Fluocinolone acetonide (intravitreal implant)

Fluocinolone acetonide (intravitreal implant)
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]

Disclaimer

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Overview

Fluocinolone acetonide (intravitreal implant) is a corticosteroid that is FDA approved for the treatment of diabetic macular edema in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure. Common adverse reactions include cataract, myodesopsia, eye pain, conjunctival hemorrhage, posterior capsule opacification, eye irritation, conjunctivitis, ocular hyperaemia, foreign body sensation in eyes, corneal oedema and headache.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

• Fluocinolone acetonide intravitreal implant 0.19 mg is indicated for the treatment of diabetic macular edema in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure.

General Dosing Information

• For ophthalmic intravitreal injection.

Administration

• The intravitreal injection procedure should be carried out under aseptic conditions, which include the use of sterile gloves, a sterile drape, a sterile caliper, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a broad-spectrum microbicide should be given prior to the injection.

• The injection procedure for ILUVIEN is as follows:

• 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.
• Visually check through the viewing window of the preloaded applicator to ensure that there is a drug implant inside.
• 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 the patient 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.

• To reduce the amount of air administered with the implant, the administration procedure requires two steps. Before inserting the needle into the eye, push the applicator 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 should move to the UP position. If the button does not rise to the UP position, do not proceed with this unit.
• 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 for point of entry into the sclera.
• Carefully remove the protective cap from the needle and inspect the tip to ensure it is not bent.
• 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 through the conjunctiva and sclera. 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.
• 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.
• Following the injection, patients should be monitored for elevation in intraocular pressure and for endophthalmitis. Monitoring may consist of a check for perfusion of the optic nerve head immediately after the injection, tonometry within 30 minutes following the injection, and biomicroscopy between two and seven days following the injection. Patients should be instructed to report without delay any symptoms suggestive of endophthalmitis.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Fluocinolone acetonide (intravitreal implant) in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Fluocinolone acetonide (intravitreal implant) in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Fluocinolone acetonide (intravitreal implant) FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Fluocinolone acetonide (intravitreal implant) in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Fluocinolone acetonide (intravitreal implant) in pediatric patients.

Contraindications

Ocular or Periocular Infections

• ILUVIEN is contraindicated in patients with active or suspected ocular or periocular infections including most viral disease of the cornea and conjunctiva including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections and fungal diseases.

Glaucoma

• ILUVIEN is contraindicated in patients with glaucoma, who have cup to disc ratios of greater than 0.8.

Hypersensitivity

• ILUVIEN is contraindicated in patients with a known hypersensitivity to any components of this product.

Warnings

Intravitreal Injection-related Effects

• Intravitreal injections, including those with ILUVIEN, have been associated with endophthalmitis, eye inflammation, increased intraocular pressure, and retinal detachments. Patients should be monitored following the intravitreal injection.

Steroid-related Effects

• Use of corticosteroids including ILUVIEN may produce posterior subcapsular cataracts, increased intraocular pressure and glaucoma.

• Use of corticosteroids may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses.

• 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.

Risk of Implant Migration

• Patients in whom the posterior capsule of the lens is absent or has a tear are at risk of implant migration into the anterior chamber.

Adverse Reactions

Clinical Trials Experience

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

• Adverse reactions associated with ophthalmic steroids including ILUVIEN include cataract formation and subsequent cataract surgery, elevated intraocular pressure, which may be associated with optic nerve damage, visual acuity and field defects, secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera.

• ILUVIEN was studied in two multicenter, randomized, sham-controlled, masked trials in which patients with diabetic macular edema were treated with either ILUVIEN (n=375) or sham (n=185).

• TABLE 1 summarizes safety data available when the last subject completed the last 36 month follow up visit for the two primary ILUVIEN trials. In these trials, subjects were eligible for retreatment no earlier than 12 months after study entry. Over the three year follow up period, approximately 75% of the ILUVIEN treated subjects received only one ILUVIEN implant.

• The most common ocular (study eye) and non-ocular adverse reactions are shown in TABLES 1 and 2:

This image is provided by the National Library of Medicine.

This image is provided by the National Library of Medicine.

Increased intraocular Pressure

This image is provided by the National Library of Medicine.

This image is provided by the National Library of Medicine.

Cataracts and Cataract Surgery

• At baseline, 235 of the 375 ILUVIEN subjects were phakic; 121 of 185 sham-controlled subjects were phakic. The incidence of cataract development in patients who had a phakic study eye was higher in the ILUVIEN group (82%) compared with Sham (50%). The median time of cataract being reported as an adverse event was approximately 12 months in the ILUVIEN group and 19 months in the Sham group. Among these patients, 80% of ILUVIEN subjects vs. 27% of sham-controlled subjects underwent cataract surgery, generally within the first 18 months (Median Month 15 for both ILUVIEN group and for Sham) of the studies.

Postmarketing Experience

• 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, possible causal connection to ILUVIEN, or a combination of these factors, include reports of drug administration error and reports of the drug being ineffective.

Drug Interactions

There is limited information regarding Fluocinolone acetonide (intravitreal implant) Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C

• There are no adequate and well-controlled studies of ILUVIEN in pregnant women. Animal reproduction studies have not been conducted with fluocinolone acetonide. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. ILUVIEN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fluocinolone acetonide (intravitreal implant) in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Fluocinolone acetonide (intravitreal implant) during labor and delivery.

Nursing Mothers

• Systemically administered corticosteroids are present in human milk and could suppress growth and interfere with endogenous corticosteroid production. The systemic concentration of fluocinolone acetonide following intravitreal treatment with ILUVIEN is low [see Clinical Pharmacology (12.3)]. It is not known whether intravitreal treatment with ILUVIEN could result in sufficient systemic absorption to produce detectable quantities in human milk. Exercise caution when ILUVIEN is administered to a nursing woman.

Pediatric Use

There is no FDA guidance on the use of Fluocinolone acetonide (intravitreal implant) in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Fluocinolone acetonide (intravitreal implant) in geriatric settings.

Gender

There is no FDA guidance on the use of Fluocinolone acetonide (intravitreal implant) with respect to specific gender populations.

Race

There is no FDA guidance on the use of Fluocinolone acetonide (intravitreal implant) with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Fluocinolone acetonide (intravitreal implant) in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Fluocinolone acetonide (intravitreal implant) in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Fluocinolone acetonide (intravitreal implant) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Fluocinolone acetonide (intravitreal implant) in patients who are immunocompromised.

Administration and Monitoring

Administration

• Intravitreal implant

Monitoring

There is limited information regarding Fluocinolone acetonide (intravitreal implant) Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Fluocinolone acetonide (intravitreal implant) and IV administrations.

Overdosage

There is limited information regarding Fluocinolone acetonide (intravitreal implant) overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Fluocinolone acetonide (intravitreal implant) Pharmacology in the drug label.

Mechanism of Action

• Corticosteroids inhibit inflammatory responses to a variety of inciting agents. They inhibit edema, 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 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.

Structure

• ILUVIEN is a sterile non-bioerodable intravitreal implant containing 0.19 mg (190 mcg) fluocinolone acetonide in a 36-month sustained-release drug delivery system. ILUVIEN is designed to release fluocinolone acetonide at an initial rate of 0.25 µg/day. ILUVIEN is preloaded into a single-use applicator to facilitate injection of the implant directly into the vitreous. The drug substance is a synthetic corticosteroid, fluocinolone acetonide.

• The chemical name for fluocinolone acetonide is (6α,11β, 16α)-6,9-difluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis-(oxy)]-pregna-1,4-diene-3,20-dione. Its chemical structure is:

This image is provided by the National Library of Medicine.

• MW 452.50; molecular formula C24H30F206

• 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.

• Each ILUVIEN consists of a light brown 3.5mm x 0.37mm implant containing 0.19 mg of the active ingredient fluocinolone acetonide and the following inactive ingredients: polyimide tube, polyvinyl alcohol, silicone adhesive and water for injection.

Pharmacodynamics

There is limited information regarding Fluocinolone acetonide (intravitreal implant) Pharmacodynamics in the drug label.

Pharmacokinetics

• In a human pharmacokinetic study of ILUVIEN, fluocinolone acetonide concentrations in plasma were below the lower limit of quantitation of the assay (100 pg/mL) at all post-administration time points from Day 7 through Month 36 following intravitreal administration of a 0.2 mcg/day or 0.5 mcg/day fluocinolone acetonide insert.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

• Long-term animal studies have not been conducted to determine the carcinogenic potential or the effect on fertility of ILUVIEN.

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

Clinical Studies

• 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 edema that had previously been treated with laser photocoagulation.

• The primary efficacy endpoint in both trials was the proportion of subjects in whom vision had improved by 15 letters or more from baseline after 24 months of follow-up.

This image is provided by the National Library of Medicine.

• Visual acuity outcomes by lens status (Phakic or Pseudophakic) at different visits are presented in FIGURE 2 and FIGURE 3. The occurrence of cataracts impacted visual acuity during the study. Patients who were pseudophakic at baseline achieved greater mean BCVA change from baseline at the Month 24 study visit.

• Figure 2: Proportion of subjects with >=15 Letters Improvement from Baseline BCVA in the Study Eye

This image is provided by the National Library of Medicine.

• Figure 3: Mean BCVA Change from Baseline

This image is provided by the National Library of Medicine.

• The BCVA outcomes for the Pseudophakic and Phakic subgroups from Studies 1 and 2 at Month 24 are presented in TABLE 5.\

This image is provided by the National Library of Medicine.

How Supplied

ILUVIEN® (fluocinolone acetonide intravitreal implant) 0.19 mg is supplied in a sterile single use preloaded applicator with a 25-gauge needle, packaged in a tray sealed with a lid inside a carton.

NDC 68611-190-02

Storage

• Storage: Store at 15° - 30° C (59° - 86° F).

Images

Drug Images

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Package and Label Display Panel

Package Label - Principal Display Panel – Carton

Package Label - Principal Display Panel – Lid

This image is provided by the National Library of Medicine.

Package Label - Principal Display Panel – Lid

This image is provided by the National Library of Medicine.

Package Label - Principal Display Panel – Inserter

This image is provided by the National Library of Medicine.

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Patient Counseling Information

Steroid-related Effects

• Advise patients that a cataract may occur after treatment with ILUVIEN. If this occurs, advise patients that their vision will decrease, and they will need an operation to remove the cataract and restore their vision.

• Advise patients that they may develop increased intraocular pressure with ILUVIEN treatment, and the increased IOP may need to be managed with eye drops, or surgery.

Intravitreal Injection-related Effects

• Advise patients that in the days following intravitreal injection of ILUVIEN, patients are at risk for potential complications including in particular, but not limited to, the development of endophthalmitis or elevated intraocular pressure.

When to Seek Physician Advice

• Advise patients that if the eye becomes red, sensitive to light, painful, or develops a change in vision, they should seek immediate care from an ophthalmologist.

Driving and Using Machines

• Inform patients that they may experience temporary visual blurring after receiving an intravitreal injection. Advise patients not to drive or use machines until this has been resolved.

Manufactured for: Alimera Sciences, Inc. 6120 Windward Parkway Alpharetta, GA 30005

Patented. See: www.alimerasciences.com

ALIMERA SCIENCES

Precautions with Alcohol

Alcohol-Fluocinolone acetonide (intravitreal implant) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Fluocinolone acetonide (intravitreal implant) Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Fluocinolone acetonide (intravitreal implant) Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.