2014年7月31日，丹麦卫生药物管理局授权ILUVIEN可上市用于治疗既有措施效果欠佳伴视觉障碍的慢性 DME。继挪威之后，丹麦是按照重复使用条列在7月份授予ILUVEN上市的第二个国家。
目前除丹麦外，还有澳大利亚、法国、德国、意大利、挪威、葡萄牙、西班牙、英国准许ILUVIEN上市，在英国、德国的市场可购到 ILUVIEN。并且其即将在比利时、捷克共和国、芬兰、爱尔兰、卢森堡、荷兰、波兰、瑞典重复使用条例适用的8个国家获批。ILUVIEN的新药上市申请目前正在接受美国FDA审核。
ILUVIEN为含有190μg丙酮化氟新龙（氟轻松）的玻璃体腔植入物，可用于治疗既往措施效果欠佳伴视力下降的慢性糖尿病黄斑水肿（DME），每个植入物的疗效可实现持续36个月缓慢释放亚微克水平的氟轻松。

ILUVIEN 190micrograms intravitreal implant in applicator
1. Name of the medicinal product
ILUVIEN 190 micrograms intravitreal implant in applicator.
2. Qualitative and quantitative composition
Each implant contains 190 micrograms of fluocinolone acetonide.
For a full list of excipients, see Section 6.1.
3. Pharmaceutical form
Intravitreal implant in applicator.
Light brown coloured cylinder, approximately 3.5mm x 0.37mm in size.
Implant applicator with 25 gauge needle.
4. Clinical particulars
4.1 Therapeutic indications
ILUVIEN is indicated for the treatment of vision impairment associated with chronic diabetic macular oedema, considered insufficiently responsive to available therapies.
4.2 Posology and method of administration
Posology
The recommended dose is one ILUVIEN implant in the affected eye. Administration in both eyes concurrently is not recommended (see Section 4.4).
An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema (see Section 5.1).
Retreatments should not be administered unless the potential benefits outweigh the risks.
Only patients who have been insufficiently responsive to prior treatment with laser photocoagulation or other available therapies for diabetic macular oedema should be treated with ILUVIEN.
Paediatric population
There is no relevant use of ILUVIEN in the paediatric population in diabetic macular oedema (DMO).
Special populations
No dosage adjustments are necessary in elderly patients, or those with renal or hepatic impairment.
Method of administration
FOR INTRAVITREAL USE ONLY.
Treatment with ILUVIEN is for intravitreal use only and should be administered by an ophthalmologist experienced in intravitreal injections. The intravitreal implant insertion should be carried out under controlled aseptic conditions, which include the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anaesthesia and a broad-spectrum microbicide should be given prior to the insertion.
1. Preoperative antibiotic drops may be administered at the discretion of the treating ophthalmologist.
2. Just prior to insertion, administer topical anaesthesia over the insertion site (inferotemporal quadrant recommended) as one drop followed by either a cotton-tipped applicator soaked in anaesthetic or as subconjunctival administration of adequate anaesthesia.
3. Administer 2-3 drops of adequate topical antiseptic into the lower fornix. The lids may be scrubbed with cotton-tipped applicators soaked with an adequate topical antiseptic. Place a sterile lid speculum. Have the subject look up and apply a cotton-tipped applicator soaked with an adequate antiseptic to the insertion site. Allow 30-60 seconds for the topical antiseptic to dry prior to insertion of ILUVIEN.
4. The exterior of the tray should not be considered sterile. An assistant (non-sterile) should remove the tray from the carton and peel the lid from the tray without touching the interior surface. Visually check through the window of the applicator system to ensure that there is a drug implant inside.
5. Remove the applicator from the tray with sterile gloved hands touching only the sterile surface and applicator.
6. To reduce the amount of air administered with the implant, administration requires a two step process. Before inserting the needle in the eye, push the button down and slide it to the first stop (the curved black marks). At the first stop, release the button and it will move to the UP position.
7. The optimal placement of the implant is inferior to the optic disc and posterior to the equator. This can be achieved by directing the needle toward the lower aspect of the optic disc. Measure 4 millimeters inferotemporal from the limbus with the aid of calipers.
8. Remove the protective cap from the needle.
9. Gently displace the conjunctiva so that after withdrawing the needle, the conjunctival and scleral needle entry sites will not align. Care should be taken to avoid contact between the needle and the lid margin or lashes. Insert the needle in the eye. To release the implant, while the button is in the up position, push the button forward to the end and remove the needle.
10. Remove the lid speculum and perform indirect ophthalmoscopy to verify the placement of the implant, adequate central retinal artery perfusion and absence of any other complications.
Following intravitreal insertion indirect ophthalmoscopy examination in the quadrant of insertion should be performed to ensure successful placement. Scleral depression may enhance visualisation of the implant. Examination should include a check for perfusion of the optic nerve head immediately after the insertion. Immediate IOP measurement may be performed at the discretion of the ophthalmologist.
Following the procedure, patients should be monitored for potential complications such as endophthalmitis, increased intraocular pressure, retinal detachments, and vitreous haemorrhages or detachments. Biomicroscopy with tonometry should be performed between two and seven days after the implant insertion.
Thereafter it is recommended that patients are monitored at least quarterly for potential complications, due to the extended duration of release of fluocinolone acetonide, of approximately 36 months (See Section 4.4).
4.3 Contraindications
An intravitreal implant with ILUVIEN is contraindicated in the presence of pre-existing glaucoma or active or suspected ocular or periocular infection including most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases.
ILUVIEN is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients listed in Section 6.1.
4.4 Special warnings and precautions for use
Intravitreal injections have been associated with endophthalmitis, elevation in intraocular pressure, retinal detachments and vitreous haemorrhages or detachments. Patients should be instructed to report without delay any symptoms suggestive of endophthalmitis. Patient monitoring within two to seven days following the injection may permit early identification and treatment of ocular infection, increase in intraocular pressure or other complication. It is recommended that intra-ocular pressure be monitored at least quarterly thereafter.
Use of intravitreal corticosteroids may cause cataracts, increased intraocular pressure, glaucoma and may increase the risk of secondary infections.
The safety and efficacy of ILUVIEN administered to both eyes concurrently have not been studied. Concurrent treatment of both eyes is not recommended until the patient's systemic and ocular response to the first implant is known.
In the FAME studies, the incidence of cataract surgery among all phakic subjects was approximately 3 fold higher in the ILUVIEN treated group (80.0%) than the sham treated group (27.3%). The median time to cataract reported as an adverse event was approximately 14 months, and phakic subjects experienced vision impairment from the development of cataract from approximately month 9 through to month 18 after implantation, prior to cataract extraction (see Section 4.8).
In the overall clinical trials population, which excluded subjects with baseline IOP>21 mmHg, the proportion of ILUVIEN treated subjects requiring treatment with IOP-lowering medication was 38% compared to 14% in the sham treated group. This proportion increased to 47% in those subjects with greater than median IOP at baseline (≥15 mmHg). Surgical interventions for the treatment of ocular hypertension were required in 4.8% of subjects treated with ILUVIEN compared to 0.5% of subjects treated with sham (see Section 4.8). Therefore, ILUVIEN should be used with caution in patients with high baseline IOP, and IOP must be monitored closely.
In the event of IOP increases that do not respond to IOP-lowering medications or IOP-lowering procedures, the ILUVIEN implant can be removed by vitrectomy.
A limited number of subjects with Type 1 diabetes were investigated in the FAME studies, though the response to ILUVIEN in these subjects was not significantly different to those subjects with Type 2 diabetes.
There is limited experience of the effect of ILUVIEN in eyes following vitrectomy. It is likely that drug clearance would be accelerated after vitrectomy, though steady state concentrations are not expected to be affected. This may shorten the duration of action of the insert.
In the FAME studies there were 24% of subjects in the sham treated group who were treated at any time with either anti-coagulant or anti-platelet medications as compared to 27% in the ILUVIEN treated subjects. Subjects treated with ILUVIEN concomitantly or within 30 days of cessation of treatment with anti-coagulant or anti-platelet medications experienced a slightly higher incidence of conjunctival haemorrhage versus the sham treated subjects (0.5% sham and 2.7% ILUVIEN treated). The only other event reported at a higher incidence rate in the ILUVIEN treated subjects was eye operation complication (0% sham and 0.3% ILUVIEN treated).
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies with other medicinal products have been performed.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no adequate data from the use of intravitreal administered fluocinolone acetonide in pregnant women. Long-term systemic treatment with glucocorticoids during pregnancy increases the risk for intra-uterine growth retardation and adrenal insufficiency of the newborn child. Studies in animals have shown teratogenic effects following systemic administration (See Section 5.3). Therefore, although the systemic exposure of fluocinolone acetonide would be expected to be very low after local, intraocular treatment, ILUVIEN is not recommended during pregnancy unless the potential benefit justifies the potential risk to the foetus.
Breast-feeding
Fluocinolone acetonide is excreted in breast milk. No effects on the child are anticipated due to the route of administration and the resulting systemic levels. However ILUVIEN is not recommended during breast feeding unless clearly necessary.
Fertility
There are no fertility data available.
4.7 Effects on ability to drive and use machines
Patients may experience temporarily reduced vision after administration of ILUVIEN and should refrain from driving or using machines until this has resolved.
4.8 Undesirable effects
Summary of the safety profile
ILUVIEN was evaluated in 768 subjects with diabetic macular oedema across the FAME clinical trials. The most frequently reported adverse drug reactions included cataract operation, cataract and increased intraocular pressure.
In the Phase 3 studies, 38.4% of subjects treated with ILUVIEN required IOP-lowering medication and 4.8% required IOP-lowering surgeries. The use of IOP-lowering medication was similar in subjects who received two or more treatments with ILUVIEN.
Two cases of endophthalmitis were reported in subjects treated with ILUVIEN during the Phase 3 studies. This represents an incidence rate of 0.2% (2 cases divided by 1,022 injections).
While the majority of subjects in the FAME clinical trials received only one implant (See Section 5.1), the long-term safety implications of retention of the non-bioerodable implant inside the eye are not known. In the FAME clinical trials, 3-year data show that events such as cataract, increased intraocular pressure and floaters occurred only slightly more frequently in subjects receiving 2 or more implants. This is considered a function of the increased exposure to the drug rather than an effect of the implant itself. In non-clinical studies, there were no indications of an increase in safety issues other than lens changes in the rabbit eyes with 2-4 implants over 24 months. The implant is made of polyimide and is essentially similar to an intraocular lens haptic; it is therefore expected to remain inert inside the eye.
Tabulated list of adverse events
The following undesirable effects were assessed to be treatment-related and are classified according to the following convention: very common (≥ 1/10); common (≥1/100 to < 1/10); uncommon (≥1/1,000 to < 1/100); rare (≥1/10,000 to < 1/1,000); and very rare (≤ 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Infections and infestations	Uncommon: endophthalmitis
Nervous system disorders	Uncommon: headache
Eye disorders	Very Common: cataract operation, cataract1, increased intraocular pressure2, floaters (myodesopsia) Common: glaucoma3, trabeculectomy, eye pain4, vitreous haemorrhage, conjunctival haemorrhage, blurred vision5, glaucoma surgery, reduced visual acuity, vitrectomy, trabeculoplasty Uncommon: retinal vascular occlusion6, optic nerve disorder, maculopathy, optic atrophy, conjunctival ulcer, iris neovascularisation, retinal exudates, vitreous degeneration, vitreous detachment, posterior capsule opacification, iris adhesions, ocular hyperaemia, sclera thinning, removal of extruded implant from sclera, eye discharge, eye pruritus
Injury, poisoning and procedural complications	Uncommon: extrusion of implant, implant in line of sight, procedural complication, procedural pain

1 Includes MedDRA terms for cataract (NOS), cataract subcapsular, cataract cortical, cataract nuclear and cataract diabetic.
2 Includes MedDRA terms for intraocular pressure increased and ocular hypertension.
3 Includes MedDRA terms for glaucoma, open angle glaucoma, borderline glaucoma, optic nerve cupping and optic nerve cup/disc ratio increased.
4 Includes MedDRA terms for eye pain, eye irritation and ocular discomfort.
5 Includes MedDRA terms for vision blurred and visual impairment.
6 Includes MedDRA terms for retinal vein occlusion, retinal artery occlusion and retinal vascular occlusion
Description of selected adverse reactions
The long-term use of corticosteroids may cause cataracts and increased intraocular pressure. The frequencies stated below reflect the findings in all patients in the FAME studies. The observed frequencies in patients with chronic DMO were not significantly different to those in the overall population.
The incidence of cataract in phakic subjects was approximately 82% in ILUVIEN treated subjects and 50% in sham treated subjects in the Phase 3 clinical trials. 80% of phakic subjects treated with ILUVIEN required cataract surgery by Year 3 compared to 27% of the sham treated subjects, with most subjects requiring surgery by 21 months. Posterior subcapsular cataract is the most common type of corticosteroid -related cataract. Surgery for this type of cataract is more difficult and may be associated with greater risk of surgical complications.
In the FAME studies subjects with a baseline IOP of > 21 mm Hg were excluded. The incidence of increased intraocular pressure was 37%, and 38% of subjects required IOP-lowering medication, with half of these requiring at least two medications to control the IOP. The use of IOP-lowering medication was similar in subjects who received retreatment with an additional implant during the study. Additionally, 5.6% (21/375) of subjects who received an implant required a surgical or laser procedure to control the IOP (trabeculoplasty 5 (1.3%), trabeculectomy 10 (2.7%), endocycloablation 2 (0.5%), and other surgical procedures 6 (1.6%)).
In the subset of subjects with greater than median IOP at baseline (≥15 mmHg), 47% required IOP-lowering medication and the proportion of surgical or laser procedures increased to 7.1%. In this subset, there were 5 (2.2%) subjects treated with trabeculoplasty, 7 (3.1%) with trabeculectomy, 2 (0.9%) with endocycloablation and 4 (1.8%) with other glaucoma surgical procedures.
4.9 Overdose
No case of overdose has been reported.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: ANTIINFLAMMATORY AGENTS, corticosteroids, plain
ATC code: S01BA15
Corticosteroids inhibit the inflammatory response to a variety of inciting agents. They inhibit the oedema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation.
Corticosteroids are thought to act by the induction of phospholipase A inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of the common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. Corticosteroids have also been shown to reduce levels of vascular endothelial growth factor, a protein which increases vascular permeability and causes oedema.
The efficacy of ILUVIEN was assessed in two randomized, multicenter, double-masked, parallel studies enrolling subjects with diabetic macular oedema who had previously been treated with laser photocoagulation at least once, each involving three years of follow-up. There were 74.4% of subjects treated with 1 implant, 21.6% with 2 implants, 3.5% with 3 implants and 0.5% with 4 implants and 0% > 4 implants). The primary efficacy endpoint in both trials was the proportion of subjects whose vision improved by 15 letters or greater after 24 months. In each of these trials, the primary endpoint was met for ILUVIEN (see Figure 1 for the integrated results of the primary efficacy endpoint).
Figure 1: Percentage of Subjects with ≥ 15 Letter Improvement Over Baseline, Integrated FAME Studies

When efficacy was assessed as a function of duration of disease, those subjects with a duration of DMO greater than the median (≥3 years) had a significant beneficial response to ILUVIEN, whilst those with shorter duration DMO did not show an additional benefit over control treatment with regard to visual improvement (Figures 2 and 3). These subgroup data support the indication in Section 4.1, of use in patients with chronic DMO (ie, duration of at least 3 years).
Figure 2: Comparison of Percent of Subjects with ≥15 letter Improvement from Baseline BCVA and Mean Change from Baseline Excess Center Point Thickness by Duration of DMO Subgroup ≥ 3 years

Figure 3: Comparison of Mean Change from Baseline Excess Center Point Thickness and Percent of Subjects with ≥15 letter Improvement from Baseline BCVA by Duration of DMO Subgroup < 3 years

The European Medicines Agency has waived the obligation to submit results of studies with ILUVIEN in all subsets of the paediatric population for the treatment of diabetic macular oedema. See Section 4.2 for information on paediatric use.
5.2 Pharmacokinetic properties
In a human pharmacokinetic study (C-01-06-002, the FAMOUS Study) fluocinolone acetonide concentrations in plasma were below the lower limit of quantitation of the assay (100 pg/mL) at all time points from Day 1 through Month 36 indicating negligible systemic exposure. The maximal aqueous humor fluocinolone acetonide concentrations were observed on Day 7 for most of the subjects. Aqueous humor fluocinolone acetonide concentrations decreased over the first 3−6 months and remained essentially the same through Month 36 for subjects who were not retreated. Subjects who were retreated experienced a second fluocinolone acetonide peak concentration similar to that following the initial dose. After retreatment, aqueous humor concentrations of fluocinolone acetonide returned to levels approximately similar to those observed at the time of first treatment.
Figure 4: FA Levels in Human Aqueous Humor in Subjects Receiving 1 Implant (FAMOUS Study)

5.3 Preclinical safety data
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
No mutagenicity, carcinogenicity, reproductive or developmental toxicity data are available for ILUVIEN. Fluocinolone acetonide has been shown to be teratogenic in mice and rabbits following systemic administration.
Environmental Risk Assessment (ERA)
The environmental risk as a result of the prescribed usage of ILUVIEN implant is negligible, in view of the extremely low dose of fluocinolone acetonide implanted.
The specially designed injection applicator of ILUVIEN presents no environmental risks, since it is immediately disposed into a container for sharp disposable medicinal/surgical items after its specific single use.
See Section 6.6 for disposal and handling.
6. Pharmaceutical particulars
6.1 List of excipients
Polyvinyl alcohol
Polyimide tube
Silicone adhesive
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
After first opening the lid, use immediately.
6.4 Special precautions for storage
Store below 30°C. Do not refrigerate or freeze.
Do not open the sealed tray until just before application.
6.5 Nature and contents of container
The implant is supplied in a single use applicator with a 25 gauge needle. Each sterile applicator contains a light brown 3.5 mm long cylindrical implant. The applicator is packaged in a plastic tray sealed with a lid.
6.6 Special precautions for disposal and other handling
Dispose of the applicator safely in a biohazard sharps container.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Alimera Sciences Limited
Centaur House
Ancells Road
Fleet
Hampshire
GU51 2UJ
United Kingdom
8. Marketing authorisation number(s)
PL 41472/0001
9. Date of first authorisation/renewal of the authorisation
04/05/2012
10. Date of revision of the text
12/2013
FDA批准Iluvien治疗糖尿病性黄斑水肿
2014年9月24日，FDA批准可缓释醋酸氟轻松的玻璃体内植入体（Iluvien）治疗既往接受过皮质类固醇治疗但眼内压未获得显著改善患者的糖尿病性黄斑水肿。
Iluvien是一个3.5mm×0.37mm的浅棕色植入装置，含有0.19mg的醋酸氟轻松（fluocinolone acetonide），一次植入可持续给药3年。据悉，Iluvien被批准可用于无需接受白内障手术治疗的患者。