ILUVIEN Intravitreal implant Ref.[7965] Active ingredients: Fluocinolone

Intravitreal injections have been associated with endophthalmitis, increase or decrease in intraocular pressure, retinal detachment and vitreous haemorrhage or detachment. Patients should be instructed to report without delay any symptoms suggestive of endophthalmitis. Patient monitoring within two to eight days following the injection may permit early identification and treatment of ocular infection, decrease or 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. It is recommended that an implant is not administered to both eyes at the same visit. Concurrent treatment of both eyes is not recommended until the patient’s systemic and ocular response to the first implant is known (see Section 4.2).

Phase 3 Diabetic Macular Oedema (FAME) Studies

80% of phakic subjects treated with fluocinolone acetonide underwent cataract surgery (See Section 4.8). Phakic patients should be closely monitored for signs of cataract after treatment.

38% of patients treated with fluocinolone acetonide required treatment with IOP-lowering medication (see Section 4.8). Fluocinolone acetonide 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.

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).

There is limited experience of the effect of fluocinolone acetonide 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 implant.

Phase 3 Uveitis Studies

In the uveitis studies, patients treated with fluocinolone acetonide intravitreal implant underwent cataract surgery. Phakic patients should be closely monitored for signs of cataract after treatment.

Additionally, some patients developed elevated intraocular pressure requiring treatment with IOP lowering medication.

Patients in studies treated with fluocinolone acetonide developed hypotony, which started within days of treatment, with many on Day 1 and mostly resolving within 1 week of onset. Patient monitoring of increased or decreased IOP immediately after and within two to eight days following the injections is recommended.

In the treatment of patients with uveitis, it is very important to exclude possible infective causes of uveitis prior to commencing therapy with ILUVIEN.

There is a potential for implants to migrate into the anterior chamber, especially in patients with posterior capsular abnormalities, such as tears. This should be taken into consideration when examining patients complaining of visual disturbance after treatment.

No interaction studies have been performed.

Pregnancy

There are limited data from the use of intravitreally administered fluocinolone acetonide in pregnant women. Animal studies are insufficient with respect to the reproductive toxicity of intravitreally administered fluocinolone acetonide (See Section 5.3). Although fluocinolone acetonide is undetectable in the systemic circulation after local, intraocular treatment, fluocinolone is nonetheless a potent corticosteroid and even very low levels of systemic exposure may present some risk to the developing foetus. As a precautionary measure it is preferable to avoid the use of ILUVIEN during pregnancy.

Breast-feeding

Systemically administered fluocinolone acetonide is excreted in breast milk. Although the systemic exposure of the breast-feeding woman to intravitreally administered fluocinolone acetonide is expected to be very low, a decision must be made whether to discontinue breast-feeding or to abstain from ILUVIEN therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

There are no fertility data available. However, effects on either male or female fertility are unlikely since the systemic exposure to fluocinolone acetonide following intravitreal administration is very low.

ILUVIEN has minor influence on the 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.

Summary of the safety profile

Diabetic Macular Oedema

Intravitreally administered fluocinolone acetonide was evaluated in 768 subjects (375 in the 0.2 µg/day/ILUVIEN group; 393 in the 0.5 µg/day group) 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.

Non-Infectious Uveitis affecting the Posterior Segment

The safety profile for the non-infectious uveitis affecting the posterior segment of the eye is based on two 36 month -pivotal uveitis studies (PSV-FAI-001 and PSV-FAI-005). Data are available currently for 36 months for PSV-FAI-001 and 12 months for PSV-FAI-005. The most frequently reported adverse drug reactions included increased intraocular pressure, cataract and conjunctival haemorrhage. The less frequently reported but more serious adverse reactions were optic disc haemorrhage and retinal detachment

Tabulated list of adverse events

The following undesirable effects were assessed to be treatment-related from the Phase III clinical trials (DMO and uveitis) and spontaneous reporting 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: cataract¹, increased intraocular pressure²

Common: glaucoma³, retinal detachment, optic disc haemorrhage*, vitreous haemorrhage, reduced visual acuity, visual field defect*, macula fibrosis*, conjunctival haemorrhage⁴ blurred vision*⁵, hypotony of eye*⁶, vitreous floaters⁷, anterior chamber cells*, vitreous opacities*, foreign body sensation in eyes*, dry eye*, photopsia*, eye pain⁸.

Uncommon: retinal vascular occlusion9, optic nerve disorder, maculopathy, optic atrophy, conjunctival ulcer, iris neovascularisation, retinal exudates, vitreous degeneration, vitreous detachment, choroidal detachment*, corneal erosion*, corneal deposits, posterior capsule opacification, iris adhesions, blepharospasm*, eye oedema*¹⁰, ocular hyperaemia, sclera thinning, eye discharge, eye pruritus

Injury, poisoning and procedural complications

Uncommon: extrusion of implant, implant in line of sight, procedural complication, procedural pain

Surgical and medical procedures

Very Common: cataract operation

Common: trabeculectomy, glaucoma surgery, vitrectomy, trabeculoplasty

Uncommon: removal of extruded implant from sclera

General disorders and administration site conditions

Uncommon: Device dislocation (implant migration)

* Observed only in patients with Uveitis

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 conjunctival haemorrhage, conjunctival hyperaemia
⁵ Includes MedDRA terms for vision blurred and visual impairment.
⁶ Includes MedDRA terms for intraocular pressure decreased
⁷ Includes MedDRA terms for myodesopsia
⁸ Includes MedDRA terms for eye pain, eye irritation and ocular discomfort.
⁹ Includes MedDRA terms for retinal vein occlusion, retinal artery occlusion and retinal vascular occlusion
¹⁰ Includes MedDRA terms for eye oedema, conjunctival oedema, corneal oedema

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.

Diabetic Macular Oedema Phase 3 Studies

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 DMO 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.

Uveitis Phase 3 Studies

Table 1: IOP, Cataract and Hypotony Adverse Events in the Intent To Treat (ITT) Population: PSV-FAI-001and PSV-FAI-005

There were no cases of endophthalmitis in the fluocinolone acetonide group in the Phase 3 uveitis studies.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard

Not applicable.