Retisert Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

RETISERT^TM (fluocinolone acetonide) is indicated for:

• Retisert is indicated for the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye in patients for which conventional therapies are no longer appropriate.

RETISERT^TM should not be used in patients with viral disease of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia and varicella.

RETISERT^TM should not be used in patients with mycobacterial infections of the eye and fungal diseases of ocular structures.

Geriatrics ( ≥ 65 years of age):

Experience of RETISERT^TM use in patients ≥ 65 years of age is limited. The safety and effectiveness has not been established.

Pediatrics ( < 18 years of age):

Experience of RETISERT^TM use in children and adolescents below the age of 18 is limited. The safety and effectiveness has not been established.

CONTRAINDICATIONS

• Patients with viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia and varicella.
• Patients with mycobacterial infection of the eye.
• Patients with fungal diseases of ocular structures.
• Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
• Patients sensitive to other corticosteroids including, but not limited to, a history or presence of uncontrolled IOP while on steroid therapy, resulting in loss of vision, or IOP > 25 mm Hg requiring 2 or more types of IOP lowering medications to lower to < 25 mm Hg.

WARNINGS AND PRECAUTIONS

General

Care must be exercised in handling RETISERT^TM in order to avoid damage to the implant, which could affect the release of fluocinolone acetonide inside the eye. RETISERT^TM must be handled only by the suture tab. Care must be taken during implantation and explantation to avoid shear forces on the implant that could separate the silicone cup reservoir (which contains a fluocinolone acetonide tablet) from the suture tab. As with all intraocular surgery, sterility of the surgical field and RETISERT^TM should be rigorously maintained. RETISERT^TM should not be re-sterilized by any method.

A high level of surgical skill is required for implantation of the RETISERT^TM Implant. Implantation should be performed by a qualified professional with

prerequisite training and thorough knowledge of the procedure to be

performed.

As with any surgical procedure there is a risk involved. Potential complications accompanying intraocular surgery to place RETISERT^TM into the vitreous cavity may include, but are not limited to, the following: choroidal detachment, endophthalmitis, hypotony, retinal detachment, vitreous haemorrhage, vitreous loss, wound dehiscence, temporary decreased visual acuity, exacerbation of intraocular inflammation and increased intraocular pressure.

If an inadequate response to RETISERT^TM therapy is seen during the first six months of treatment, consideration should be given to alternative treatment modalities since the patient’s condition may not be responsive to treatment with intravitreal fluocinolone acetonide.

Retisert has not been evaluated in patients requiring chronic high dose systemic corticosteroid therapy (more than 15 mg prednisone or equivalent daily) to manage non-ocular diseases. When alternate treatment modalities are added to address an inadequate response to RETISERT^TM, follow-up care must consider the possibility that the steroid is contributing to the total clinical response and that the additive benefit of RETISERT^TM could diminish as the drug is depleted after 30 to 36 months. Follow-up schedules should be similar to those used for RETISERT^TM monotherapy.

After surgical implantation of RETISERT^TM, patients may experience a temporary decrease in visual acuity or blurred vision for up to one month. Patients should not drive or use machines until their vision has recovered.

Patients should be warned that cataract formation occurs in almost all phakic eyes during the course of RETISERT^TM treatment and this may progress to a stage that, without surgical extraction of the cataract, could affect their ability to drive and use machines.

In vitro stability studies show that the strength of the adhesive bond between the silicone cup reservoir and the suture tab is reduced with prolonged hydration, indicating a potential for the separation of these components. Physicians should monitor the integrity of the implant during ophthalmologic examinations.

Removal of RETISERT^TM

The safety of the depleted implant is unknown. Removal of RETISERT^TM (before or at the end of drug delivery which may be suggested by the recurrence of clinical signs more than 24 months post-implantation) is at the discretion of the physician and must be based on the risk and benefit balance of implant removal against further surgery. It is important to note that implant separation (floating silicone cup) has been reported up to 5 years post-implantation which necessitated immediate surgery. These findings are based on the available data; therefore, the possibility of implant separation after 5 years is unknown.

Removal of the RETISERT^TM implant in the presence of vitreous bands should be done carefully. There is a risk of retinal traction during removal of the implant in such patients. To avoid this complication, a vitrectomy might be considered before removal of the implant.

Removal of RETISERT^TM from the eye may be performed by cutting the sutures over the insertion incision and carefully grasping the anchoring suture to effect removal. Care should be taken to avoid shear forces that might separate the drug-containing cup from the suture tab. The explantation incision may need to be larger than the implantation incision in order to avoid damage to the implant during the removal operation. An infusion line may be necessary to avoid globe collapse especially in vitrectomised eyes.

Ophthalmologic

Based on clinical trials with RETISERT^TM, within an average post-implantation period of approximately 2 years, nearly all phakic eyes are expected to develop cataracts and require cataract surgery. Cataracts were surgically extracted in 95.9% of implanted phakic study eyes versus 19.9% (37/186) in phakic fellow eyes and 19.3% (11/57) in phakic study eyes of patients treated with standard of care systemic therapies. At approximately 2.5 years post-implantation, glaucoma filtering surgeries were required to manage the pressure increase in 30.9% of the patients implanted with RETISERT^TM 0.59 mg. IOP lowering surgeries were required for 1.8% (5/275) of fellow eyes and for 2.7% (2/74) of study eyes of patients treated with standard of care systemic therapies.

Following implantation of RETISERT^TM, nearly all patients will experience an immediate and temporary decrease in visual acuity in the implanted eye which lasts for approximately one to four weeks post-operatively. This decrease in visual acuity is probably a result of the surgical procedure.

Prolonged use of corticosteroids may result in elevated intraocular pressure with possible development of glaucoma with damage to the optic nerve, defects in visual acuity and visual fields, posterior subcapsular cataract formation, delayed wound healing and perforation of the globe where there is thinning of the sclera.

Steroids should be used with caution in the presence of glaucoma. Patients must be monitored for elevated intraocular pressure (IOP).

Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. Fungal and viral infections of the cornea are particularly prone to develop coincidentally with long-term applications of steroids. The possibility of fungal invasion should be considered in any persistent corneal ulceration where steroid treatment has been used. In purulent conditions of the eye, steroids may mask infection or enhance existing infection. Since resistance to infections is known to be reduced by corticosteroids, simultaneous bilateral implantation is not recommended, in order to limit the potential for bilateral post-operative infection.

After exhausting all other surgical treatment options, if a patient experiences a sustained IOP of 25 mm Hg or more whilst using two or more types of antiglaucoma medication for at least two months or if the IOP is accompanied by progressive visual field deterioration, removal of RETISERT^TM should be considered. If RETISERT^TM appears damaged or is dislocated, the implant should be removed. If a patient develops late onset endophthalmitis, particularly in the absence of other risk factors, reassessment of the wound integrity or removal of RETISERT^TM should be considered.

Carcinogenesis and Mutagenesis

Long term animal studies have not been performed on RETISERT^TM to evaluate the carcinogenic potential.

Nonclinical data reveal no special hazard for humans based on conventional studies of genotoxicity.

Dependence/Tolerance

There is no abuse potential with RETISERT^TM

Endocrine and Metabolism

Disturbances on the corticosteroids HPA axis in humans were not evaluated. However, effects are not expected due to the negligible systemic exposure to fluocinolone acetonide from RETISERT^TM

Neurologic

RETISERT^TM is not expected to impair mental ability.

Peri-Operative Considerations

The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation.

Special Populations

Pregnant Women: Adequate data from the use of fluocinolone acetonide in pregnant women are not available. Studies in animals have shown reproductive toxicity (SEE TOXICOLOGY). The potential risk for humans is unknown. RETISERT^TM should not be used during pregnancy unless clearly necessary.

Adequate and well-controlled studies in pregnant women have not been conducted. RETISERT^TM should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Nursing Women: It is not known whether intraocular administration of fluocinolone acetonide will result in sufficient systemic absorption to produce detectable quantities in human milk. Systemically administered steroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. A decision on whether to continue breastfeeding should be made taking into account the benefit of breastfeeding to the child and the benefit of RETISERT^TM therapy to the mother.

Pediatrics (<18 years of age): Experience of RETISERT^TM use in children and adolescents below the age of 18 is limited. The safety and effectiveness have not been established.

Geriatrics ( ≥ 65 years of age): Experience of RETISERT^TM use in patients > 65 years of age is limited. The safety and effectiveness has not been established.

Renal/hepatic Impairment: Negligible quantities of fluocinolone acetonide from RETISERT^TM are excreted via the systemic circulation. No specific precautions for treatment of patients with renal or hepatic impairment are necessary.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The majority of the adverse events experienced by subjects implanted with RETISERT^TM were related to the underlying disease process, the effect of corticosteroid, and the surgical implantation procedure.

Commonly reported ocular adverse events of the implanted eye included increased intraocular pressure, glaucoma, cataract, worsened cataract, conjunctival haemorrhage, conjunctival hyperaemia, reduced visual acuity, maculopathy, hypotony, post-operative wound complications, eye irritation, blurred vision, vitreous floaters, posterior capsular opacification, unusual sensation in the eye and pruritis.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Two study designs were utilized in the pivotal clinical trials: 0.59 mg fluocinolone acetonide implant vs. standard of care (SOC) treatment (BLP 415-002); and 0.59 mg vs. 2.1 mg fluocinolone acetonide implant (BLP 415-001). Additional safety and efficacy data was obtained from two additional studies conducted in subjects with a clinical diagnosis of posterior uveitis: BLP 415-001J/JF and BLP 415-004. Two dosage strengths of the fluocinolone acetonide implant were evaluated in the clinical trials, 0.59 mg and 2.1 mg. Only safety data for the 0.59 mg strength is presented here.

The most common ocular adverse event observed in eyes treated with RETISERT^TM 0.59 mg was increased intraocular pressure (57.3%).

Ocular adverse events reported at an incidence of ≥ 20% in implanted eyes included eye pain, cataract (worsened or de novo), conjunctival haemorrhage, conjunctival hyperaemia, reduced visual acuity, postoperative wound complications, hypotony, maculopathy, eye irritation, glaucoma, and postoperative complications. Some of these events were transient and associated with the implantation surgery.

The most common ocular adverse events observed in the non-study eye included increased intraocular pressure, eye pain, cataract (de novo and aggravated) and reduced visual acuity.

Based on clinical trials with RETISERT^TM, within an average post-implantation period of approximately 2 years, nearly all phakic eyes are expected to develop cataracts and require cataract surgery.

At approximately 2.5 years post-implantation, glaucoma filtering surgeries were required to manage the pressure increase in 30.9% of the patients implanted with RETISERT^TM 0.59 mg.

Table #1 shows the occurrence of ocular adverse events for the study eye versus the non-study eye (≥1%).

Table #1: Ocular Adverse Event Occurring in ≥ 1% of Study Eyes

Less Common Clinical Trial Ocular Adverse Events ( < 1%, Study Eye)

Eye Disorders: cataract nuclear, eyelid disorder NOS, lens disorder NOS, scleral disorder NOS, retro-orbital pain, abnormal sensation in eye, painful red eyes, eye infection bacterial, NOS, eye infection NOS, Vogt-Koyanagi-Harada syndrome, staphyloma, herpes ophthalmic NOS, cellulitis orbital, conjunctivitis viral NOS, conjunctivitis bacterial NOS, open angle glaucoma NOS, glaucoma aggravated, chorioretinal atrophy, chorioretinal scar, photophobia aggravated, contact lens intolerance, retinal tear (excl detachment), retinal scar, macular degeneration, retinal oedema, retinal cyst, macular cyst, retinal deposits, dermatitis eyelid, eyelid margin crusting, meibomian gland discharge, optic nerve disorder NOS, halo vision, optic neuropathy NOS, retinal vasculitis, eyelid function disorder NOS, blepharospasm, keratoconjunctivitis sicca, corneal erosion, corneal perforation, sub epithelial opacities, choroidal haemorrhage, punctate keratitis, keratopathy band, corneal haze, corneal calcification, iris convex, Koeppe nodules, conjunctival follicles, conjunctival erosion, anterior chamber inflammation, retinal vascular disorder NOS, retinal neovascularisation, retinal infarction, corneal cyst NOS, iritis, uveitis NOS, iridocyclitis, eye injury NOS, retinal exudates retinopathy proliferative, astigmatism, anisometropia, myopia aggravated, refractive errors NOS, corneal defect, corneal infiltrates, episcleritis NOS, lens dislocation, eye haemorrhage, trichiasis, growth of eyelashes, blepharophimosis, blindness night, blindness NOS, strabismus, eyelid tumour, eye degenerative disorder NOS, retinitis pigmentosa, colour blindness, optic disc haemorrhage, xanthopsia

General Disorders and Administration Site Conditions: adverse drug reaction NOS, injection site oedema

Infections and Infestations: scleritis NOS, nasopharyngitis

Immune System Disorders: drug hypersensitivity, allergy to chemicals NOS, hypersensitivity NOS

Injury, Poisoning and Procedural Complications: procedural site reaction, post procedural pain, cataract fragments in eye postoperative, fibrin deposition on lens postoperative, drug toxicity NOS, abrasion NOS

Investigations: corneal staining, intraocular pressure abnormal

Neoplasms Benign, Malignant and Unspecified (Incl Cysts and Polyps): skin papilloma, Nervous System Disorders: headache NOS, hypoaesthesia, nystagmus NOS

Skin and Subcutaneous Tissue Disorders: rash NOS, pyogenic granuloma, skin ulcer NOS, photosensitivity reaction NOS, dermatitis contact

Surgical and Medical Procedures: eye operation NOS, intraocular lens dislocation, suture removal, conjunctival injection

Vascular Disorders: hypotension NOS, hyperaemia Non-ocular adverse events ( ≥ 1%, implanted patients)

Most common non-ocular events reported included headache, nasopharyngitis, arthralgia, pyrexia, nausea, influenza, and vomiting.

Table #2 shows the occurrence of non-ocular adverse events (≥1%) in implanted patients.

Table #2: Non-ocular Adverse Events occurring in ≥ 1% of Implanted Patients

Less Common Clinical Trial Non-Ocular Adverse Events ( < 1%, implanted patients)

Blood and Lymphatic System Disorders: leucopenia NOS, leukocytes, lymphadenopathy, thrombocytopenia, neutropenia,

Cardiac Disorders: arrhythmia NOS, bradycardia NOS, left ventricular hypertrophy, cardiac sarcoidosis, palpitations, cyanosis NOS, coronary artery disease NOS, atrial fibrillation, acute coronary syndrome, endocarditis bacterial NOS

Congenital, Familial and Genetic Disorders: congenital atrial septal defect

Ear and Labyrinth Disorders: tinnitus, ear disorder NOS, deafness NOS, labyrinthitis NOS

Endocrine Disorders: cushingoid, Cushing’s syndrome, thyroid nodule, hypothyroidism, goitre, thyroid disorder NOS, thyrotoxicosis, autoimmune thyroiditis, adrenal insufficiency NOS

Eye Disorders: photopsia, diplopia, glare, eyelid oedema, visual acuity reduced, orbital oedema, posterior capsule opacification

Gastrointestinal Disorders: retching, aphthous stomatitis, abdominal pain lower, tooth disorder NOS, periodontal disorder NOS, gastrointestinal discomfort, stomach discomfort, dysphagia, irritable bowel syndrome, irritable bowel syndrome aggravated, inflammatory bowel disease NOS, Crohn’s disease aggravated, throat irritation, odynophagia, dry mouth, aptyalism, abdominal distension, hiatus hernia, oesophagitis NOS, lip ulceration, rectal haemorrhage, colonic polyp, tongue ulceration, diverticulitis NOS, intestinal obstruction NOS, gastrointestinal infection NOS, inguinal hernia NOS, duodenal ulcer, glossodynia, salivary gland enlargement NOS, gingival oedema, diverticulum intestinal, anal discomfort, rectocele

General Disorders and Administration Site Conditions: malaise, facial pain, axillary pain, general symptom NOS, ill-defined disorder NOS, ulcer NOS, chest tightness, energy increased, drug intolerance NOS, adverse drug reaction NOS, injection site swelling, injection site pain, injection site extravasation, discomfort NOS, feeling hot, chest mass NOS

Hepatobiliary Disorders: cholelithiasis, cholecystitis NOS, hyperbilirubinaemia, jaundice NOS, hepatic cyst NOS, bile duct stone,

Investigations: gastrointestinal obstruction NOS, enlarged prostate, glycosylated haemoglobin increased, protein urine present, blood urine present, urinary occult blood positive, urine oxalate quantitative, specific gravity urine increased, red blood cells urine, glucose urine present, neutrophil count increased, blood potassium decreased, blood potassium increased, blood viscosity increase, enzyme abnormality NOS, blood creatine increased, blood creatinine increased, red blood cell count decreased, mean cell haemoglobin increased, hematocrit decreased, blood in stool, laboratory test abnormal NOS, nuclear magnetic resonance imaging abnormal, heart rate irregular, activated partial thromboplastin time prolonged, csf abnormal NOS, platelet count increase, blood prolactin increased

Immune System Disorders: insect bite allergy, allergy to insect sting, Behcet’s syndrome, sarcoidosis NOS, systemic lupus erythematosus,

Infections and Infestations: laryngitis NOS, peritonsillar abscess NOS, sinusitis chronic NOS, pyelonephritis NOS, herpes simplex, herpes viral infection, fungal infection NOS, vaginosis fungal NOS, respiratory tract infection NOS, infection NOS, abscess limb, parasitic infection NOS, localized infection, cellulitis, rash pustular, tooth abscess, tooth infection, dry socket NOS, pharyngitis streptococcal, streptococcal infection NOS, candidal infection NOS, haemophilus infection NOS, scabies infestation, leprosy NOS, hepatitis C, erythema infectiosum

Injury, Poisoning and Procedural Complications: road traffic accident, injury NOS, arthropod bite, wound NOS, accident NOS, wound haemorrhage, traumatic haematoma, animal bite, back injury NOS, tooth injury, muscle strain, tendon injury, ligament injury NOS, epicondylitis, joint sprain, foot fracture, fibula fracture, femur fracture, clavicle fracture, wrist fracture, postoperative wound site erythema, postoperative wound infection, post procedural pain, thermal burn, concussion

Metabolism and Nutrition Disorders: diabetes mellitus NOS, diabetes mellitus non insulin-dependent, anorexia, dehydration, hypoglycaemia NOS, obesity, gout

Musculoskeletal and Connective Tissue Disorders: polyarthralgia, joint effusion, musculoskeletal discomfort, muscle spasms, neck stiffness, limb discomfort NOS, contractures NOS, arthrosis NOS, joint stiffness, ankylosing spondylitis, fibromyalgia, myofascial pain syndrome, swelling NOS, neck swelling, bunion, bone spur, aseptic necrosis bone, bone lesion NOS, exostosis, myofascial spasm, muscle atrophy, myokymia, localized osteoarthritis, spinal osteoarthritis, tendonitis, ganglion, plantar fasciitis, fibula fracture, ankle fracture, coccydynia, pain in jaw, rotator cuff syndrome, upper limb fracture NOS

Neoplasms Benign, Malignant and Unspecified (Incl Cysts and Polyps): cyst NOS, adenoma benign NOS, skin carcinoma NOS, basal cell carcinoma, squamous cell carcinoma of skin, benign breast neoplasm NOS, fibroadenoma of breast, brain neoplasm NOS, metastases NOS, thyroid adenoma NOS, oesophageal carcinoma NOS, small cell carcinoma, central nervous system lymphoma, uterine fibroids

Nervous System Disorders: frequent headaches, neurological disorder NOS, ageusia, burning sensation NOS, somnolence, depressed level of consciousness, vasovagal attack, syncope, peripheral nerve injury, gait abnormal NOS, balance impaired NOS, peripheral neuropathy NOS, neuropathy NOS, multiple sclerosis aggravated, brain herniation, spinal stenosis NOS, radiculitis brachial, cerebrovascular accident, vasculitis cerebral, memory impairment convulsions NOS, trigeminal neuralgia, mental impairment NOS, aphasia, cerebral oedema, demyelinating polyneropathy NOS, facial palsy, third nerve paralysis, hyperreflexia, facial bones fracture

Psychiatric Disorders: depression aggravated, stress symptoms, nervousness, panic attack, emotional distress

Renal and Urinary Disorders: dysuria, difficulty in micturition, calculus renal NOS, urine abnormal NOS, haematuria, glycosuria, cystitis NOS, calculus urinary, calculus ureteric, renal disorder NOS, kidney infection NOS, polyuria, cystocele

Reproductive System and Breast Disorders: menstruation irregular, uterine fibroids, endometriosis, breast cancer NOS, ovarian cyst, cervical carcinoma stage III, cervical polyp, vaginitis, menorrhagia, vulvovaginal dryness, vaginal pain, prostatitis, benign prostatic hyperplasia

Respiratory, Thoracic and Mediastinal Disorders: tonsillitis NOS, haemoptysis, throat irritation, sneezing, upper respiratory tract congestion, apnoeic attack, sinus congestion, asthma aggravated, chronic obstructive airways disease, rhinorrhoea, epistaxis, nasal turbinate hypertrophy, nasal septum deviation, rhinitis NOS, nasal congestion, rhinitis allergic NOS, respiratory tract infection viral NOS, pulmonary sarcoidosis, pulmonary granuloma NOS, laryngitis viral NOS, pleural effusion, hilar lymphadenopathy, metastases to lung

Social Circumstances: aborted pregnancy

Skin and Subcutaneous Tissue Disorders: skin eruption, exanthema, eczema NOS, dermatitis allergic, eczema seborrhoeic, skin lesion NOS, skin disorder NOS, dry skin, alopecia, acne NOS, urticaria NOS, uticaria NOS, sweating increased, rosacea, skin desquamation NOS, erythema nodosum, psoriasis, lichen planus, increase tendency to bruise, pigmentation disorder NOS, cutaneous sarcoidosis, granuloma annulare, erythema, photosensitivity reaction NOS, paronychia, epidermal cyst, rash papular, skin striae, scrotal ulcer, cellulitis

Surgical and Medical Procedures: tooth disorder NOS, tooth extraction NOS, hysterectomy NOS, nephrectomy, circumcision, nerve block

Vascular Disorders: hypertension aggravated, carotid artery stenosis, carotid artery occlusion, cerebral infarction, cerebellar infarction, vertebral artery occlusion, vertebro basilar insufficiency, haematoma NOS, thrombosis NOS, Raynaud’s phenomenon, cerebrovascular accident, blood pressure inadequately controlled, pulmonary embolism, venous thrombosis deep limb, aortic aneurysm

Post-Market Adverse Drug Reactions

RETISERT^TM has been marketed in the US since June of 2005. Since product approval to date (December 2007) in the U.S., twelve (12) spontaneous post-marketing cases have been reported with Restisert: 1 case of retinal detachment, 1 case of IOP decrease/ vitreous floaters/blurred vision/eye swelling/eye inflammation (reported by the patient), 1 case of scleral thinning, 1 case of menstrual disorder/tinnitus/headache/visual acuity reduced, 1 case of hypotony, 1 case of CMV retinitis, 1 case of endophthalmitis and 5 cases of lack of efficacy (one was determined to be for an unapproved indication of ocular lymphoma due to initial misdiagnosis of posterior uveitis). One case of lack of efficacy cataract, retinal tear, hyphaema and photophobia were also reported.

One published paper reported 4 cases of vitreous bands extending from the posterior pole of the eye to the implant. Three of the 4 cases developed vitreous bands more than 3 years after implantation (Lowder et al., 2007).

Implant separation (floating silicone cup) has been observed up to 5 years post implantation which necessitated immediate surgery. These findings are based on the available data; therefore, the possibility of implant separation after 5 years is unknown. Refer to Warnings and Precautions, General section.

Compared to the safety of the clinical trials up to December 2007, no unique emerging safety issues or signals have been detected in the post-marketing data.

DRUG INTERACTIONS

No interaction studies (i.e., drug-drug, drug- herb, drug-food and drug-laboratory tests) have been performed. Because of the negligible systemic levels of fluocinolone acetonide generated by the implant, interactions at the systemic level are not expected.

DOSAGE AND ADMINISTRATION

Dosing Considerations

RETISERT^TM is for intravitreal implantation only.

The RETISERT^TM is surgically implanted into the posterior segment of the affected eye through a pars plana incision and held in place with an anchoring suture. Clinical study data indicate that the therapeutic effect of RETISERT^TM is maintained for approximately 3 years. The effective length of treatment time varies between patients and after 2 years post implantation patients should be closely monitored for clinical signs of uveitis recurrence. Following depletion of fluocinolone acetonide from RETISERT^TM, which may be suggested by recurrence of uveitis more than 24 months post-implantation, RETISERT^TM may be removed at the physician’s discretion based on the risk and benefit balance of implant removal. The safety and efficacy of re-implantation as well as the safety of the depleted implant have not been established (see Warnings and Precautions).

The average release rate of fluocinolone acetonide from the implant was estimated to be 0.4 µg/ day.

Recommended Dose and Dosage Adjustment

The recommended dosage is one intravitreal implant. The implant is inserted intravitreally and provides continuous release of fluocinolone acetonide for 30-36 months.

Missed Dose Not applicable.

OVERDOSAGE

No information is available on overdosage in humans. Given the nature of the product (i.e., surgical implantation by physician), it is unlikely that overdose could occur. However, if signs and symptoms of overdose with RETISERT^TM occur, treatment should be symptomatic.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the oedema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. There is no generally accepted explanation for the mechanism of action of ocular corticosteroids. However, corticosteroids are thought to act by the induction of phospholipase A2 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 their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. Corticosteroids are capable of producing a rise in intraocular pressure.

Pharmacodynamics

Directly applied to the inflamed eye, corticosteroids exert an anti-inflammatory effect. In the case of RETISERT^TM, subjects in the clinical studies were implanted during a period of relative remission of their ocular inflammatory disease. Thus, it was not possible to observe an immediate anti-inflammatory effect. As well, the implantation surgery, like any ocular surgery, elicits a relatively brief period of inflammation. The intent of the product is not to have a rapid onset, but to have an extended duration of effect.

The sustained release of fluocinolone acetonide from RETISERT^TM results in a reduction of uveitic inflammatory recurrences and in the area of cystoid macular oedema over approximately three years. Overall, the sustained anti-inflammatory effect preserves visual acuity, except when affected by cataract development.

Pharmacokinetics

In a subset of patients who received the intravitreal implant, and had blood samples taken at various times (weeks 1, 4 and 34) after implantation, plasma levels of fluocinolone acetonide were below the limit of detection (0.2 ng/mL) at all times. Aqueous and vitreous humour samples were assayed for fluocinolone acetonide in a further subset of patients. Whilst detectable concentrations of fluocinolone acetonide were seen throughout the observation interval (up to 34 months), the concentrations were highly variable, ranging from below the limit of detection (0.2 ng/ml) to 589 ng/ml.

Special Populations and Conditions

Pediatrics: RETISERT^TM has only been used in a limited number of paediatric patients. The safety and effectiveness has not been established.

Geriatrics: Experience of RETISERT^TM use in patients ≥ 65 years of age is limited. The safety and effectiveness has not been established.

STORAGE AND STABILITY

Store at 15-25°C in the original container. Do not freeze.

SPECIAL HANDLING INSTRUCTIONS

Care must be exercised in handling of the RETISERT^TM in order to avoid damage to the implant, which could affect the release of fluocinolone acetonide inside the eye. RETISERT^TM must be handled only by the suture tab. Care must be taken during implantation and explantation to avoid sheer forces on the implant that could separate the silicone cup reservoir (which contains a fluocinolone acetonide tablet) from the suture tab. As with all intraocular surgery, sterility of the surgical field and RETISERT^TM should be rigorously maintained. RETISERT^TM should not be resterilized by any method.

DOSAGE FORMS, COMPOSITION AND PACKAGING

RETISERT^TM is an intravitreal implant containing a 0.59 mg fluocinolone acetonide tablet with the following inactive ingredients: microcrystalline cellulose, polyvinyl alcohol and magnesium stearate. The tablet is encased in a silicone elastomer cup containing a release orifice and a polyvinyl alcohol membrane positioned between the tablet and the orifice. The cup assembly is attached to a silicone suture tab with silicone adhesive. RETISERT^TM is approximately 3 mm wide, 2 mm thick and 5 mm long.

Each RETISERT^TM implant is packed in a clear polycarbonate case with a twist off cap. The case and cap are overwrapped with a foil pouch and placed in a polyethylene peelable overwrap. Each implant is placed in a carton. The pack contains one RETISERT^TM implant.

Patented CA 2367092 2007

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Fluocinolone acetonide

Chemical names: Pregna-1,4-diene-3,20-dione,6,9-difluoro-11,21-dihydroxy-16,17-[(1- methyl-ethylidene)bis(oxy)]-,(6α,11β,16α)-

6α,9α-Difluoro-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20- dione cyclic 16,17-acetal with acetone

6α,9α-Difluoro-11β,21-dihydroxy-16α,17α-isopropylidenedioxypregna-1,4-diene-3,20-dione

6α,9α-Difluoro-16α-hydroxyprednisolone 16,17-acetonide

Molecular formula and molecular mass: C₂₄H₃₀F₂O₆(anhydrous), 452.50

Structural formula:

Physicochemical properties:

Appearance/Description: White or almost white, odourless, crystalline powder

Purity: 98.0 – 102.0%, calculated on the dried basis

Melting Point: 265- 266^oC (crystals from acetone + hexane)

Optical Rotation: +95^o (chloroform)

Hydrate: Anhydrous form is used; also occurs as dihydrate

Solubility: Practically insoluble in water

1 in 10 acetone

1 in 45 alcohol

1 in 26 dehydrated alcohol

1 in 15 to 25 chloroform

1 in 350 ether

Soluble in methyl alcohol

Absorbance: 238 nm (log ∈ 4.21)

Partition Coefficient: 2.5 (octanol/water)

Polymorphs: Multiple polymorphic forms exist

Isomers: None

CLINICAL TRIALS

Given the unique nature of the product and patient population for RETISERT^TM, a typical Phase I, Phase II and Phase III development path was not appropriate. In particular, it was considered inappropriate to test this product in healthy volunteers for Phase I safety evaluation.

Evaluation of a wide range of doses from 0.59 mg (the lowest manufacturable dose) to 15 mg showed that the higher doses tended to have greater effects on elevating intraocular pressure. Thus, as the investigations progressed, lower doses were used. Based upon the safety profile on intraocular pressure, and the perception from the Investigators that the treatments were effective, for subsequent studies, the 0.59 mg and 2.1 mg intravitreal implants were used.

Two study designs were utilized in the pivotal clinical trials: 0.59 mg fluocinolone acetonide implant vs. standard of care (SOC) treatment (BLP 415-002); and 0.59 mg vs. 2.1 mg fluocinolone acetonide implant (BLP 415-001). Two dosage strengths of the fluocinolone acetonide implant were evaluated in the clinical trials, 0.59 mg and 2.1 mg.

In both designs, subjects with either unilateral or bilateral non-infectious uveitis affecting the posterior segment of the eye were enrolled. For subjects with bilateral disease, the more severely affected eye was chosen to be the study eye. It was expected that for bilateral subjects, the less severely affected eye had to be controlled with only periocular injections for 1 year. The control for the 415-002 study design was the group of subjects enrolled in the standard of care (SOC) arm, which required administration of systemic corticosteroids and if necessary, administration of systemic non-steroidal immunosuppressive agents for a minimum period of 6 months.

For the study design employed in the BLP 415-001 study, two types of controls were employed: 1) a historical control; and 2) a dose-comparison (0.59 mg vs. 2.1 mg) for both safety and efficacy evaluations.

Study demographics and trial design

Table #3- Summary of patient demographics for clinical trials in specific indication

Study results

RETISERT^TM was shown to be efficacious for the treatment of uveitis affecting the posterior segment of the eye as demonstrated by the results of the clinical trials. In the assessment of efficacy, the primary efficacy variable for the BLP 415-002 study design was the time to first protocol defined recurrence of uveitis in the study eye occurring in the 24 months after randomization for the SOC group and the 24 months after Visit 7 for the implant group. The first 12 weeks to Visit 7 were excluded for the implant group to allow post-operative inflammation therapy to be discontinued to prevent post-operative inflammation from being recorded as a recurrence, and to allow the tapering of previous anti-inflammatory systemic therapy. For the BLP 415-001 uveitis study the primary efficacy analyses involved a comparison of the rates of protocol-defined recurrences of uveitis before and after implantation.

BLP 415-002

The time to recurrence of uveitis for implant vs. SOC study eyes was evaluated by Kaplan Meier methods (freedom from recurrence). A clinically significant impact of RETISERT^TM was observed as evidenced by the freedom from uveitis recurrence through two years of study, but the Kaplan Meier analysis did not demonstrate a statistically significant difference between the implant and SOC study eyes when both observed and inferred recurrences were considered (p=0.065). It was noted that many of the failures were not due to clinical signs of inflammation but instead, due to inferred failures because of excess exposure to systemic immunosuppression resulting from incorrect tapering. These observations were recorded as uveitis recurrence.

To better understand the impact of failures inferred for reasons not associated with ocular inflammation, a supplementary analysis considering these cases, censored instead of failed, was conducted. For the supplementary analysis, each subject with an inferred failure was re-assessed to determine if they failed for reasons associated with ocular inflammation. A failure was reported in a total of 67 subjects (in the implant and SOC treatment groups); of those failures, 26 were inferred (18 in the implant group and 8 in the SOC group). Only 3 of the 11 implant failures reported for Time 0 were due to clinical signs, accounting for the biggest difference between the primary and supplemental Kaplan-Meier plots. The slope of the supplemental survival curve for the study eyes clearly demonstrated the benefits of the implant treatment. The time-to-recurrence of uveitis in the implant study eyes was considerably longer than the SOC study eyes (p=0.0008).

When the efficacy of the implant was stratified according to the SOC type at baseline (prior to study initiation), greater efficacy of the implant (prevention of recurrence) was shown for patients that took corticosteroids alone at baseline. Evidence of efficacy of the implant was also shown for patients that took corticosteroids and one immunosuppressant at baseline, but the difference was not statistically significant. Because of the limited number of patients taking corticosteroids and two immunosuppressants at baseline, no conclusions could be reached for that sub-group.

When the number of recurrences in the 52-week pre-treatment period was compared to the 2- year post-treatment period, there was a statistically significant difference in favour of the implant study eye (p=0.0 140) compared to the SOC study eye. Visual acuity was maintained in both the SOC and the implanted eyes during the course of the study. Differences were not statistically significant (p=0.655).

BLP 415-001

The primary efficacy measure for the BLP 415-001 study was a comparison of rates of recurrence between the pre-implantation and the 34 week, 1 year, 2 year, and 3 year postimplantation time points, recurrences were imputed (assumed) for these time points when a subject was not seen within 10 weeks of their scheduled visits.

For both dose groups combined, uveitis recurrence rates in study eyes were reduced from 59.7% (166/278) during the one year pre-implantation period to 32.7% (9 1/278) at 3 years post-implantation, using observed data only (p<0.0001), (40.7% [113/278] using imputed data [p<0.0001]). In the 0.59 mg dose group, 1 year pre- and 3 years post-implantation uveitis recurrence rates for study eyes were 61.8% and 20.0%, respectively, using observed data only (30.0% using imputed data at 3 years). The differences for both observed and imputed data were statistically significant (p< 0.0001). In the 2.1 mg dose group, uveitis recurrence rates for study eyes for the 1 year period prior to implantation and 3 years post-implantation were 58.3% and 41.1%, respectively, using observed data (p = 0.0006), (47.6% using imputed data at 3 years [p = 0.0314]). For both dose groups combined, uveitis recurrence rates in fellow eyes increased from 25.5% (70/275) during the one year pre-implantation period to 57.1% (157/275) at 3 years post-implantation, using observed data only (p<0.0001), (63.3% [174/275] using

imputed data [p<0.0001]). A reduced need for systemic therapy and for periocular injections (in study eyes) to control uveitis was observed by the 3-year post-implantation visit, compared with the enrollment visit (p<0.0001 for each dose group and both dose groups combined). The mean change from baseline in visual acuity of implanted eyes was statistically insignificant in both dose groups. On average, reductions in visual field were small, less than 2dB, but were statistically significant for both implanted and fellow eyes, p<0.005.

For study eyes in both dose groups combined, 56.8% (54/95) of eyes showed a reduction in the area of CME between baseline and 3 years post-implantation, compared with 24.2% (23/95) of fellow eyes (p<0.0001). An analysis of the change in mean area of CME from baseline to each post-implantation visit showed that in the 0.59 mg dose group, mean CME area decreased up to 34 weeks post-implantation and remained relatively constant thereafter.

Conclusion

The two pivotal studies, BLP 415-002 and BLP 415-001 were confirmatory of each other in demonstrating that RETISERT^TM is highly efficacious in controlling inflammation secondary to non-infectious uveitis affecting the posterior segment of the eye.

DETAILED PHARMACOLOGY

Animal Pharmacology

Sixteen 0.5 µg/day implants and sixteen 0.1 µg/day implants were implanted into the vitreous of the right eye of NZW rabbits fourteen days after subcutaneous injection of tuberculin antigen. Control animals (n=14) received empty implants. A masked observer graded corneal neovascularization, anterior chamber (AC) flare cell, iris congestion, and vitreous opacity on days 1-7, 9, 16 and 21 after uveitis induction. Animals were sacrificed on days 6 and 9 for aqueous WBC count, and protein measurement. Retinal function was evaluated by ERG. Histological sections of enucleated eyes were studied under light microscopy.

By clinical criteria, treated eyes were significantly less inflamed than untreated eyes. Anterior chamber cell flare and vitreous opacity were significantly reduced (p≤0.02) in both drug implant groups compared with control animals. Overall, inflammation was suppressed to a greater degree with the 0.5-µg/day implant compared to the 0.1-µg/day implant but there was no significant difference between 0.1- and 0.5-ȝg/d implants. As compared to the control eyes, treated eyes had a reduction in aqueous WBC count and protein concentration, and had lower inflammatory grade at histopathologic examination; however, these differences were not statistically significant. It is concluded that the fluocinolone acetonide intravitreal implant suppresses ocular inflammation in a rabbit model of severe uveitis. (Mruthyunjaya, 2006).

Safety Pharmacology

No specific safety pharmacology experiments with the intravitreal implant have been done. Although some local ocular secondary pharmaceutical effects were observed, systemic secondary pharmacological actions are not expected to occur as systemic levels of fluocinolone acetonide resulting from the implant are negligible.

Pharmacokinetics-Distribution

In a one-year study, 24 rabbits received a 0.59 mg intravitreal implant. Based on the amount of fluocinolone acetonide remaining in the intravitreal implants after removal, the in-vivo release rate was indirectly estimated to be 0.76 μg/ day.

TOXICOLOGY

Toxicology studies investigated primarily 0.59, 2.1 and 6 mg fluocinolone acetonide intravitreal implants.

Rabbit and dog studies were conducted using intravitreal implants to assess ocular and systemic uptake, as well as the safety of the fluocinolone acetonide released from the implant. These studies investigated primarily 0.59, 2.1 and 6 mg fluocinolone acetonide intravitreal implants. In summary, fluocinolone acetonide intravitreal implants were well tolerated in rabbits, while in dogs significant abnormal findings were made.

Overall, results of rabbit studies suggested that the implant was well tolerated. However, in a one-year study in NZ black/satin cross rabbits, the electroretinography tests showed low b-wave amplitude without change in latencies. These changes were however not consistent and it is not clear whether or not these changes were related the fluocinolone acetonide implants.

A one-year study was conducted in 54 beagle dogs, 36 received fluocinolone acetonide intravitreal implants (0.59 mg, or 2.1 mg, or 6.0 mg) in one eye and 18 received a sham implant or no implant at all. Findings included the following:

• Eleven dogs had severe ocular lesions associated with ocular inflammation. It is not clear whether the ocular inflammation was a post-surgical complication per se or was due to fluocinolone acetonide implants
• Corneal opacities that were interpreted as species-specific to dogs with no relevance to humans
• Increased incidence of cataracts might have been due to fluocinolone acetonide, or to the mechanical contact between the implant and posterior surface of the lens.
• Findings in the adrenal glands (microvacuolar change and/or cortical atrophy). It is not clear whether these findings were related to fluocinolone acetonide or to corticosteroids received from other routes (eye ointment/drops, or systemic).

Significant, fluocinolone acetonide implant related, systemic toxic effects were not observed in both species. Some, generally minimal to mild, histopathological changes to liver, adrenals and thymus were observed in the dogs. However, the surgical procedures involved in inserting the implants into the dog’s eye necessitated the administration of topical and systemic corticosteroids to control inflammation. The exact cause of the histopathological effects cannot be established, but it appears likely that they were caused by the long-term supplementary use of therapeutic corticosteroids. Similar findings were not observed in rabbits, which did not require additional corticosteroid therapy.

Single Dose Toxicity

After implantation, the implant is intended to stay in the vitreous for a prolonged period of time. Therefore the toxicity studies performed with the implants involved long-term exposure. These studies showed that the implanted fluocinolone acetonide implants did not cause any acute toxic effects.

Acute toxicity of the empty intravitreal implant was assessed from a medical device standpoint after intraperitoneal/intravenous injection of implant extracts in mice and after intravenous injection of implant extracts in rabbits. These studies showed that extracts of the implant do not induce any systemic toxicity.

Reproduction Toxicity

No adequate animal reproduction studies have been conducted with fluocinolone acetonide. Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. When fluocinolone acetonide was administered subcutaneously at a dose of 0.13 mg/kg/day (approximately 10,000 times the daily clinical dose from RETISERT^TM), during days 6 to 18 of pregnancy in the rabbit, abortions were induced at the end of the third and at the beginning of the fourth gestational week (Kilhström and Lundberg, 1987). When fluocinolone acetonide was administered subcutaneously to rats and rabbits during gestation at a maternally toxic dose of 50 µg/kg/day (approximately 4,000 times the clinical dose from RETISERT^TM), abortions and malformation were seen in a few surviving foetuses (Casilli et al, 1977).

At doses exceeding the intended clinical dose by many orders of magnitude considering the release rate from the implant and the negligible, if any, systemic uptake of fluocinolone acetonide from the implant, fluocinolone acetonide could potentially be teratogenic. This is considered a class effect of glucocorticosteroids. No evidence of toxic effects on the reproductive organs was observed in the 1-year studies in dogs and rabbits

Long-term animal studies have not been performed on RETISERT^TM to evaluate the effect of fluocinolone acetonide on fertility.

Genotoxicity

The standard battery of in vitro and in vivo genotoxicity studies were conducted with fluocinolone acetonide in accordance with the ICH guidances.

Fluocinolone acetonide demonstrated no mutagenic potential in in vitro (Ames test and Mouse Lymphoma test) and in vivo (Micronucleus test) tests. Most of the published data report that fluocinolone acetonide is both non-carcinogenic as well as an inhibitor of DNA synthesis and an inhibitor of tumour promotion. Based on the absence of suspicious toxic effects in the long term implant studies, the negative mutagenic potential and the negligible systemic exposure resulting from the intravitreal implant, further investigation into the carcinogenic potential of fluocinolone acetonide did not seem warranted. Non-clinical data reveal no special hazard for humans based on conventional studies of genotoxicity.

The genotoxic potential of the empty RETISERT^TM was assessed in specific biocompatibility studies. These studies were part of the biocompatibility testing package. The three studies (in vitro and in vivo) studies showed that the RETISERT^TM implant extracts did not present any mutagenicity risk.

Carcinogenicity

Long-term animal studies have not been performed on RETISERT^TM to evaluate the carcinogenic potential.

No evidence of preneoplastic or hyperplastic lesions was observed in the 1-year toxicity studies in implanted dogs and rabbits. There was no relevant local ocular reaction or other pathophysiological response to fluocinolone acetonide following long-term implantation either.

The majority of studies dealing with fluocinolone acetonide’s carcinogenic potential show that it is an inhibitor of chemically-induced tumours as well as an inhibitor of tumour promoter-induced formation of adducts when co-administered. Two published studies however found some tumour enhancement effect of fluocinolone (Fukao et al., 1988; Woodworth et al., 1986).

Topical Toxicity

The two long-term intravitreal implant studies have shown good local tolerance of the complete, drug-containing implant.

Corticosteroids in sufficient dosage are known to diminish tissue repair processes (Schimmer and Parker, 2001; Martindale’s Extra Pharmacopoeia, 1996b), but there has been no evidence of harm due to that activity in the toxicity tests.

Immunotoxicity

No immunotoxicity studies have been conducted on RETISERT^TM.

It is anticipated that fluocinolone acetonide will exhibit the same effects as other corticosteroids on the immune system (Martindale’s Extra Pharmacopoeia, 1996b; Schimmer and Parker, 2001).

The potential risk for immunotoxic effect (suppression of host response) cannot be excluded, especially in the implanted eye, and should be considered when prescribing RETISERT^TM (see Warnings and Precautions).

Biocompatibiity

A comprehensive set of conventional experiments has been done to explore local tolerance, cytotoxicity, sensitizing potential, and genotoxicity of blank RETISERT^TM implants not containing fluocinolone acetonide.

The device was tested for haemolytic potential and cytotoxicity of saline, oil or DMSO extracts and of the solid plastics in contact with cell cultures, extensive genotoxicity testing was done in vitro and in vivo, and sensitizing potential, pyrogenicity of extracts, muscle irritancy and effect on tissue repair after in vivo implantation were investigated.

In general the extracts and the device itself showed no harmful action in any of the tests. The blank device and aqueous and sometimes oil extracts did produce slight cytotoxic/cytostatic effects in certain but not all studies, but usually within the limit of acceptability of USP 26/NF 21 (2003). There was no evidence of any potential for an unacceptable level of tissue damage or irritancy, sensitization, pyrogenicity, haemolysis or genotoxicity.

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