Consumer medicine information

Iluvien

Fluocinolone acetonide

BRAND INFORMATION

Brand name

Iluvien

Active ingredient

Fluocinolone acetonide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Iluvien.

What is in this leaflet

This leaflet answers some common questions about Iluvien.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of your taking this medicine against the benefits they expect it will have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

What Iluvien is used for

Iluvien is a tiny tube that is inserted into the eye and releases very small amounts of the active ingredient, fluocinolone acetonide, for up to 3 years. Fluocinolone acetonide belongs to a group of medicines called corticosteroids.

Iluvien is used to treat vision loss associated with diabetic macular oedema when other available treatments have failed to help. Diabetic macular oedema is a condition that affects some people with diabetes, and causes damage to the light-sensitive layer at the back of the eye responsible for central vision, the macula. The active ingredient helps to reduce the inflammation and the swelling that builds up in the macula in this condition. Iluvien can therefore help to improve the damaged vision or stop it from getting worse.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is not addictive.

This medicine is available only with a doctor’s prescription.

Before you are given it

When you must not receive it

You must not be given Iluvien:

  • If you are allergic (hypersensitive) to fluocinolone acetonide or any of the other ingredients of Iluvien listed at the end of this leaflet (see Product Description).
    Some of the symptoms of an allergic reaction may include:
    - shortness of breath
    - wheezing or difficulty breathing
    - swelling of the face, lips, tongue or other parts of the body
    - rash, itching or hives on the skin
  • If you have an infection of any kind in or around your eye.
  • If you have glaucoma (high pressure inside your eye that caused damage to the optic nerves).

Before you are given it

Your doctor must know about all of the following before you are given this medicine.

Tell your doctor if:

  • You are taking any medicines to thin the blood.
  • You have had herpes simplex infection in your eye in the past (an ulcer on the eye that has been there a long time).
  • You have higher than normal pressure in the eye, with or without it affecting your sight.
  • You have had previous cataract surgery.
  • You are pregnant or planning to become pregnant. There is no experience of using Iluvien in pregnant women; therefore the potential risks are unknown.
  • You are breast-feeding or planning to breast-feed. Iluvienis not recommended during breast-feeding because it is not known whether Iluvien passes into human milk.

If you have not told your doctor about any of the above, tell them before Iluvien is administered.

Children and adolescents (below 18 years of age)

The use of Iluvien in children and adolescents has not been studied and is therefore not recommended.

Taking or being given other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

These medicines may be affected by Iluvien or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medications.

Your doctor and pharmacist have more information on medicines to be careful with or avoid after Iluvien has been injected.

How it is given

The Iluvien implant will be given by your eye doctor as a single injection into your eye. Afterwards, your doctor will monitor your vision regularly.

Before the injection, your doctor will use antibiotic eye drops and wash your eye carefully to prevent infection. Your doctor will also give you a local anaesthetic to prevent any pain that the injection might cause.

The injection of ILUVIEN into both eyes at the same time has not been studied and is not recommended. Your doctor should not inject ILUVIEN into both eyes at the same time.

How much is given

One implant of Iluvien is inserted into the eye and releases very small amounts of the active ingredient for up to 3 years.

If the effect of the implant wears off and your doctor recommends it, another implant may be injected into your eye.

The injection of Iluvien into both eyes at the same time has not been studied and is not recommended. Your doctor should not inject Iluvien into both eyes at the same time.

If you have any further questions on the use of this product, ask your doctor.

If you are given too much (Overdose)

As this medicine is administered directly by your doctor, overdose is unlikely. You doctor will decide on any necessary measures to avoid any problems.

After you are given it

Things you must do

If you experience any problems after the injection, tell your doctor.

Iluvien is given as an injection into the eye.

In rare cases, the injection can cause an infection in your eye.

Contact your eye doctor as soon as possible if you experience any of the following signs of inflammation or infection in your eye:

  • Hazy or decreased vision
  • Eye pain
  • Worsening redness of your eye
  • A feeling of spots in front of your eye
  • Increased sensitivity to light after your injection

In rare cases, Iluvien may also cause changes to the retina.

Contact your eye doctor as soon as possible if you experience:

  • Flashing lights
  • Partially blocked vision.

Injection with Iluvien may also cause the following:

  • Increase in pressure inside your eye
  • Clouding of your eye’s natural lens (cataract)

It is important to identify and treat these as soon as possible.

Your doctor may ask you to use antibiotic eye drops in order to prevent any possible eye infection. Please follow the instructions carefully.

In some patients eye pressure may increase with the possible development of glaucoma. This is something you may not notice; therefore you must be monitored by your doctor with visits to the clinic. You may require medication or a procedure to treat the increased eye pressure.

In the majority of patients who have not yet had an operation for cataracts, a clouding of the eye’s natural lens (a cataract) may develop gradually (within months to longer than a year) after treatment with Iluvien. If this occurs your vision will gradually decrease, and you are likely to need an operation to remove the cataract. Your doctor will help you to decide when is the most appropriate time to perform this operation, but you should be aware that until you are ready for your operation your vision may be as bad or worse than it was before you received your Iluvien injection.

There is a potential for the Iluvien implant to move from the back to the front of the eye. There is a increased risk of this if you have had previous cataract surgery. A sign that the implant may have moved to the front of the eye could be distorted vision or other visual disturbance, or you may notice a change in the appearance of your eye at the front. Please tell your doctor if you notice anything unusual that may lead you to suspect the implant has moved.

Keep all of your scheduled appointments that your doctor makes for you.

Things to be careful of

Be careful driving or operating machinery until you know how Iluvien affects you.

After Iluvien treatment you may experience some temporary vision blurring. If this happens, do not drive or use machines until this resolves.

Side Effects

Tell your doctor, nurse, or pharmacist as soon as possible if you do not feel well after being given Iluvien.

Like all medicines, Iluvien can cause side effects, mostly in the eye, although not everybody gets them.

Tell your doctor immediately if you develop any of the following:

  • increased eye pain, discomfort or irritation
  • worsening redness of your eye
  • Sudden increase in floaters (spots or specks in your vision)
  • decreased vision
  • bleeding in the eye

Occasionally the injection may cause an infection inside the eye, pain or redness in the eye, or a detachment or tear of the retina. It is important to identify and treat these as soon as possible.

Other side effects may include:

  • increased eye pressure
  • clouding of the eye’s natural lens(a cataract).
  • blurred vision
  • worsening vision

Increased pressure in the eye which damages the optic nerve (glaucoma) may be more likely if the pressure inside your eye is higher than average before treatment.

Your doctor will discuss the risks of this with you before treatment. The symptoms you might experience and what you should do if you experience these symptoms are described in the section After you are given it.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

Some of these side effects (for example, an increase in the pressure inside your eye) can only be found when your doctor does tests to check your progress.

Storage

It is unlikely you will have to store Iluvien at home. Your medicine will be stored by the doctor or pharmacy.

If you do have to store it please:

Keep Iluvien out of the reach and sight of children.

Do not use Iluvien after the expiry date which is stated on the carton and inner wrap after EXP. The expiry date refers to the last day of that month.

Keep your medicine in a cool dry place where the temperature stays below 25°C. Do not refrigerate or freeze.

Keep the preloaded applicator with 25-gauge needle in the sealed tray. Once the sealed tray is opened, it must be used immediately.

Product Description

What it looks like

Iluvien consists of a tiny light brown tube (approximately 3.5 mm x 0.37 mm) which is preloaded in an applicator system. The preloaded applicator is placed in a polycarbonate tray and sealed with a peelable lid. Each sealed tray is provided in a carton which includes the product information.

Ingredients

The active substance is fluocinolone acetonide.

Each intravitreal implant contains 190 micrograms fluocinolone acetonide.

The other ingredients are:

  • Excipients: Polyvinyl Alcohol, water for injection
  • Drug delivery system (implant): PMDA/ODA copolymer tubing, MED-1137 RTV silicone adhesive, polyvinyl alcohol, water for injection

Iluvien does not contain gluten, tartrazine or any other azo dyes.

Sponsor

In Australia:

Specialised Therapeutics Alim Pty Ltd
Level 2, 17 Cotham Road
Kew VIC 3101
AUSTRALIA
Ph: 1300 798 820
Fax: 1800 798 829
www.stbiopharma.com

Please check with your doctor or pharmacist for the latest Consumer Medicine Information.

Australian Registration Number

Iluvien Intravitreal Implant in Applicator:

AUST R 306543

Last revised: July 2019.

Published by MIMS November 2022

BRAND INFORMATION

Brand name

Iluvien

Active ingredient

Fluocinolone acetonide

Schedule

S4

 

1 Name of Medicine

Iluvien fluocinolone acetonide 190 micrograms intravitreal implant in applicator.

2 Qualitative and Quantitative Composition

Iluvien is a non-biodegradable intravitreal implant in a drug delivery system containing 0.19 mg fluocinolone acetonide, designed to release fluocinolone acetonide for 36 months.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Iluvien is a sterile non-bioerodable intravitreal implant which is inside a single use applicator with a 25 gauge needle. The implant is a light brown colour and cylindrical in shape with dimensions 3.5 mm long x 0.37 mm in diameter. The applicator is packaged in a plastic tray sealed with a lid.

4 Clinical Particulars

4.1 Therapeutic Indications

Iluvien is indicated for the treatment of diabetic macular oedema (DME) in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure (IOP).

4.2 Dose and Method of Administration

For ophthalmic intravitreal injection.
The recommended dose is one Iluvien implant in the affected eye. Administration in both eyes concurrently has not been studied and is not recommended (see Section 4.4 Special Warnings and Precautions for Use).
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 Pharmacodynamic Properties).
Retreatments should not be administered unless the potential benefits outweigh the risks.

Paediatric population.

There is no relevant use of intravitreally administered fluocinolone acetonide in the paediatric population in diabetic macular oedema (DME).
The safety and efficacy of fluocinolone acetonide in the paediatric population has not been established.

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 injection procedure should be carried out under controlled aseptic conditions, which include 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 injection. Further information is provided in the Healthcare Professional materials available from the Sponsor.
The injection procedure for Iluvien is as follows:
1. Preoperative antibiotic drops may be administered at the discretion of the treating ophthalmologist.
2. Just prior to injection, administer topical anaesthesia over the injection 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 injection site. Allow 30-60 seconds for the topical antiseptic to dry prior to injection 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 examine the tray and lid for damage. If damaged, do not use unit.
If acceptable, the assistant should peel the lid from the tray without touching the interior surface.
5. Visually check through the viewing window of the preloaded applicator to ensure that there is a drug implant inside.
6. Remove the applicator from the tray with sterile gloved hands touching only the sterile interior tray surface and applicator.
The protective cap on the needle should not be removed until Iluvien is ready to be injected.
Prior to injection, the applicator tip must be kept above the horizontal plane to ensure that the implant is properly positioned within the applicator.
7. To reduce the amount of air administered with the implant, the administration procedure requires two steps. Before injecting the needle in the eye, push the button down and slide it to the first stop (at the curved black marks alongside the button track). At the first stop, release the button and it will move to the UP position. If the button does not rise to the UP position, do not proceed with this unit.
8. Optimal placement of the implant is inferior to the optic disc and posterior to the equator of the eye. Measure 4 millimeters inferotemporal from the limbus with the aid of calipers.
9. Carefully remove the protective cap from the needle and inspect the tip to ensure it is not bent.
10. 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. Inject the needle in the eye. To release the implant, while the button is in the UP position, advance the button by sliding it forward to the end of the button track and remove the needle.

Note.

Ensure that the button reaches the end of the track before removing the needle.
11. Remove the lid speculum and perform indirect ophthalmoscopy to verify placement of the implant, adequate central retinal artery perfusion and absence of any other complications. Scleral depression may enhance visualisation of the implant. Examination should include a check for perfusion of the optic nerve head immediately after the injection. 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 IOP, retinal detachments, and vitreous haemorrhages or detachments. Biomicroscopy with tonometry should be performed between two and seven days after the implant injection.
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 Special Warnings and Precautions for Use).

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 List of Excipients.

4.4 Special Warnings and Precautions for Use

Intravitreal injection-related effects.

Intravitreal injections have been associated with endophthalmitis, elevation in IOP, retinal detachments and vitreous haemorrhages or detachments. Patients should be instructed to report without delay any symptoms suggestive of endophthalmitis.

Steroid-related effects.

Use of intravitreal corticosteroids may cause cataracts, increased IOP, glaucoma and may increase the risk of secondary infections.
Corticosteroids are not recommended to be used in patients with a history of ocular herpes simplex because of the potential for reactivation of the viral infection.

Patient monitoring.

Patient monitoring within two to seven days following the injection may permit early identification and treatment of ocular infection, increase in IOP or other complication. It is recommended that intra-ocular pressure be monitored at least quarterly thereafter.
The risk of raised intra-ocular pressure from Iluvien can be reliably predicted from a patient's response to other topical or intra-ocular steroids. A trial of ocular steroids prior to the use of Iluvien is recommended. Iluvien is not recommended in patients who develop ocular hypertension that cannot be controlled with topical treatment.

Concurrent administration.

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 Dose and Method of Administration).

Phase 3 diabetic macular oedema (FAME) studies.

In the DME studies, 80% of phakic subjects treated with fluocinolone acetonide underwent cataract surgery (see Section 4.8 Adverse Effects (Undesirable Effects)). Phakic patients should be closely monitored for signs of cataract after treatment.
In DME, 38% of patients treated with fluocinolone acetonide required treatment with IOP-lowering medication (see Section 4.8 Adverse Effects (Undesirable Effects)). The rise in IOP is normally manageable with IOP lowering medications.

Implant migration.

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.

Use in the elderly.

No dosage adjustments are necessary in elderly patients.

Paediatric use.

There is no relevant use of Iluvien in the paediatric population in diabetic macular oedema (DME).

Effects on laboratory tests.

Interactions with laboratory tests have not been established.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Specific drug-drug interaction studies were not conducted with fluocinolone acetonide. However, given that fluocinolone acetonide is administered as an intravitreal implant and systemic exposure following its administration is extremely low, the likelihood of drug-drug interactions is unlikely.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no human data on the effect of Iluvien on fertility. The effects of intravitreally administered fluocinolone acetonide on fertility were not assessed in animal studies. However, effects on either male or female fertility are unlikely since the systemic exposure to fluocinolone acetonide following intravitreal administration is very low.
(Category C)
There are no studies of Iluvien in pregnant women. Administration of fluocinolone acetonide to pregnant rats and rabbits produced embryofetal lethality and/or malformations. Other corticosteroids have also been shown to be teratogenic in multiple laboratory animal species. 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.
 It is not known whether intravitreally administered fluocinolone acetonide is excreted in human milk. There are no data on the effects of intravitreally administered fluocinolone acetonide on the breastfed infant, or the effects on milk production. Systematically administered corticosteroids are detected in human milk. A decision should be made on whether to discontinue breastfeeding or to abstain from fluocinolone acetonide treatment taking into account the potential benefit of Iluvien to the mother and the potential benefit of breastfeeding to the infant.

4.7 Effects on Ability to Drive and Use Machines

Iluvien's effects on ability to drive and use machines were not assessed during clinical development and hence are unknown.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

Intravitreally administered fluocinolone acetonide was evaluated in 768 subjects (375 in the 0.2 microgram/day/Iluvien group; 393 in the 0.5 microgram/day group) with diabetic macular oedema across the two Phase 3 clinical trials. The most frequently reported adverse drug reactions included cataract operation, cataract and increased IOP.
In the Phase 3 studies, 38.4% of subjects treated with Iluvien and 14.1% of subjects receiving sham treatment required IOP-lowering medication. In addition, 4.8% of subjects treated with Iluvien and 0.5% of subjects in the sham group required IOP-lowering surgeries. The use of IOP-lowering medication was similar in subjects who received two or more treatments with Iluvien. See Table 1.
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 DME clinical trials received only one implant (see Section 5.1 Pharmacodynamic Properties), 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 (IOP) 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.

Description of selected adverse reactions.

The long-term use of corticosteroids may cause cataracts and increased IOP. The frequencies stated below reflect the findings in all patients in the DME studies. The observed frequencies in patients with chronic DME 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 DME studies, subjects with a baseline IOP of > 21 mmHg were excluded. The incidence of increased IOP 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%)).
Twenty four percent of subjects in the sham treated group 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).
The following reactions have been identified during post-marketing use of Iluvien in clinical practice. Because they are reported voluntarily, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting (reporting rate > 0.05%), possible causal connection to Iluvien, or a combination of these factors. See Table 2.

Reporting of adverse events.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems and [email protected].

4.9 Overdose

No case of overdose has been reported.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Anti-inflammatory agents, corticosteroids, plain. ATC code: S01BA15.

Mechanism of action.

Corticosteroids inhibit inflammatory responses to a variety of inciting agents including multiple inflammatory cytokines. They inhibit oedema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. Corticosteroids have also been shown to reduce levels of vascular endothelial growth factor, a protein which increases vascular permeability and causes oedema.
Corticosteroids are thought to act by inhibition of phospholipase A2 via induction of inhibitory proteins collectively called lipocortins. It is postulated that these proteins control biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting release of the common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2.

Clinical trials.

The efficacy of Iluvien was assessed in two three year, randomized (2:1, active: sham), multicenter, double-masked, parallel-groups studies that enrolled patients with diabetic macular oedema (DME) that had previously been treated with laser photocoagulation.
The primary efficacy endpoint in both trials was the proportion of subjects in whom BCVA had improved by 15 letters or more from baseline after 24 months of follow-up.
The safety and efficacy of Iluvien was assessed in two randomized, multicenter, double-masked, parallel-group 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. In clinical trials, around 25% of patients received repeated treatment, with no major difference in outcome. Patients with vision loss and retinal thickening were eligible for re-treatment with fluocinolone acetonide at 12 months, where vision loss was defined as reduction of 5 or more letters in visual acuity and retinal thickening was defined as a minimum increase of 50 microns at the centre of the fovea as per optical coherence tomography (OCT).
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). This benefit was maintained at month 36, where the proportion of subjects whose vision improved by 15 letters or greater in the integrated dataset was statistically significantly greater for Iluvien (28.7%) than for the control (18.9%) (p = 0.018). A statistically significant difference was seen as early as week 3 (p=0.011) in the integrated dataset.
Reduction in retinal thickness was rapid and maintained over 36 months in patients treated with Iluvien (Figure 2).

5.2 Pharmacokinetic Properties

Absorption.

Iluvien 190 micrograms intravitreal implant releases very small amounts of fluocinolone acetonide directly into the vitreous humour. In the 24-month repeat-dose toxicity study, absorption into the systemic circulation was not detectable (> 200 picogram/mL) in rabbits administered intravitreal implants releasing fluocinolone acetonide at 0.2, 0.5 or 1.0 microgram/day.

Distribution.

In a 24 month intravitreal repeat dos toxicity study, fluocinolone acetonide concentrations in aqueous humour of pigmented rabbits were generally below the limit of quantitation (200 picogram/mL) at the majority of time points. Vitreous humour, lens, choroid, pigmented epithelium and iris/ciliary body had measurable concentrations of fluocinolone acetonide at all time points. Fluocinolone acetonide levels fell below 200 picogram/mL in the cornea and retina, typically after Day 89.
Following a small initial peak release, near steady vitreous humour, lens, cornea, retina, choroid and pigmented epithelium and iris/ciliary body tissue concentrations of fluocinolone acetonide were maintained for up to the 24 months in pigmented rabbits administered fluocinolone acetonide insert (0.2, 0.5 or 1.0 microgram/day) intravitreally. The left and right eye mean tissue concentrations declined very gradually with elimination half-lives (t1/2) generally exceeding 2000 hours. In general, ocular tissue fluocinolone acetonide concentrations increased with the dose level and at the mid and high dose levels, concentrations were seen to increase following administration of the second fluocinolone acetonide insert at 12 months.

Metabolism.

No drug metabolism/elimination studies have been conducted. There are also no reports of metabolite effects or systemic effects from fluocinolone acetonide or other corticosteroids administered intravitreally. The metabolism of corticosteroids is primarily by hepatic mechanisms. Ocular metabolism of fluocinolone acetonide released from the implant is not expected and is most likely that fluocinolone acetonide is eliminated by distribution into the systemic circulation, producing very low levels over a prolonged period of time.
The most active organ for metabolism of corticosteroids is the liver, and these low levels of fluocinolone acetonide are most likely metabolised by hepatic esterification. Because of the very limited systemic exposure expected from the fluocinolone acetonide insert, meaningful levels of fluocinolone acetonide metabolites or parent drug are not likely to occur. This is supported by the fact that plasma and urine levels of fluocinolone acetonide in rabbits were consistently below the limit of quantitation (200 picogram/mL) in the 24-month intravitreal repeat dose study despite exaggerated dosing (of up to 1.0 microgram/day). Furthermore, plasma levels of fluocinolone acetonide in patients treated with the drug product were below the limit of detection (< 100 picogram/mL) at all times for both doses of 0.2 and 0.5 microgram/day (FAMOUS Study).

Clinical pharmacokinetic studies.

In a human pharmacokinetic study of Iluvien, fluocinolone acetonide concentrations in plasma were below the lower limit of quantitation of the assay (100 picogram/mL) at all post-administration time points from Day 7 through Month 36 following intravitreal administration of a 0.2 microgram/day or 0.5 microgram/day fluocinolone acetonide insert.
In a human pharmacokinetic study (FAMOUS Study) fluocinolone acetonide concentrations in plasma were below the lower limit of quantitation of the assay (100 picogram/mL) at all time points from Day 1 through Month 36 indicating negligible systemic exposure. The maximal aqueous humour fluocinolone acetonide concentrations were observed on Day 7 for most of the subjects. Aqueous humour fluocinolone acetonide concentrations decreased over the first 3-6 months and remained essentially the same through Month 36 for subjects who were not retreated (Figure 3). Subjects who were retreated experienced a second fluocinolone acetonide peak concentration similar to that following the initial dose. After retreatment, aqueous humour concentrations of fluocinolone acetonide returned to levels approximately similar to those observed at the time of first treatment.

5.3 Preclinical Safety Data

Genotoxicity.

Fluocinolone acetonide was not genotoxic in vitro in the bacterial reverse mutation (Ames) test (S. typhimurium and E. coli) and the mouse lymphoma TK assay in vitro, or in the in vivo mouse bone marrow micronucleus assay.

Carcinogenicity.

Long-term animal studies have not been conducted to determine the carcinogenic potential of fluocinolone acetonide insert.
No carcinogenicity data are available for intravitreally administered fluocinolone acetonide. However, intravitreally administered fluocinolone acetonide was not detectable systemically in rabbits for up to 24 months (at ocular exposures up to 11 fold higher than the clinical dose of 0.2 microgram/day, based on vitreous humour volume) and thus no systemic effects are anticipated.

Local effects.

Local effects (focal degenerative lesions affecting fibers in the posterior polar and posterior cortical regions of the lens) were observed in rabbits at doses of intravitreal fluocinolone acetonide in excess of the clinically used dose. Local effects (focal retinal scarring) were also seen in rabbits treated with both placebo and fluocinolone acetonide containing device. This scarring was not seen clinically in humans and is postulated to be due to anatomical differences between the rabbit and human eye.

6 Pharmaceutical Particulars

6.1 List of Excipients

Iluvien contains the following excipients: polyvinyl alcohol.
The drug delivery system consists of: PMDA/ODA copolymer tubing, MED-1137 RTV silicone adhesive, polyvinyl alcohol.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

Iluvien has a shelf life of 2 years. After first opening the lid, use immediately.
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°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

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.

6.7 Physicochemical Properties

Chemical structure.

Chemical Name: (6α, 11β, 16α)-6,9-difluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis- (oxy)]-pregna-1,4-diene-3,20-dione.
Molecular weight: 452.50 g/mol.
Molecular formula: C24H30F2O6.
Structural Formula:

CAS number.

CAS Registry No: 67-73-2.
Fluocinolone acetonide is a white or almost white, microcrystalline powder, practically insoluble in water, soluble in methanol, ethanol, chloroform and acetone, and sparingly soluble in ether.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (S4).

Summary Table of Changes