Summary of Product Characteristics Updated 11-Nov-2014 | Allergan Ltd
PosologyPost-operative inflammation:One drop instilled into the eye three times daily starting 24 hours pre-operatively and continuing for up to three weeks post-operatively.
Paediatric populationThere is no relevant use of ACULAR in the paediatric population in the indication: For the prophylaxis and reduction of inflammation following cataract surgery.
Method of administrationOcular use.Instil one drop of the solution into the inferior conjunctival sac of the eye to be treated, while pulling the lower eyelid gently downwards and looking upwards.If ACULAR is used concomitantly with other topical eye medications there must be an interval of at least 5 minutes between the two medications.
Immune system disordersCommon: Hypersensitivity including localised allergic reactions
Nervous system disordersCommon: Headache
Eye DisordersVery Common: Eye irritation (including burning sensation)Eye pain (including stinging)Common: Superficial (punctate) keratitis Eye and/or eyelid oedemaOcular pruritusConjunctival hyperaemia Eye infection Eye inflammation Iritis Keratic precipitates Retinal haemorrhage Cystoid macular oedema Eye trauma Increased intraocular pressureBlurred and/or diminished visionUncommon: Corneal ulcerCorneal infiltratesEye drynessEpiphoraNot known: Corneal damage, e.g. thinning, erosion, epithelial breakdown and perforation*
Respiratory, thoracic and mediastinal disordersNot known: Bronchospasm or exacerbation of asthma***Occasional post marketing reports of corneal damage including corneal thinning, corneal erosion, epithelial breakdown and corneal perforation have been received. These occurred mainly in patients using concomitant topical corticosteroids and/or with predisposing co-morbidity (see section 4.4).**There have been post-marketing reports of bronchospasm or exacerbation of asthma, in patients, who have either a known hypersensitivity to aspirin/non-steroidal anti-inflammatory drugs or a past medical history of asthma, associated with the use of ACULAR which may be contributory.None of the typical adverse reactions reported with the systemic non-steroidal anti-inflammatory agents (including ketorolac trometamol) have been observed at the doses used in topical ophthalmic therapy.Reporting of suspected adverse reactionsReporting 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:Yellow Card SchemeWebsite: www.mhra.gov.uk/yellowcard
|Rabbit aqueous humor bioavailability:|
|Mean concentration of total radioactivity||0.856 µg-equiv./ml @ 0.5 hr|
|1.607 µg-equiv./ml @ 2 hr|
|AUC (0-8 hr)||9.39 µg-equiv. hr/ml|
|Total AUC||13.53 µg-equiv. hr/ml|
|Absolute ocular bioavailability||3.7%|
DistributionAfter ophthalmic doses were administered to rabbits, peak concentrations of radioactivity were achieved within 1 hour in the ocular tissues and were highest in the cornea (6.06 mcg-eq/ml). At 1 hour, the majority of the radioactivity (0.9% of administered dose) was recovered from the sclera (0.58%) and cornea (0.24%), and smaller amounts were recovered from the aqueous humor (0.026%), vitreous humor (0.023%), retina-choroid (0.018%), iris-ciliary body (0.007%) and lens (0.002%).Relative to plasma AUC values, the AUC's in rabbits were higher for cornea (104 fold), sclera (27 fold), iris-ciliary body (5.8 fold), retina-choroid (5.6 fold), aqueous humor (3.3 fold) and approximately one-half in the vitreous humor and lens. After ophthalmic administration, concentrations of drug-related radioactivity were higher in the ocular tissues and lower in plasma compared with those after IV dosing.
Systemic AbsorptionAfter ophthalmic doses in the rabbit, ketorolac was absorbed rapidly into the systemic circulation (Tmax, 15 min). Plasma half-lives after ophthalmic doses (6.6 - 6.9 hr) were longer than those after IV administration (1.1 hr), suggesting that removal of drug from eye into the venous circulation may be rate-limiting. By comparison of drug levels in aqueous humor after intracameral injection vs. plasma levels after IV administration, ketorolac was shown to clear more rapidly from plasma (6 ml/min) than from the anterior chamber (11 mcl/min).In the cynomolgus monkey, peak plasma levels of ketorolac occurred at 1.1 hr after the ophthalmic dose. The plasma half-life of ketorolac was similar after ophthalmic (1.8 hr) and IV doses (1.6 hr).The majority of the ophthalmic dose was excreted in urine (66% in rabbit and 75% in monkey) and a small amount in faeces (11% in rabbit and 2% in monkey). The extent of systemic absorption after ophthalmic dosing averaged 73% in the rabbit and 76% in the cynomolgus monkey.
MetabolismAfter ophthalmic administration in rabbits, ketorolac represented the major component (more than 90%) of radioactivity in aqueous humor and plasma and the p-hydroxy metabolite accounted for 5% of radioactivity in plasma. Ketorolac was also the major component (96%) of plasma radioactivity after ophthalmic dosing in monkeys.After ophthalmic dosing in the rabbit, 72%, 17% and 6% of the total radioactivity in urine was comprised of intact ketorolac, p-hydroxy ketorolac and other polar metabolites, respectively. After IV dosing, the relative proportions of total radioactivity in urine averaged 6% as intact ketorolac, 68% as p-hydroxy ketorolac and 22% as polar metabolites. In the monkey, intact ketorolac and its polar metabolite accounted for 32% and 65% of the total radioactivity in urine, respectively, after ophthalmic dosing, and 50% and 49% of the radioactivity in urine, respectively, after IV dosing. Thus, the metabolism of ketorolac was qualitatively similar after ophthalmic and IV administration in the monkey and rabbit.b) Characteristics in patientsKetorolac tromethamine solutions (0.1% or 0.5%) or vehicle were instilled into the eyes of patients approximately 12 hours and 1 hour prior to surgery. Concentrations of ketorolac in aqueous humor sampled at the time of surgery were at the lower limit of detection (40 ng/ml) in 1 patient and below the quantitation limit in 7 patients dosed with 0.1% ketorolac tromethamine. The average aqueous humor level of ketorolac in patients treated with 0.5% ketorolac tromethamine was 95 ng/ml. Concentrations of PGE2 in aqueous humor were 80 pg/ml, 40 pg/ml and 28 pg/ml in patients treated with vehicle, 0.1% ketorolac tromethamine and 0.5% ketorolac tromethamine, respectively.In the 21-day multiple dose (TID) tolerance study in healthy subjects, only 1 of 13 subjects had a detectable plasma level pre-dose (0.021 µg/ml). In another group of 13 subjects, only 4 subjects showed very low plasma levels of ketorolac (0.011 to 0.023 µg/ml) 15 minutes after the ocular dose.Thus, higher levels of ketorolac in the aqueous humor and very low or no detectable plasma levels after ophthalmic doses, suggest that the use of ketorolac tromethamine by the ophthalmic route in treatment of ocular disorders results in quite low systemic absorption in patients.
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