/or high pigment epithelial

retinal detachment. Withhold treatment in patients: with rhegmatogenous retinal detachment or stage 3 or 4 macular holes; with retinal break and do not resume treatment until the break is adequately repaired. Withhold treatment and do not resume before next scheduled treatment if there is: decrease in best-corrected visual acuity of ≥30 letters compared with the last assessment; central foveal subretinal haemorrhage, or haemorrhage ≥50%, of total lesion area. Do not treat in the 28 days prior to or following performed or planned intraocular surgery. Eylea 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. Populations with limited data: There is limited experience of treatment with Eylea in patients with ischaemic, chronic CRVO. In patients presenting with clinical signs of irreversible ischaemic visual function loss, the treatment is not recommended.

There is limited experience in DMO due to type I diabetes or in diabetic patients with an HbA1c over 12% or with proliferative diabetic retinopathy.

Eylea has not been studied in patients with active systemic infections, concurrent eye conditions such as retinal detachment or macular hole, or in diabetic patients with uncontrolled hypertension. This lack of information should be considered when treating such patients. Interactions: No available data. Fertility, pregnancy & lactation: Not recommended during pregnancy unless potential benefit outweighs potential risk to the foetus. No data available in pregnant women. Studies in animals have shown embryo-foetal toxicity. Women of childbearing potential have to use effective contraception during treatment and for at least 3 months after the last injection. Not recommended during breastfeeding. Excretion in human milk: unknown.

Male and female fertility impairment seen in animal studies with high systemic exposure not expected after ocular administration with very low systemic exposure. Effects on ability to drive and use machines: Possible temporary visual disturbances. Patients should not drive or use machines if vision inadequate. Undesirable effects: Very common: conjunctival haemorrhage (phase III studies: increased incidence in patients receiving anti-thrombotic agents), eye pain, visual acuity reduced. Common: retinal pigment epithelium tear, detachment of the retinal pigment epithelium, retinal degeneration, vitreous haemorrhage, cataract (nuclear or subcapsular), corneal abrasion or erosion, corneal oedema, increased intraocular pressure, blurred vision, vitreous floaters, vitreous detachment, injection site pain, foreign body sensation in eyes, increased lacrimation, eyelid oedema, injection site haemorrhage, punctate keratitis, conjunctival or ocular hyperaemia.

Uncommon: Injection site irritation, abnormal sensation in eye, eyelid irritation.

Serious: cf. CI/W&P - in addition: endophthalmitis, cataract, transient increased intraocular pressure, vitreous detachment, retinal detachment or tear, hypersensitivity (incl. allergic reactions), vitreous haemorrhage, cortical cataract, lenticular opacities, corneal epithelium defect/erosion, vitritis, uveitis, iritis, iridocyclitis, anterior chamber flare, blindness. Consult the SmPC in relation to other side effects. Overdose: Monitor intraocular pressure and treat if required. Incompatibilities: Do not mix with other medicinal products.

Special Precautions for Storage: Store in a refrigerator (2°C to 8°C). Do not freeze. Unopened vials may be kept at room temperature (below 25°C) for up to 24 hours before use. Legal Category: POM. Package Quantities & Basic NHS Costs: Single vial pack £816.00. MA Number(s): EU/1/12/797/002.

Further information available from: Bayer plc, Bayer House, Strawberry Hill, Newbury, Berkshire RG14 1JA, United Kingdom. Telephone: 01635 563000.

Date of preparation: August 2014 Eylea® is a trademark of the Bayer Group

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard.

Adverse events should also be reported to Bayer plc.

Tel.: 01635 563500, Fax.: 01635 563703, Email: phdsguk@bayer.co.uk

Cited comment and opinion reflect the views of speakers and participants and do not necessarily reflect those of Bayer HealthCare.

L.GB.11.2014.8659 Date of preparation: November 2014

Supplement November 2014