SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

TRIESENCE 40 mg/ml suspension for injection

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml vial with suspension for injection contains 40 mg triamcinolone acetonide For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Suspension for injection White suspension pH 6.2 - 7.9

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

TRIESENCE 40 mg/ml, suspension for injection is indicated for visualization during vitrectomy.

This medicinal product is for diagnostic use only.

4.2    Posology and method of administration

Posology

Adults, including the elderly:

The recommended dose of TRIESENCE 40 mg/ml, suspension for injection is 1 to 4 mg (25 to 100 microliters of 40 mg/ml suspension) administered intravitreally.

Paediatric population:

The safety and efficacy of TRIESENCE 40 mg/ml suspension for injection in patients below 18 years has not been established. No data are available

Renal and Hepatic Impairment

No dose adjustment is required in patients with renal impairment (glomerular filtration rate below 20 ml/min) or hepatic impairment. TRIESENCE 40 mg/ml, suspension for injection is removed from the eye following the surgery.

Method of administration Intravitreal use

STRICT ASEPTIC TECHNIQUE IS MANDATORY. Triesence must be administered by a qualified ophthalmologist experienced in intravitreal injections under aseptic conditions.

A 27 or 30 G x ‘A inch needle should be attached to the luer adaptor, to allow the administration of the product.

The vial should be vigorously shaken for 10 seconds before use to ensure a uniform suspension. Prior to withdrawal, the suspension should be inspected for clumping or granular appearance (agglomeration). An agglomerated product results from exposure to freezing temperatures and should not be used. After withdrawal, TRIESENCE 40 mg/ml, suspension should be injected into the vitreous without delay to prevent settling in the syringe. Careful technique should be employed to avoid the possibility of entering a blood vessel or introducing organisms that can cause infection.

The standard injection procedure should be carried out under aseptic surgical conditions during the vitrectomy procedure which includes the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anaesthesia and a broad-spectrum microbicide should be given prior to the injection.

Before the conclusion of surgery, the remaining TRIESENCE 40 mg/mL suspension for injection is removed from the eye as much as possible using continuous aspiration or irrigation.

Following the vitrectomy procedure patients should be monitored for endophthalmitis (See Section 4.4). Standard post operative care should be provided and follow up should be consistent with the underlying etiology that was the basis for the vitrectomy. Patients should be instructed to report any symptoms suggestive of endophthalmitis without delay.

Each vial should only be used for the treatment of a single eye during a single vitrectomy procedure.

No special dosage modification is required for any of the populations that have been studied (e.g., gender, elderly).

TRIESENCE 40 mg/ml, suspension can be diluted with a Balanced Salt Solution (on a per mL basis BSS contains the following: Sodium Chloride 6.4 mg; Potassium Chloride 0.75 mg; Calcium Chloride 0.48 mg; Magnesium Chloride 0.3 mg; Sodium Acetate 3.9 mg; Sodium Citrate 1.7 mg; Sodium Hydroxide and/or Hydrochloric

Acid, 6.5 to 8.5 to achieve a target pH of 7.5; Water for Injection) prior to its use during vitrectomy. Depending on the surgeon preference, the range of dilution with Alcon’s Balanced Salt Solution is typically from 1 in 10 or 1 in 20. In a clinical study, TRIESENCE 40 mg/ml, suspension was administered as a 2 mg/ml suspension by diluting 0.05 ml of the TRIESENCE 40 mg/ml, suspension into 0.95 ml sterile irrigating solution. Following this dilution, a 100 microliter volume was then injected into the vitreous.

Important note: Triamcinolone acetonide crystals begin to settle immediately. As such the solution should be mixed immediately prior to instillation. To mix, a small sterile air bubble is drawn into the syringe (smaller than the diameter of the syringe) and the ends of syringe are rocked up and down to guide the air bubble through the syringe to help distribute the crystals evenly. The air bubble should be removed and the prepared solution used immediately.

For further instructions on the correct administration/use of this product, see sections

6.2 and 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

TRIESENCE 40 mg/ml, suspension for injection should not be used in active ocular herpes simplex.

4.4 Special warnings and precautions for use

TRIESENCE has only been used as a single intravitreal injection for diagnostic reasons. No data for therapeutic use are available and repeated or long-term use has not been studied. Therefore, Triesence 40 mg/mL suspension for injection should not be used in therapeutic situations.

TRIESENCE 40 mg/ml, suspension for injection is for intravitreal use only. It should not be administered intravenously. Strict aseptic technique is mandatory (See Section 4.2. Method of administration)

Triamcinolone acetonide is a glucocorticosteroid. Corticosteroids may mask some signs of infection, and new or latent infections may appear during their use. There may be decreased resistance and inability to localize infection when corticosteroids are used. Corticosteroids may enhance the establishment of secondary ocular infections due to fungi, bacteria or viruses (e.g. vaccinia, varicella). Physicians should ask patients if they have had recent or ongoing infections. If an infection occurs during corticosteroid therapy, it should be promptly controlled by suitable antimicrobial therapy. The use of corticosteroids may increase the rate of occurrence of infectious complications.

Corticosteroids should be used cautiously in patients with ocular herpes simplex, particularly those with an underlying autoimmune disorder, because of the risk of corneal perforation. Corticosteroids should not be used in active ocular herpes simplex (See Section 4.3).

As expected with intravitreal injections, transient increases in intraocular pressure may be seen. Therefore, the perfusion of the optic nerve head should be verified and elevation of intraocular pressure should be managed appropriately post injection. The risk of corticosteroid-induced IOP elevation is increased in predisposed patients (e.g. diabetes). Increases in intraocular pressure associated with triamcinolone acetonide injection have been observed in 20-60% of patients when patients have been treated for therapeutic indications. This may lead to glaucoma with possible damage to the optic nerve. Effects on intraocular pressure may last up to 6 months following injection and are usually managed by topical glaucoma therapy. A small percentage of patients may require aggressive non-topical treatment. Intraocular pressure as well as perfusion of the optic nerve head should be monitored and managed appropriately. This is especially important in paediatric patients, as the risk of corticosteroid-induced ocular hypertension may be greater in children and may occur earlier than in adults. TRIESENCE is not approved for use in paediatric patients.

There are no data regarding the use of TRIESENCE 40 mg/ml, suspension for injection in patients with ocular hypertension or glaucoma, or patients with a history of chronic or recurrent ocular inflammation. The surgeon should carefully evaluate the risks versus the benefits to determine the suitability of TRIESENCE for use in these patients.

The rate of infectious culture positive endophthalmitis is 0.5% when utilized for therapeutic treatment indications. Proper aseptic techniques should always be used when administering triamcinolone acetonide during vitrectomy procedures to prevent the risk of endophthalmitis. In addition, patients should be monitored following the injection to permit early treatment should an infection occur.

Prolonged use of topical and intravitreal corticosteroids may produce cataracts, particularly posterior subcapsular cataracts (See Section 4.8). This risk is increased in predisposed patients (e.g. diabetes).

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. No clinically relevant interactions have been described with TRIESENCE.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited data from the use TRIESENCE 40 mg/ml, suspension for injection in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). TRIESENCE 40 mg/ml, suspension for injection is not recommended for use during pregnancy.

Breast-feeding

It is unknown whether TRIESENCE 40 mg/ml, suspension for injection is excreted in human milk. A decision should be made whether to discontinue breast-feeding or to abstain from TRIESENCE 40mg/ml suspension for injection taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Studies have not been performed to evaluate the effect of an ocular injection of TRIESENCE 40mg/ml on fertility.

4.7 Effects on ability to drive and use machines

TRIESENCE 40 mg/ml, suspension for injection will be used as part of a surgical procedure. The effect on a patient’s vision due to the procedure may have a major influence on the ability to drive and use machines. The patient must be made aware that after surgery and until visual acuity returns to normal, driving a vehicle or operating dangerous machinery is prohibited.

4.8 Undesirable effects

Summary of the safety profile

In two multi-center clinical trials, 92 patients were exposed to a single intravitreal injection of approximately 1 to 4 mg of triamcinolone acetonide for visualization during vitreoretinal surgery. Adverse reactions reported with triamcinolone acetonide in these two trials included single reports of increased intraocular pressure and retinal artery occlusion.

Tabulated summary of adverse reactions

The following undesirable effects are classified according to the following convention: very common (> 1/10), common (> 1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000), or not known (cannot be estimated from the available data). Within each frequencygrouping, undesirable effects are presented in order of decreasing seriousness. The adverse reactions were obtained from the two Alcon clinical trials and post-marketing spontaneous reports.

System Organ Classification	Frequency	Adverse reactions
Eye Disorders	Uncommon:	retinal artery occlusion, intraocular pressure increased.
	Not Known:	endophthalmitis, non-infectious endophthalmitis hypopyon, visual acuity reduced.

Description of selected adverse events

Data from published literature: Forty-four (44) published articles evaluating the use of triamcinolone acetonide in triamcinolone-assisted vitrectomy were analyzed for safety data. Elevated intraocular pressure was the most frequently reported adverse event experienced by the patients in these articles. Elevated intraocular pressure that occurred during the immediate postoperative period was transient. Elevated intraocular pressure is a common postoperative complication of vitrectomy and in some of these articles elevated intraocular pressure was specifically considered not to have been associated with triamcinolone acetonide.

In the literature, events reported with the use of triamcinolone acetonide for visualization during vitrectomy are listed below. Most of these events were likely due to the surgical procedure, however, a possible causal relationship cannot be ruled out. These events included (in alphabetical order): cataract formation or progression, corneal defects (persistent corneal epithelial defect, lesions, or opacity), oedema (cystoid, macular, or corneal), the development of fibrous membranes (subretinal neovascular or preretinal), haemorrhage (vitreous, subretinal, or intraretinal), intraocular lens displacement, intra-operative bleeding, iris synechiae, macular pucker, ocular inflammation, opacity of the corneal stroma, posterior capsule rupture, proliferative vitreoretinopathy (PVR), retinal detachment, retinal rupture, and retinal tears. In most cases, residual triamcinolone acetonide disappeared without intervention and was not associated with any complications.

Elevated intraocular pressure, endophthalmitis and cataract formation/progression have been noted to occur at higher incidences when triamcinolone acetonide or other corticosteroids have been used for therapeutic indications, as compared to use for visualization (See Section 4.4).

Paediatric population

TRIESENCE 40 mg/ml, suspension for injection should not be used in patients below 18 years as efficacy and safety in this group have not been established.

Reporting of suspected adverse reactions

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

4.9 Overdose

No case of overdose has been reported. As this product is administered by a physician under controlled circumstances, the risk of accidental patient overdose is minor or negligible.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Opthalmologicals, and anti-inflammatory agents, corticosteroids, plain ATC code: S01BA 05

Triamcinolone acetonide is a glucocorticosteroid that has been used as an antiinflammatory agent for the treatment of various ocular diseases. Following intravitreal injection, dispersal of water-insoluble triamcinolone acetonide particles within the vitreous chamber provides contrast to the transparent vitreous humor and membranes. Therefore, intraocular triamcinolone acetonide is indicated for use during vitrectomy to visualize the vitreous, the inner limiting membrane, and pathologic epiretinal membranes.

The safety and efficacy for TRIESENCE 40 mg/mL suspension for injection was evaluated in two Phase III, observer-masked, multi-center clinical trials. In the two clinical studies, TRIESENCE™ suspension at doses up to 4 mg was administered through a surgical port into the eyes of all patients (32 patients in one clinical trial and 60 patients in another clinical trial) and surgeons removed as much of the product as possible before the conclusion of the surgeries. The video records made during each surgery and capturing visualization before and after injection of the study product were evaluated for degree of visualization by an independent masked reader. Following the study surgery, all patients completed safety evaluation at Day 1, Day 3, and Day 7 (Exit visit). Results from both studies demonstrated that TRIESENCE 40 mg/mL suspension for injection is highly effective when used as a visualization aid during vitrectomy in adult and elderly patients.

The design of clinical studies allowed for surgeons to use variable amount of TRIESENCE 40 mg/mL suspension for injection at their discretion for a total dose of approximately 1 to 4 mg. Subgroup analysis were performed on one clinical study demonstrated the consistency of the findings across subgroups as well as similarity to the overall result, indicating minimal effect of dose on the effectiveness of the suspension when used as a contrast/imaging agent to facilitate visualization during pars plana vitrectomy.”

5.2 Pharmacokinetic properties

Aqueous humor pharmacokinetics of triamcinolone acetonide have been assessed in 5 patients following a single intravitreal administration (4 mg) of triamcinolone acetonide. Aqueous humor samples were obtained from 5 patients (5 eyes) via an anterior chamber paracentesis on Days 1, 3, 10, 17 and 31 post-injection. Peak aqueous humor concentrations of triamcinolone ranged from 2151 to 7202 ng/mL, half-life 76 to 635 hours, and the area under the concentration-time curve (AUC0-t) from 231 to 1911 ng.h/mL following the single intravitreal administration. The mean elimination half-life was 18.7 ± 5.7 days in 4 nonvitrectomized eyes (4 patients). In a patient who had undergone vitrectomy (1 eye), the elimination half-life of triamcinolone from the vitreous was much faster (3.2 days) relative to patients that had not undergone vitrectomy. The pharmacokinetic profile of Triesence was assessed in clinical study C-08-055. In this study triamcinolone acetonide plasma concentrations were measured for a subset of patients (n = 22) to assess systemic exposure of triamcinolone acetonide after instillation of Triamcinolone Acetonide Suspension into the vitreous cavity for visualization during pars plana vitrectomy. Blood samples were collected on Day 0 at predose and 3 hours (± 1 hour) post-instillation of Triamcinolone Acetonide Suspension and on Day 7. In 2 of 22 patients, triamcinolone acetonide was quantifiable in plasma 3 hours after administration of Triesence on Day 0. On Day 7, there were no patients with quantifiable triamcinolone acetonide plasma concentrations on Day 7.

Preclinical safety data

Non-clinical data for triamcinolone acetonide reveal no special hazard for humans. Dose related teratogenic effects in rats and rabbits administered triamcinolone acetonide included cleft palate and/or internal hydrocephaly and axial skeletal defects, whereas the effects observed in monkeys were cranial malformations. These effects occurred at dosages similar to or lower than that produced by administering a 4 mg triamcinolone acetonide injection into the eye of a 50 kg human. The findings observed in these triamcinolone acetonide reproductive toxicity studies are similar to those noted with other corticosteroids. The fact that the administered dose of triamcinolone acetonide remains in the eye only for the duration of the surgical procedure provides risk mitigation for the potential adverse effects associated with prenatal exposure to triamcinolone acetonide. Therefore, with the exception of the reproductive and developmental toxicity effects noted above, the effects of triamcinolone acetonide in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure following intraocular use so as to convey little relevance to clinical use.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride Carmellose sodium Polysorbate 80 Potassium chloride Calcium chloride (dihydrate) Magnesium chloride (hexahydrate) Sodium acetate (trihydrate)

Sodium citrate

Sodium hydroxide (for pH-adjustment) Hydrochloric acid (for pH-adjustment) Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Shelf life

2 years

Once the vial is opened, suspension must be used immediately.

6.4 Special precautions for storage

Do Not Freeze. Keep the vial in the outer carton in order to protect from light. For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Type 1 single use glass vial with a chlorobutyl stopper and an aluminum cap. Each vial contains 1 ml of suspension. Each labelled vial is sealed in a polycarbonate blister with a backing material which provides tamper evidence and is stored in a carton.

6.6 Special precautions for disposal and other handling

For single use only. Any unused product or waste material should be disposed of in accordance with local requirements. Do not use TRIESENCE 40 mg/ml, suspension for injection if the vial is cracked or damaged in any way.

7 MARKETING AUTHORISATION HOLDER

Alcon Laboratories (UK) Ltd Frimley Business Park,

Frimley, Camberley,

Surrey, GU16 7SR,

United Kingdom

MARKETING AUTHORISATION NUMBER(S)

PL 00649/0380

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

16/03/2016

10    DATE OF REVISION OF THE TEXT

16/03/2016