Mrs Deepali Varma is Consultant Ophthalmologist and Lead Clinician at Macular Service, Sunderland Eye Infirmary, Sunderland SR2 9HP A guide to Age-related macular degeneration Introduction The macula is a specialised area of the retina responsible for high acuity central vision and the perception of colour (Hirsch and Curcio, 1989). Age-related macular degeneration is a potentially blinding degenerative condition of the macula and the leading cause of loss of vision in older people in the developed world (Klein et al, 1992; Mitchell et al, 1995). The condition usually affects people who are over 50 years old and the risk increases significantly with age. The condition affects more women than men and estimates from the Royal National Institute of the Blind and National Institute of Health and Clinical Excellence (NICE) indicate there may be 26 000 people with exuda- tive age-related macular degeneration now eligible for treatment in the UK each year, approximately 450 new cases per million per year. Types of age-related macular degeneration Age-related macular degeneration occurs in two forms: dry (non-neovascular) and wet (neovascu- lar). It can also be classified into early and late age-related macular degeneration (Ferris et al, 2013). LUC15 - C059 March 2015 The production of this promotional guide was supported by an educational grant from Novartis Pharmaceuticals who were involved in reviewing the content.
Transcript
Mrs Deepali Varma is Consultant Ophthalmologist and Lead Clinician at Macular Service, Sunderland Eye Infirmary, Sunderland SR2 9HP
A guide toAge-related macular degeneration
IntroductionThe macula is a specialised area of the retina responsible for high acuity central vision and the perception of colour (Hirsch and Curcio, 1989). Age-related macular degeneration is a potentially blinding degenerative condition of the macula and the leading cause of loss of vision in older people in the developed world (Klein et al, 1992; Mitchell et al, 1995). The condition usually affects people who are over 50 years old and the risk increases significantly with age. The condition affects more women than men and estimates from the Royal National Institute of the Blind and National Institute of Health and Clinical Excellence (NICE) indicate there may be 26 000 people with exuda-tive age-related macular degeneration now eligible for treatment in the UK each year, approximately 450 new cases per million per year.
Types of age-related macular degenerationAge-related macular degeneration occurs in two forms: dry (non-neovascular) and wet (neovascu-lar). It can also be classified into early and late age-related macular degeneration (Ferris et al, 2013).
LUCENTIS® treatment has CHANGED...
For UK: Adverse events should be reported. Reporting forms and information can be found at https://yellowcard.mhra.gov.uk/ Adverse events should also be reported to Novartis Pharmaceuticals UK Limited on (01276) 698370 or [email protected]
LUC14-C239 November 2014
LUCENTIS®▼ (RANIBIZUMAB) ABBREVIATED UK PRESCRIBING INFORMATION Please refer to the SmPC before prescribing LUCENTIS 10mg/ml solution vial for injection, or LUCENTIS 10 mg/ml solution for injection in pre-filled syringe. Presentations: A glass single-use vial containing 0.23ml solution containing 2.3mg of ranibizumab (10mg/ml) and a pre-filled syringe containing 0.165 ml, equivalent to 1.65 mg ranibizumab (10mg/ml). Indications: The treatment in adults of neovascular (wet) age-related macular degeneration (AMD), the treatment of visual impairment due to diabetic macular oedema (DMO), the treatment of visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO), and the treatment of visual impairment due to choroidal neovascularisation (CNV) secondary to pathologic myopia (PM). Administration and Dosage: Available as a single-use vial and a single dose pre-filled syringe, for intravitreal use only. LUCENTIS must be administered by a qualified ophthalmologist experienced in intravitreal injections under aseptic conditions. The recommended dose is 0.5 mg (0.05ml). The interval between two doses injected into the same eye should be at least four weeks. Treatment is initiated with one injection per month until maximum visual acuity is achieved and/or there are no signs of disease activity i.e. no change in visual acuity or in other signs and symptoms of the disease under continued treatment. In patients with wet AMD, DMO and RVO, initially, three or more consecutive, monthly injections may be needed. Thereafter, monitoring and treatment intervals should be determined by the physician and should be based on disease activity, as assessed by visual acuity and/or anatomical parameters. If, in the physician’s opinion, visual and anatomic parameters indicate that the patient is not benefiting from continued treatment, LUCENTIS should be discontinued. Monitoring for disease activity may include clinical examination, functional testing or imaging techniques (e.g. optical coherence tomography or fluorescein angiography). If patients are being treated according to a treat-and-extend regimen, once maximum visual acuity is achieved and/or there are no signs of disease activity, the treatment intervals can be extended stepwise until signs of disease activity or visual impairment recur. The treatment interval should be extended by no more than two weeks at a time for wet AMD and may be extended by up to one month at a time for DMO. For RVO, treatment intervals may also be gradually extended, however there are insufficient data to conclude on the length of these intervals. If disease activity recurs, the treatment interval should be shortened accordingly.In the treatment of visual impairment due to CNV secondary to PM, many patients may only need one or two injections during the first year, while some patients may need more frequent treatment. LUCENTIS and laser photocoagulation in DMO and in macular oedema secondary to BRVO: There is some experience of LUCENTIS administered concomitantly with laser photocoagulation. When given on the same day, LUCENTIS should be administered at least 30 minutes after laser photocoagulation. LUCENTIS can be administered in patients who have received previous laser photocoagulation. LUCENTIS and Visudyne photodynamic therapy in CNV secondary to PM: There is no experience of concomitant administration of LUCENTIS and Visudyne. Before treatment, evaluate the patient’s medical history for hypersensitivity. Children and adolescents: Not recommended for use in children and adolescents due to a lack of data. Elderly: No dose adjustment is required in the elderly. There is limited experience in patients older than 75 years with DMO Hepatic and renal impairment: Dose adjustment is not needed in these populations. Contraindications: Hypersensitivity to the active substance or excipients.
Patients with active or suspected ocular or periocular infections. Patients with active severe intraocular inflammation. Special warnings and precautions for use: LUCENTIS is for intravitreal injection only. Intravitreal injections have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract. Monitor during week following injection for infections. Patients should be instructed to report symptoms suggestive of any of the above without delay. Transient increases in intraocular pressure (IOP) within 1 hour of injection and sustained IOP increases have been identified. Both IOP and perfusion of the optic nerve head should be monitored and managed appropriately. Limited data on bilateral use of LUCENTIS (including same-day administration) do not suggest an increased risk of systemic adverse events compared with unilateral treatment. There is a potential for immunogenicity with LUCENTIS which may be greater in subjects with DMO. Patients should report an increase in severity of intraocular inflammation. LUCENTIS should not be administered concurrently with other anti-VEGF agents (systemic or ocular). Withhold dose and do not resume treatment earlier than the next scheduled treatment in the event of the following: a decrease in best corrected visual acuity (BCVA) of ≥30 letters compared with the last assessment of visual acuity; an intraocular pressure of ≥30 mmHg; a retinal break; a subretinal haemorrhage involving the centre of the fovea, or if the size of the haemorrhage is ≥50% of the total lesion area; performed or planned intraocular surgery within the previous or next 28 days. Risk factors associated with the development of a retinal pigment epithelial (RPE) tear after anti-VEGF therapy for wet AMD include a large and/or high pigment epithelial retinal detachment. When initiating LUCENTIS therapy, caution should be used in patients with these risk factors for RPE tears. Discontinue treatment in cases of rhegmatogenous retinal detachment or stage 3 or 4 macular holes. There is only limited experience in the treatment of subjects with DMO due to type I diabetes. LUCENTIS has not been studied in patients who have previously received intravitreal injections, in patients with active systemic infections, proliferative diabetic retinopathy, or in patients with concurrent eye conditions such as retinal detachment or macular hole. There is also no experience of treatment with LUCENTIS in diabetic patients with an HbA1c over 12% and uncontrolled hypertension. In PM patients there are no data on the use of LUCENTIS in patients with extrafoveal lesions and only limited data on its use in those who have had previous unsuccessful therapy with verteporfin photodynamic therapy. Systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events have been reported following intravitreal injection of VEGF inhibitors. There are limited data on safety in the treatment of DMO, macular oedema due to RVO and CNV secondary to PM patients with prior history of stroke or transient ischaemic attacks. Caution should be exercised when treating such patients. There is limited experience with treatment of patients with prior episodes of RVO and of patients with ischaemic BRVO and CRVO. Treatment is not recommended in RVO patients presenting with clinical signs of irreversible ischaemic visual function loss. Interactions: No formal interaction studies have been performed. In DMO and BRVO adjunctive use of laser therapy and LUCENTIS was not associated with any new ocular or non-ocular safety findings. In clinical studies for the treatment of visual impairment due to DMO, the outcome with regard to visual acuity or central retinal subfield thickness (CSFT) in patients treated with LUCENTIS was not affected by concomitant treatment with thiazolidinediones. Pregnancy and lactation: Women of childbearing potential should use effective contraception during
treatment. No clinical data on exposed pregnancies are available. Ranibizumab should not be used during pregnancy unless the expected benefit outweighs the potential risk to the foetus. For women who wish to become pregnant and have been treated with ranibizumab, it is recommended to wait at least 3 months after the last dose of ranibizumab before conceiving. Breast-feeding is not recommended during the use of LUCENTIS Driving and using machines: The treatment procedure may induce temporary visual disturbances and patients who experience these signs must not drive or use machines until these disturbances subside. Undesirable effects: Most adverse events are related to the injection procedure. Serious adverse events reported include endophthalmitis, blindness, retinal detachment, retinal tear and iatrogenic traumatic cataract. The safety data below include adverse events experienced following the use of LUCENTIS in the entire clinical trial population. Those marked * were only seen in the DMO population. Very Common: Intraocular pressure increased, headache, vitritis, vitreous detachment, retinal haemorrhage, visual disturbance, eye pain, vitreous floaters, conjunctival haemorrhage, eye irritation, foreign body sensation in eyes, lacrimation increased, blepharitis, dry eye, ocular hyperaemia, eye pruritus, arthralgia, nasopharyngitis. Common: Urinary tract infection*, anaemia, retinal degeneration, retinal disorder, retinal detachment, retinal tear, detachment of the retinal pigment epithelium, retinal pigment epithelium tear, visual acuity reduced, vitreous haemorrhage, vitreous disorder, uveitis, iritis, iridocyclitis, cataract, cataract subcapsular, posterior capsule opacification, punctuate keratitis, corneal abrasion, anterior chamber flare, vision blurred, injection site haemorrhage, eye haemorrhage, conjunctivitis, conjunctivitis allergic, eye discharge, photopsia, photophobia, ocular discomfort, eyelid oedema, eyelid pain, conjunctival hyperaemia, cough, nausea, allergic reactions, hypersensitivity, anxiety. Product-class-related adverse reactions: 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 LUCENTIS clinical trials in patients with AMD, DMO, RVO and PM and there were no major differences between the groups treated with ranibizumab compared to control. Please refer to the SmPC for full listing of all undesirable effects. Legal category: POM, UK Basic NHS cost: £742.17 Marketing authorisation number: single dose vial EU/1/06/374/001, single dose pre-filled syringe EU/1/06/374/003 Marketing authorisation holder: Novartis Europharm Limited, Frimley Business Park, Camberley, GU16 7SR, United Kingdom. Full prescribing information, including SmPC, is available from: Novartis Pharmaceuticals, Frimley Business Park, Frimley, Camberley, Surrey, GU16 7SR. Telephone: 01276 692255. Fax: 01276 692508.
*LUCENTIS® is licensed in visual impairment due to diabetic macular oedema. **LUCENTIS® is licensed in visual impairment due to macular oedema secondary to retinal vein occlusion. References 1. LUCENTIS® Summary of Product Characteristics. Available at: www.medicines.org.uk/emc [Accessed November 2014]
LUCENTIS®: FLEXIBILITY AT EVERY STEP
• Flexible dosing and monitoring regimen for a personalised treatment approach for:
Wet Age Related Macular Degeneration (wAMD) Diabetic Macular Oedema (DMO)* Retinal Vein Occlusion (RVO)**
• There is no longer a requirement to have
monthly monitoring.
• Monitoring and treatment intervals can now be determined by the physician, based on disease activity as assessed by visual acuity and/or anatomical parameters.1 You can now choose a Treat & Extend regimen.
SEE YOUR SUCCESS THROUGH THE EYES OF YOUR PATIENTS
The production of this promotional guide was supported by an educational grant from Novartis Pharmaceuticals who were involved in reviewing the content.
Dry age-related macular degeneration in the early stages is characterized by drusen and retinal pigment epithelium disturbances. Drusen occur as a result of deposition of lipid material beneath the retinal pigment epithelium and within Bruch’s membrane, and are seen as pale yellow deposits in the macula on fundus examination (Figure 1) (Ferris et al, 2013). Areas of hyperpigmentation and hypopigmentation can also be seen in the early stages as a result of morphological alteration in the retinal pigment epithelium. Generally drusen and retinal pigment epithelium irregulari-ties are not associated with disturbances of central visual function (Ferris et al, 2013).
A proportion of people (12.9% patients with drusen and 17.8% with retinal pigment epithelium irregularities respectively; Klein et al, 2007) with these early changes will progress slowly to advanced age-related macular degeneration with extensive atrophy of cells known as geographical atrophy (Figure 2). This is characterized by a sharply demar-cated scalloped area of partial or complete depig-mentation, with large choroidal vessels visible as a result of atrophy of the overlying retinal pigment epithelium. Three ocular factors predict the pro-gression of age-related macular degeneration (Ferris et al, 2013): presence of large drusen, retinal pig-ment epithelial abnormalities and the presence of late age-related macular degeneration in one eye.
Wet age-related macular degeneration is char-acterized by choroidal neovascularisation, the
development of immature blood vessels that grow between the retinal pigment epithelium cells and the photoreceptor cells in the centre of the retina. These vessels easily haemorrhage and cause lesions on the macula (Figure 3), leading to visual impair-ment. This egress of blood and serum causes the separation of Bruch’s membrane, retinal pigment epithelium and retina from each other. It also results in the accumulation of intraretinal fluid which leads to a generalised thickening of the retina or the formation of cystic spaces. These pathological manifestations cause photo-receptors to become misaligned. Degenerative changes occur with cell loss and eventual fibrosis, also known as disciform scar (Bressler et al, 2006). In certain cases neovascularisation can also arise de
Figure 1. Colour fundus photograph of the right eye showing drusen, a form of dry age-related macular degeneration.
Figure 2. Colour fundus photograph showing geographical atrophy at the macula of the right eye.
Figure 3. Colour fundus photograph of the left eye showing wet age-related macular degeneration (macular haemorrhage and pigment epithelial detachment).
novo in the macular retina, referred to as retinal angiomatous proliferation (Bressler et al, 2006).
Another variant of age-related macular degen-eration is idiopathic polypoidal choroidopathy (Imamura et al, 2010) which consists of neovascu-larisation and polyps, primarily in the choroid. It is seen in younger people than age-related macular degeneration, it more often occurs adjacent to the optic disc and in the nasal macula, and the poly-poidal neovascular complexes may leak and bleed.
Signs and symptomsDry age-related macular degeneration accounts for 90% of age-related macular degeneration. This tends to lead to gradual but potentially significant reduction in central vision, while wet age-related macular degeneration leads to rapid and severe loss of vision (Kanski, 1999). Common presenting symptoms for wet age-related macular degenera-tion, besides visual loss, include metamorphopsia, distortion and scotoma of sudden onset. Sometimes patients do not notice visual symptoms when the first eye is affected.
When exudative age-related macular degenera-tion occurs in the second eye, patients suddenly become unable to read, drive and see fine detail such as facial expressions and features. Examination of the macula usually reveals an exudative macular lesion along with other features of early age-related
macular degeneration such as drusen and pigmen-tary irregularities (Kanski, 1999). Subretinal or choroidal neovascularisation may be visible as grey green lesions (Kanski, 1999) that may or may not be accompanied by haemorrhages (pre-retinal, intraretinal or subretinal), exudates and retinal pigment epithelium detachment.
InvestigationsRetinal imaging is an integral part of patient man-agement. Following measurement of visual acuity, colour fundus photography, optical coherence tomography, fundus fluorescein angiography, indocyanine green angiography and fundus autofluorescence are commonly used for diagnosis of age-related macular degeneration and monitor-ing response to therapy.
Optical coherence tomography (Figure 4) is a non-invasive investigative modality that relies on the analysis of wave patterns of reflected laser light to produce an image (Gianni et al, 2009). The new generation Fourier domain optical coherence tomographs capture around 20 000 A scans/minute and achieve a resolution of between 5 and 10 μm (Gianni et al, 2009) allowing more retinal detail to be visualized. Optical coherence tomography may be used for screening the macula before performing more invasive imag-ing such as fundus fluorescein angiography.
Figure 4. Spectral domain optical coherence tomograph of the left eye macula showing thickened retina raised by the vascularised pigment epithelial detachment.
Fundus fluorescein angiography is the gold standard for diagnosing choroidal neovascularisa-tion in wet age-related macular degeneration. Fundus fluorescein angiography is a sequence of images of the fundus taken over a 10-minute period after injecting fluorescein isothiocyanate (a non-toxic dye) into a suitable peripheral vein. Classification of the neovascular lesion includes a description of the composition of the neovascular complex after stereoscopic review of the entire angiogram sequence.
Indocyanine green is an alternative dye to fluo-rescein, which is used to visualize the choroidal circulation. It is especially indicated in cases of suspected polypoidal choroidal vasculopathy and juxtapapillary choroidal neovascularisation to identify underlying polyps in the larger choroidal vasculature (Kanski, 1999).
ManagementPreventionBesides increasing age, risk factors for age-related macular degeneration include genetic predisposi-tion (Yates et al, 2007), nutritional factors and cigarette smoking.
SmokingCigarette smoking is a well-established risk factor for the development of both dry and wet age-related macular degeneration. Current smokers have a two to three-fold increased risk of develop-ing age-related macular degeneration and there is a dose–response relationship with pack-years of smoking (Mitchell et al, 2002). All patients with macular degeneration should be advised to stop smoking.
Nutrition Macular pigments (lutein, zeaxanthin) are impor-tant for optimal visual performance because of their antioxidant properties (Snellen et al, 2002). These pigments are replenished through intake of a diet rich in green leafy vegetables and yellow fruits. The Age-Related Eye Disease Study Research Group (2001) found that very high doses
of antioxidants (daily dose vitamin C 500 mg, vitamin 400 IU, beta-carotene 15 mg (25 000 IU) and zinc 80 mg, along with copper 2 mg to prevent anaemia) reduced the patient’s relative risk of pro-gression to advanced age-related macular degen-eration by 25%.
SunlightThe relationship between sunlight exposure and macular degeneration is not clear (Ham et al, 1976). Different wavelengths of light can pene-trate the eye to different degrees, with UV radia-tion mainly being absorbed or deflected by the lens and cornea. There is laboratory evidence that exposure of the macula to blue wavelengths of light can lead to changes similar to macular degen-eration (Fletcher et al, 2008).
There is also evidence that high levels of pig-ment in the form of lutein and zeaxanthin, which absorb blue light, have a protective effect on the development of macular degeneration (Beatty et al, 2000).
TreatmentDry age-related macular degenerationCurrently treatment for dry or non-neovascular age-related macular degeneration is limited and consists mainly of counselling, smoking cessation, visual rehabilitation (low vision aids and assess-ment by an eye care liaison officer where available) and prescription of vitamins to reduce risk of pro-gression in those expected to benefit. Clinical trials of novel treatments for dry age-related macular degeneration are taking place but are not currently available in clinical practice (Royal College of Ophthalmologists, 2013).
Wet age-related macular degenerationPhotodynamic therapyThe photosensitising dye verteporfin (Visudyne, Novartis) is given intravenously followed by the delivery of laser light (wavelength 689 nm) to the choroidal neovascularisation lesion. The energy from the laser is taken up by verteporfin, leading to damage to proliferating vascular endothelial
cells and thrombotic occlusion of blood vessels within the choroidal neovascularisation lesion. There is minimal damage to the overlying retina (Miller et al, 1999), but this treatment only pre-vents further visual loss. Photodynamic therapy is currently only recommended in patients with idi-opathic polypoidal choroidopathy.
Anti-vascular endothelial growth factorsThe introduction of intravitreal anti-VEGF (anti-vascular endothelial growth factor) agents has rev-olutionized the management of wet age-related macular degeneration. It heralds a new era of vision improvement treatment regimens that pre-vent blindness, reduce the social burden and improve quality of life for people suffering from age-related macular degeneration.
VEGF-A is a pro-angiogenic growth factor that also stimulates vascular permeability and has a major role in the pathology of choroidal neovascu-larisation. It exists in a number of different iso-forms. Various agents have been developed to block its activity in the management of wet age-related macular degeneration. Licensed anti-VEGF agents include pegaptanib, ranibizumab and aflibercept.
Pegaptanib sodium (Macugen, Eyetech/Pfizer), the first licensed anti-VEGF, binds and blocks the VEGF-A 165 isoform (Pfizer, 2013). Although treatment with pegaptanib will reduce the risk of moderate and severe visual loss most patients will still lose some vision over 2 years (Gragoudas et al, 2004) so, in practice, pegaptanib has no role in the management of age-related macular degeneration.
Ranibizumab (Lucentis▼, Genetech Inc/Novartis) is a humanised Fab fragment of a mono-clonal antibody that binds to and inhibits the action of all isoforms of VEGF-A (Novartis Pharmaceuticals, 2014). Two randomised, con-trolled, double-blind studies were published in which ranibizumab was delivered by intravitreal injection on a 4-weekly basis over 2 years.
In the MARINA study (Rosenfeld et al, 2006) eyes with wet age-related macular degeneration
were treated with ranibizumab (0.3 mg or 0.5 mg*) at monthly intervals or sham injections. At 12 months 94.6% of those given 0.5 mg had lost fewer than 15 letters of vision, compared to 62.2% in the sham injection group. Visual acuity improved by 15 or more letters in 33.8% of the 0.5 mg group compared to 5% in the sham injec-tion group. Mean visual acuity improved by 7.2 letters in the 0.5 mg group but dropped by 10.4 letters in the sham injection group. These results were highly significant (P<0.001) and were main-tained at 24 months.
In the ANCHOR study (Brown et al, 2006) eyes with wet age-related macular degeneration were randomised to receive either ranibizumab (0.3 mg or 0.5 mg) with sham photodynamic therapy or photodynamic therapy with sham intravitreal injections. Visual acuity improved by 15 or more letters in 40.3% of the 0.5 mg group compared to 5.7% in the photodynamic therapy treated group. Mean visual acuity improved by 11.3 letters in the 0.5 mg group but dropped by 9.5 letters in the photodynamic therapy treated group†.
Aflibercept (Eylea▼, Regeneron) is a fusion protein which inhibits all isoforms of VEGF-A, VEGF-B as well as placental growth factor (Bayer, 2015). In phase 3 trials (Heier et al, 2012) patients with wet age-related macular degeneration were randomised to one of four regimens: monthly aflibercept 0.5 mg, monthly aflibercept 2 mg, 2-monthly aflibercept 2 mg and monthly ranibizu-mab 0.5 mg. Each aflibercept arm was non-inferi-or to monthly ranibizumab with regard to the proportion losing less than three lines of best cor-rected visual acuity, average number of letters gained at 1 year and anatomical outcomes.
Ranibizumab and aflibercept are both recom-mended by NICE for treatment of wet age-related macular degeneration (NICE, 2012, 2013; Royal College of Ophthalmologists, 2013). Ranibizumab
* NB the 0.3 mg dose of ranibizumab is not approved for use in the UK† The current summary of product characteristics should always be consulted before prescribing
† The current summary of product characteristics should always be consulted before prescribing
intravitreal injection is recommended as an option for the treatment of wet age-related macular degen-eration (NICE, 2012). The recommended dose is 0.5 mg and the treatment is initiated with one injec-tion per month until maximum visual acuity is achieved and/or there are no signs of disease activity, i.e. no change in visual acuity and in other signs and symptoms of the disease under continued treat-ment. In patients with wet age-related macular degeneration, three or more consecutive monthly injections may be needed initially. Thereafter, mon-itoring and treatment intervals should be deter-mined by the physician and should be based on disease activity, as assessed by visual acuity and/or anatomical parameters (Novartis Pharmaceuticals, 2014). If patients are being treated according to a treat-and-extend regimen, once maximum visual acuity is achieved and/or there are no signs of dis-ease activity, the treatment intervals can be extended stepwise until signs of disease activity or visual impairment recur. The treatment interval should be extended by no more than 2 weeks at a time† (Novartis Pharmaceuticals, 2014).
The recommended dose for aflibercept is 2 mg and treatment should be given monthly for three consecutive doses, followed by one injection every 2 months (NICE, 2013). The summary of product characteristics states that there is no need for monitoring between injections. After the first 12 months of treatment, the treatment interval may be extended based on visual and anatomical outcomes. In this case the schedule for monitoring should be determined by the treating doctor†.
Patients should be advised of the need for fre-quent monitoring when starting intravitreal drug treatment for age-related macular degeneration. Treatment and follow-up may need to be contin-ued for up to and beyond 2 years. A major limita-tion of VEGF inhibition therapy is the need for repeated intravitreal injection with its attendant risks of endophthalmitis, retinal detachment and
traumatic cataract. Further research is required into the appropriate duration and optimal regi-men in terms of frequency of injections.
Ionising radiation Radiotherapy can inactivate rapidly proliferating cells, and therefore could be of potential benefit in wet age-related macular degeneration by its effect on the capillary endothelium of choroidal neovas-cularisation. It can be delivered from a source external to the body (teletherapy) or locally (brachytherapy). The ‘I-Ray plus anti-VEGF treat-ment for patients with Wet AMD’ study (INTREPID) investigated a single dose of external beam stereotactic radiotherapy for patients with wet age-related macular degeneration requiring ongoing injections of anti-VEGF treatments. At 1 year treatment with radiotherapy reduced the number of injections needed, with a favourable safety profile (Jackson et al, 2013).
Management Figure 5 gives a management algorithm for age-related macular degeneration (Royal College of Ophthalmologists, 2013). Treatment of wet age-related macular degeneration with licensed anti-VEGF agents is recommended if all of the fol-lowing circumstances apply in the eye to be treated: ��The best corrected visual acuity is between 6/12 and 6/96 ��There is no permanent structural damage to the central fovea ��The lesion size is less than or equal to 12 disc areas in greatest linear dimension ��There is evidence of recent presumed disease progression (blood vessel growth as indicated by fundus fluorescein angiography or recent visual acuity changes).
ConclusionsStaff and patients need to be aware of the need to treat wet age-related macular degeneration urgently.
Patients with suspected wet age-related macular degeneration should be told to contact the clinic if
they have not received an appointment for treat-ment or further assessment within 2 weeks, also if their follow-up appointment has been extended beyond 4–6 weeks unless instructed by the treating clinician. Self-monitoring for progression to wet age-related macular degeneration in the other eye includes regular use of an Amsler grid to detect distortion.
The importance of ongoing regular eye exam-inations must be clearly explained to the patient, especially if he/she is likely to be discharged from the hospital system. Individuals should be advised to attend their optician at least every 2 years or more frequently if appropriate.
The author has received travel sponsorships, speaker fees and participated in research studies sponsored by Novartis, Bayer and Allergan Pharmaceuticals. The author would like to thank Sunderland Eye Infirmary (City Hospitals Sunderland NHS Foundation Trust) and the Royal College of Ophthalmologists for permission to reproduce images.
Age-Related Eye Disease Study Research Group (2001) A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 119(10): 1417–36
Bayer (2015) Eylea 40mg/ml solution for injection in a vial Summary of product characteristics. www.medicines.org.uk/emc/medicine/27224
Beatty S, Koh H, Phil M, Henson D, Boulton M (2000) The role of oxidative stress in the
Figure 5. Management of age-related macular degeneration (AMD). From Royal College of Ophthalmologists (2013).
Referred as AMD or self referral with blurring/distortion in central visual field
Medical, family, social and medication history Best corrected visual acuity, biomicroscopy, tomography, photography
Early/intermediate AMD in both eyes Manage in community
Advise on risk factors for progression
Wet AMD
Fundus fluorescein angiography Indocyanine green angiography
Consider other exudative maculopathies, central serous chorioretinopathy, perifoveal telangiectasia, retinal
vein occlusion, diabetic macular oedema, other causes of choroidal neovascularisation. Define choroidal
neovascularisation type, location and size
Eye Clinic Liaison Officer Refer for low vision rehabilitation, Royal National
Institute of Blind People and Macular Society. Advise on risk factors for progression
Follow Royal College of Ophthalmologists guidelines for anti-VEGF (vascular endothelial growth factor)
initiation. Consider combination therapies for specific wet AMD types
Geographical atrophy
Late AMD in either or both eyes
Monitor monthly with best corrected visual acuity and optical coherence
tomography for re-treatment decisions. Discontinue treatment if futile
Klein R, Klein B, Linton RL (1992) Prevalence of age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology 99: 933–43
Klein R, Klein BE, Knudtson MD, Meuer SM, Swift M, Gangnon RE (2007) Fifteen-year cumulative incidence of age-related macular degeneration: the Beaver Dam Eye Study. Ophthalmology 114(2): 253–62
Miller JW, Schmidt-Erfurth U, Sickenberg M et al (1999) Photodynamic therapy with verteporfin for choroidal neovascularization caused by age-related macular degeneration: results of a single treatment in a phase 1 and 2 study. Arch Ophthalmol 117(9): 1161–73
Mitchell P, Smith W, Attebo K, Wang JJ (1995) Prevalence of age-related maculopathy in Australia. The Blue Mountains Eye Study. Ophthalmology 102(10): 1450–60
Mitchell P, Wang JJ, Smith W, Leeder SR (2002) Smoking and the 5-year incidence of age-related maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol 120(10): 1357–63
National Institute for Health and Clinical Excellence (2012) Macular degeneration (age related) – ranibizumab and pegaptanib. NICE technology Appraisal TA155. www.nice.org.uk/Guidance/TA155 (accessed 15 February 2015)
National Institute for Health and Clinical Excellence (2013) Aflibercept solution for injection for treating wet age related macular degeneration. NICE technology Appraisal TA294. www.nice.org.uk/Guidance/TA294 (accessed 15 February 2015)
Novartis Pharmaceuticals (2014) Ranibizumab (Lucentis) Summary of product characteristics. www.medicines.org.uk/emc/medicine/28939
Pfizer (2013) Macugen 0.3 mg solution for injection Summary of product characteristics. www.medicines.org.uk/emc/medicine/17843
Rosenfeld PJ, Brown DM, Heier JS et al (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355(14): 1419–31
Royal College of Ophthalmologists (2013) Guidelines on AMD treatment. Royal College of Ophthalmologists, London
Snellen EL, Verbeek AL, Van Den Hoogen GW, Cruysberg JR, Hoyng CB (2002) Neovascular age-related macular degeneration and its relationship to antioxidant intake. Acta Ophthalmol Scand 80(4): 368–71
Yates JR, Sepp T, Matharu BK et al (2007) Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med 357(6): 553–61
pathogenesis of age-related macular degeneration. Surv Ophthalmol 45(2): 115–34
Brown DM, Kaiser PK, Michels M et al (2006) Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 355(14): 1432–44
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Heier JS, Brown DM, Chong V et al (2012) Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 119(12): 2537–48
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Jackson TL, Chakravarthy U, Kaiser PK et al (2013) Stereotactic radiotherapy for neovascular age-related macular degeneration: 52-week safety and efficacy results of the INTREPID Study. Ophthalmology 120(9): 1893–900
UK ABBREVIATED PRESCRIBING INFORMATIONVISUDYNE® (verteporfin)Presentation: Glass vial containing 15 mg of verteporfin as powder. Visudyne should be reconstituted in 7.0 ml water for injections to produce 7.5 ml of a 2.0 mg/ml solution. Indications: Treatment of adults with exudative (wet) age-related macular degeneration with predominantly classic subfoveal choroidal neovascularisation (CNV) or adults with subfoveal CNV secondary to pathological myopia. Dosage and administration: A ten minute intravenous infusion of Visudyne at a dose of 6mg/m2 body surface area in 30 ml infusion solution. This is followed by the activation of Visudyne 15 minutes after the start of the infusion using a diode laser generating non-thermal red light (wavelength 689 nm±3nm). At the recommended light intensity of 600 mW/cm2, it takes 83 seconds to deliver the required light dose of 50 J/cm2. Reevaluate every 3 months, if recurrent CNV leakage occurs, Visudyne therapy may be given up to 4 times per year. Contraindications: Porphyria, known hypersensitivity to verteporfin or to any of the excipients, or severe hepatic impairment. Precautions: Due to photosensitivity, avoid exposure of unprotected skin, eyes or other body organs to direct sunlight or bright indoor light for48 hours after infusion. UV sunscreens are not effective at protecting against photosensitivity reactions. Exercise caution in moderate hepatic impairment, biliary obstruction and treatment under general anaesthesia. If severe decrease of vision (equivalent to 4 lines or more) occurs within 1 week after treatment, do not re-treat at least until vision completely recovers to pretreatment level. If extravasation occurs, stop infusion immediately. Protect the affected area thoroughly from bright direct light until swelling and discolouration have disappeared. Visudyne contains small amounts of butylated hydroxytoluene which may be irritant to eyes, skin and mucous membranes, it should be washed off extensively with water in the event of direct contact. Patients should be under close medical supervision during Visudyne infusion. Chest pain, vasovagal reactions (posture related) and hypersensitivity reactions have been reported. Interactions: No interaction studies have been conducted in humans. Concomitant use of other photosensitising agents (e.g. tetracyclines, sulphonamides, phenothiazines, sulphonylurea, hypoglycaemic agents, thiazide diuretics, and griseofulvin) could increase the potential for photosensitivity reactions. Fertility, pregnancy and lactation: There are no human fertility data for verteporfin. Visudyne should be used in pregnant women only if the benefit justifies the potential risk to the foetus. Do not administer to nursing mothers or interrupt breast-feeding for 48 hours after administration. Effects on ability to drive and use machines: Do not drive or use machines as long as symptoms such as abnormal vision persist.
Undesirable effects: Most adverse reactions were mild to moderate, transient in nature and similar in patients with either pathological myopia or AMD. The most frequently reported adverse reactions to Visudyne are injection site reactions and visual impairment. Reported frequency of ocular adverse reactions: Common (≥1/100 to <1/10): Severe reduced visual acuity, visual impairment such as reduced visual acuity, blurred, fuzzy vision, or photopsia, visual field defect such as scotoma, grey or dark haloes and black spots. Uncommon (≥1/1,000 to <1/100): Retinal detachment (non-rhegmatogenous), subretinal/retinal haemorrhage, vitreous haemorrhage. Rare (≥1/10,000 to <1/1,000): Retinal or choroidal vessel non-perfusion. Frequency not known: Retinal pigment epithelial tear, macular oedema, retinal oedema. Reported frequency of systemic adverse reactions : Common (≥1/100 to <1/10): Hypercholesteraemia, nausea, photosensitivity reaction, injection site pain, injection site oedema, injection site inflammation, injection site extravasation, asthenia, infusion-related reaction primarily presented as back pain. Uncommon (≥1/1,000 to <1/100): Hyperesthesia, hypertension, injection site hypersensitivity, injection site haemorrhage, injection site discoloration, pyrexia, pain. Frequency not known: Hypersensitivity, vasovagal reactions, myocardial infarction, injection site blister, infusion-related chest pain. Overdose: May result in non-selective non-perfusion of normal retinal vessels, with possibility of severe vision decrease and/or the prolongation of the period during which the patient remains photosensitive.Prescribers should consult the Summary of Product Characteristics for full information about other side effects. Legal category: POM. Packaging quantities: Each vial containing 15 mg verteporfin. Price: UK £850. Marketing authorisation number: EU/1/00/140/001 Marketing authorisation holder: Novartis Europharm Limited, Frimley Business Park, Camberley, GU16 7SR, United Kingdom Date of preparation: 21 November 2014Visudyne is a registered Trade Mark.Full prescribing information, including SmPC, is available from: Novartis Pharmaceuticals,Frimley Business Park, Frimley, Camberley, Surrey, GU16 7SR. Telephone: 01276 692255.Fax: 01276 692508.
Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported toNovartis Pharmaceuticals UK Ltd on (01276) 698370 or [email protected].
(VIS14-C002 November 2014)
LUCENTIS® treatment has CHANGED...
For UK: Adverse events should be reported. Reporting forms and information can be found at https://yellowcard.mhra.gov.uk/ Adverse events should also be reported to Novartis Pharmaceuticals UK Limited on (01276) 698370 or [email protected]
LUC14-C239 November 2014
LUCENTIS®▼ (RANIBIZUMAB) ABBREVIATED UK PRESCRIBING INFORMATION Please refer to the SmPC before prescribing LUCENTIS 10mg/ml solution vial for injection, or LUCENTIS 10 mg/ml solution for injection in pre-filled syringe. Presentations: A glass single-use vial containing 0.23ml solution containing 2.3mg of ranibizumab (10mg/ml) and a pre-filled syringe containing 0.165 ml, equivalent to 1.65 mg ranibizumab (10mg/ml). Indications: The treatment in adults of neovascular (wet) age-related macular degeneration (AMD), the treatment of visual impairment due to diabetic macular oedema (DMO), the treatment of visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO), and the treatment of visual impairment due to choroidal neovascularisation (CNV) secondary to pathologic myopia (PM). Administration and Dosage: Available as a single-use vial and a single dose pre-filled syringe, for intravitreal use only. LUCENTIS must be administered by a qualified ophthalmologist experienced in intravitreal injections under aseptic conditions. The recommended dose is 0.5 mg (0.05ml). The interval between two doses injected into the same eye should be at least four weeks. Treatment is initiated with one injection per month until maximum visual acuity is achieved and/or there are no signs of disease activity i.e. no change in visual acuity or in other signs and symptoms of the disease under continued treatment. In patients with wet AMD, DMO and RVO, initially, three or more consecutive, monthly injections may be needed. Thereafter, monitoring and treatment intervals should be determined by the physician and should be based on disease activity, as assessed by visual acuity and/or anatomical parameters. If, in the physician’s opinion, visual and anatomic parameters indicate that the patient is not benefiting from continued treatment, LUCENTIS should be discontinued. Monitoring for disease activity may include clinical examination, functional testing or imaging techniques (e.g. optical coherence tomography or fluorescein angiography). If patients are being treated according to a treat-and-extend regimen, once maximum visual acuity is achieved and/or there are no signs of disease activity, the treatment intervals can be extended stepwise until signs of disease activity or visual impairment recur. The treatment interval should be extended by no more than two weeks at a time for wet AMD and may be extended by up to one month at a time for DMO. For RVO, treatment intervals may also be gradually extended, however there are insufficient data to conclude on the length of these intervals. If disease activity recurs, the treatment interval should be shortened accordingly.In the treatment of visual impairment due to CNV secondary to PM, many patients may only need one or two injections during the first year, while some patients may need more frequent treatment. LUCENTIS and laser photocoagulation in DMO and in macular oedema secondary to BRVO: There is some experience of LUCENTIS administered concomitantly with laser photocoagulation. When given on the same day, LUCENTIS should be administered at least 30 minutes after laser photocoagulation. LUCENTIS can be administered in patients who have received previous laser photocoagulation. LUCENTIS and Visudyne photodynamic therapy in CNV secondary to PM: There is no experience of concomitant administration of LUCENTIS and Visudyne. Before treatment, evaluate the patient’s medical history for hypersensitivity. Children and adolescents: Not recommended for use in children and adolescents due to a lack of data. Elderly: No dose adjustment is required in the elderly. There is limited experience in patients older than 75 years with DMO Hepatic and renal impairment: Dose adjustment is not needed in these populations. Contraindications: Hypersensitivity to the active substance or excipients.
Patients with active or suspected ocular or periocular infections. Patients with active severe intraocular inflammation. Special warnings and precautions for use: LUCENTIS is for intravitreal injection only. Intravitreal injections have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract. Monitor during week following injection for infections. Patients should be instructed to report symptoms suggestive of any of the above without delay. Transient increases in intraocular pressure (IOP) within 1 hour of injection and sustained IOP increases have been identified. Both IOP and perfusion of the optic nerve head should be monitored and managed appropriately. Limited data on bilateral use of LUCENTIS (including same-day administration) do not suggest an increased risk of systemic adverse events compared with unilateral treatment. There is a potential for immunogenicity with LUCENTIS which may be greater in subjects with DMO. Patients should report an increase in severity of intraocular inflammation. LUCENTIS should not be administered concurrently with other anti-VEGF agents (systemic or ocular). Withhold dose and do not resume treatment earlier than the next scheduled treatment in the event of the following: a decrease in best corrected visual acuity (BCVA) of ≥30 letters compared with the last assessment of visual acuity; an intraocular pressure of ≥30 mmHg; a retinal break; a subretinal haemorrhage involving the centre of the fovea, or if the size of the haemorrhage is ≥50% of the total lesion area; performed or planned intraocular surgery within the previous or next 28 days. Risk factors associated with the development of a retinal pigment epithelial (RPE) tear after anti-VEGF therapy for wet AMD include a large and/or high pigment epithelial retinal detachment. When initiating LUCENTIS therapy, caution should be used in patients with these risk factors for RPE tears. Discontinue treatment in cases of rhegmatogenous retinal detachment or stage 3 or 4 macular holes. There is only limited experience in the treatment of subjects with DMO due to type I diabetes. LUCENTIS has not been studied in patients who have previously received intravitreal injections, in patients with active systemic infections, proliferative diabetic retinopathy, or in patients with concurrent eye conditions such as retinal detachment or macular hole. There is also no experience of treatment with LUCENTIS in diabetic patients with an HbA1c over 12% and uncontrolled hypertension. In PM patients there are no data on the use of LUCENTIS in patients with extrafoveal lesions and only limited data on its use in those who have had previous unsuccessful therapy with verteporfin photodynamic therapy. Systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events have been reported following intravitreal injection of VEGF inhibitors. There are limited data on safety in the treatment of DMO, macular oedema due to RVO and CNV secondary to PM patients with prior history of stroke or transient ischaemic attacks. Caution should be exercised when treating such patients. There is limited experience with treatment of patients with prior episodes of RVO and of patients with ischaemic BRVO and CRVO. Treatment is not recommended in RVO patients presenting with clinical signs of irreversible ischaemic visual function loss. Interactions: No formal interaction studies have been performed. In DMO and BRVO adjunctive use of laser therapy and LUCENTIS was not associated with any new ocular or non-ocular safety findings. In clinical studies for the treatment of visual impairment due to DMO, the outcome with regard to visual acuity or central retinal subfield thickness (CSFT) in patients treated with LUCENTIS was not affected by concomitant treatment with thiazolidinediones. Pregnancy and lactation: Women of childbearing potential should use effective contraception during
treatment. No clinical data on exposed pregnancies are available. Ranibizumab should not be used during pregnancy unless the expected benefit outweighs the potential risk to the foetus. For women who wish to become pregnant and have been treated with ranibizumab, it is recommended to wait at least 3 months after the last dose of ranibizumab before conceiving. Breast-feeding is not recommended during the use of LUCENTIS Driving and using machines: The treatment procedure may induce temporary visual disturbances and patients who experience these signs must not drive or use machines until these disturbances subside. Undesirable effects: Most adverse events are related to the injection procedure. Serious adverse events reported include endophthalmitis, blindness, retinal detachment, retinal tear and iatrogenic traumatic cataract. The safety data below include adverse events experienced following the use of LUCENTIS in the entire clinical trial population. Those marked * were only seen in the DMO population. Very Common: Intraocular pressure increased, headache, vitritis, vitreous detachment, retinal haemorrhage, visual disturbance, eye pain, vitreous floaters, conjunctival haemorrhage, eye irritation, foreign body sensation in eyes, lacrimation increased, blepharitis, dry eye, ocular hyperaemia, eye pruritus, arthralgia, nasopharyngitis. Common: Urinary tract infection*, anaemia, retinal degeneration, retinal disorder, retinal detachment, retinal tear, detachment of the retinal pigment epithelium, retinal pigment epithelium tear, visual acuity reduced, vitreous haemorrhage, vitreous disorder, uveitis, iritis, iridocyclitis, cataract, cataract subcapsular, posterior capsule opacification, punctuate keratitis, corneal abrasion, anterior chamber flare, vision blurred, injection site haemorrhage, eye haemorrhage, conjunctivitis, conjunctivitis allergic, eye discharge, photopsia, photophobia, ocular discomfort, eyelid oedema, eyelid pain, conjunctival hyperaemia, cough, nausea, allergic reactions, hypersensitivity, anxiety. Product-class-related adverse reactions: 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 LUCENTIS clinical trials in patients with AMD, DMO, RVO and PM and there were no major differences between the groups treated with ranibizumab compared to control. Please refer to the SmPC for full listing of all undesirable effects. Legal category: POM, UK Basic NHS cost: £742.17 Marketing authorisation number: single dose vial EU/1/06/374/001, single dose pre-filled syringe EU/1/06/374/003 Marketing authorisation holder: Novartis Europharm Limited, Frimley Business Park, Camberley, GU16 7SR, United Kingdom. Full prescribing information, including SmPC, is available from: Novartis Pharmaceuticals, Frimley Business Park, Frimley, Camberley, Surrey, GU16 7SR. Telephone: 01276 692255. Fax: 01276 692508.
*LUCENTIS® is licensed in visual impairment due to diabetic macular oedema. **LUCENTIS® is licensed in visual impairment due to macular oedema secondary to retinal vein occlusion. References 1. LUCENTIS® Summary of Product Characteristics. Available at: www.medicines.org.uk/emc [Accessed November 2014]
LUCENTIS®: FLEXIBILITY AT EVERY STEP
• Flexible dosing and monitoring regimen for a personalised treatment approach for:
Wet Age Related Macular Degeneration (wAMD) Diabetic Macular Oedema (DMO)* Retinal Vein Occlusion (RVO)**
• There is no longer a requirement to have
monthly monitoring.
• Monitoring and treatment intervals can now be determined by the physician, based on disease activity as assessed by visual acuity and/or anatomical parameters.1 You can now choose a Treat & Extend regimen.
SEE YOUR SUCCESS THROUGH THE EYES OF YOUR PATIENTS
